Identification of ibuprofen targeting CXCR family members to alleviate metabolic disturbance in lipodystrophy based on bioinformatics and in vivo experimental verification.

Background: Lipodystrophy is a rare disease that is poorly diagnosed due to its low prevalence and frequent phenotypic heterogeneity. The main therapeutic measures for patients with clinical lipodystrophy are aimed at improving general metabolic complications such as diabetes mellitus, insulin resistance, and hypertriglyceridemia. Therefore, there is an urgent need to find new biomarkers to aid in the diagnosis and targeted treatment of patients with congenital generalized lipodystrophy (CGL). Methods: Dataset GSE159337 was obtained via the Gene Expression Omnibus database. First, differentially expressed genes (DEGs) between CGL and control samples were yielded via differential expression analysis and were analyzed for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment to explore the functional pathways. Next, protein-protein interaction analysis and the MCC algorithm were implemented to yield candidate genes, which were then subjected to receiver operating characteristic (ROC) analysis to identify biomarkers with an area under the curve value exceeding 0.8. Moreover, random forest (RF), logistic regression, and support vector machine (SVM) analyses were carried out to assess the diagnostic ability of biomarkers for CGL. Finally, the small-molecule drugs targeting biomarkers were predicted, and ibuprofen was further validated in lipodystrophy mice. Results: A total of 71 DEGs in GSE159337 were sifted out and were involved in immune receptor activity, immune response-regulating signaling pathway, and secretory granule membrane. Moreover, CXCR2, TNFSF10, NLRC4, CCR2, CEACAM3, TLR10, TNFAIP3, and JUN were considered as biomarkers by performing ROC analysis on 10 candidate genes. Meanwhile, RF, logistic regression, and SVM analyses further described that those biomarkers had an excellent diagnosis capability for CGL. Eventually, the drug-gene network included ibuprofen-CXCR1, ibuprofen-CXCR1, cenicriviroc-CCR2, fenofibrate-JUN, and other relationship pairs. Ibuprofen treatment was also validated to downregulate CXCR1 and CXCR2 in peripheral blood mononuclear cells (PBMCs) and improve glucose tolerance, hypertriglyceridemia, hepatic steatosis, and liver inflammation in lipodystrophy mice. Conclusion: Eight biomarkers, namely, CXCR2, TNFSF10, NLRC4, CCR2, CEACAM3, TLR10, TNFAIP3, and JUN, were identified through bioinformatic analyses, and ibuprofen targeting CXCR1 and CXCR2 in PBMCs was shown to improve metabolic disturbance in lipodystrophy, contributing to studies related to the diagnosis and treatment of lipodystrophy.

Leptin replacement therapy in the management of lipodystrophy syndromes.

Lipodystrophy syndromes are rare diseases of genetic or acquired origin, characterized by quantitative and qualitative defects in adipose tissue. The metabolic consequences of lipodystrophy syndromes, such as insulin resistant diabetes, hypertriglyceridemia and hepatic steatosis, are frequently very difficult to treat, resulting in significant risks of acute and/or chronic complications and of decreased quality of life. The production of leptin by lipodystrophic adipose tissue is decreased, more severely in generalized forms of lipodystrophy, where adipose tissue is absent from almost all body fat depots, than in partial forms of the disease, where lipoatrophy affects only some parts of the body and can be associated with increased body fat in other anatomical regions. Several lines of evidence in preclinical and clinical models have shown that leptin replacement therapy could improve the metabolic complications of lipodystrophy syndromes. Metreleptin, a recombinant leptin analogue, was approved as an orphan drug to treat the metabolic complications of leptin deficiency in patients with generalized lipodystrophy in the USA or with either generalized or partial lipodystrophy in Japan and Europe. In this brief review, we will discuss the benefits and limitations of this therapy, and the new expectations arising from the recent development of a therapeutic monoclonal antibody able to activate the leptin receptor.

GLP-1 receptor agonist improves metabolic disease in a pre-clinical model of lipodystrophy.

Aims: Individuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed. Here we performed the first detailed investigation of the effects of a glucagon like peptide-1 receptor (GLP-1R) agonist in lipoatrophic diabetes, using mice with generalised lipodystrophy. Methods: Lipodystrophic insulin resistant and glucose intolerant seipin knockout mice were treated with the GLP-1R agonist liraglutide either acutely preceding analyses of insulin and glucose tolerance or chronically prior to metabolic phenotyping and ex vivo studies. Results: Acute liraglutide treatment significantly improved insulin, glucose and pyruvate tolerance. Once daily injection of seipin knockout mice with liraglutide for 14 days led to significant improvements in hepatomegaly associated with steatosis and reduced markers of liver fibrosis. Moreover, liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. Conclusions: GLP-1R agonist liraglutide significantly improved lipoatrophic diabetes and hepatic steatosis in mice with generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition.

The blockade of the TGF-ß pathway alleviates abnormal glucose and lipid metabolism of lipodystrophy not obesity.

TGF-ß is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2-SREBP-1c mice and ob/ob mice, were used. TGF-ß pathway showed up-regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF-ß inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre-administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild-type levels in aP2-SREBP-1c mice. In contrast, TGF-ß inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF-ß blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF-ß pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.

A retrospective study on side effects of first-line antiretroviral drugs on HIV patients based on 1A, 2A, and 5A regimen records at Zomba Central Hospital, Malawi.

AIDS is an incurable disease that is common in Africa. Patients with HIV/AIDS having a CD4 count of less than 240 are put on life prolonging ARV drugs. The ARVs have serious side effects on some patients which may be handled by treating them or switching patient's drug to one with no or less serious side effects. However, before doing this, more understanding of the circumstances that lead to a side effect is vital. We use statistical analyses to link side effects of 1A, 2A, and 5A treatment regimens to the patient's social and demographic characteristics based on hospital data records. A retrospective review of patients' master cards (2011-2014) was done to assess adverse effects associated with different ARV regimens. Out of the 901 patients that showed side effects, 65.37% were females aged 31-40 and 34.63% were males. Comparatively, 1A regimen showed more side effects than 2A and 5A regimens. Age, gender and occupation correlated significantly with regimen symptoms (p< 0.05). Unlike men, women had the following extra side effects; cough, peripheral neuropathy and leg pains as compared to lipodystrophy. Our results show that old people (50years+) are less likely to get skin rash and other symptoms compared to lipodystrophy (RRR=0.973). Further, the probability of either having cough (0.0021, p< 0.05), or skin rash (0.0021, p< 0.05), as a side effect, on average, decreases as age increases with the same sex and weight. The probability of having peripheral neuropathy (0.0042, p< 0.01), however, increases with age. Knowledge of HIV patient's socio-demographics and the patient's regimen side effects can be utilised to appropriately manage severe ARV side effects. A therapy consideration that takes into account chemicals in ARV regimen responsible for specific side effects can be directed to patients with compatible socio-demographic characteristics.

Lipodistrofias primarias: presentación clínica y diagnóstico / Clinical presentation and treatment of primary lipodystrophies

Lipodystrophies are a heterogeneous group of syndromes defined by a severe reduction of the adipose tissue. These can be congenital or acquired. Anatomically, they can be partial or generalized. The etiology of several lipodystrophies is well known. However, the cause of many others remains unknown. The commonest lipodystrophy worldwide is secondary to highly active anti-retroviral therapy in HIV-infected patients. By contrast, primary lipodystrophies (those not associated to any known disease or condition) are much less common and represent a diagnostic challenge. The major complications of lipodystrophies are metabolic, often resulting in severe insulin resistance, diabetes and dyslipidemia. No cure is available for lipodystrophies but the supplementation with recombinant leptin potently controls the metabolic abnormalities when there is a leptin deficiency. Herein, we review the clinical presentation, diagnostic process and therapeutic principles of the main primary lipodystrophy syndromes.

Impacto na qualidade de vida em pacientes usuários de medicação retroviral e submetidos à gluteoplastia: estudo de coorte histórica / Gluteal contour restoration in antiretroviral users and its quality-of-life related impacts: a historical cohort study

INTRODUÇÃO: Desde a introdução do tratamento do HIV com uso da terapia antirretroviral altamente ativa, a mortalidade por essa doença foi reduzida drasticamente em todo o mundo. Um dos parefeitos relacionados à utilização desses fármacos é a lipodistrofia glútea. O objetivo deste trabalho é verificar o impacto da correção dessa deformidade na qualidade de vida de pacientes com HIV. MÉTODOS: Foi conduzido um estudo de coorte histórica com 23 pacientes submetidos à gluteoplastia com implante intramuscular, entre janeiro de 2010 e dezembro de 2014, avaliando a qualidade de vida por meio do em Nottingham Health Profile em. As informações foram coletadas de julho a agosto de 2015. A análise estatística foi feita utilizando-se o em Related-Samples McNemar Test em. RESULTADOS: strong Houve diferença significativa entre o pré-operatório e pós-operatório em 19 das 38 perguntas. CONCLUSÃO: É possível afirmar que a reconstrução glútea melhora a qualidade de vida de pacientes HIV positivos acometidos por lipodistrofia glútea relacionada a antirretrovirais.

INTRODUCTION: Since the introduction of highly active antiretroviral therapy for the treatment of human immunodeficiency virus (HIV), disease mortality has been dramatically reduced worldwide. One related side effect from the use of these drugs is gluteal lipodystrophy. The aim of this study is to assess the quality-of-life impact of correcting this deformity in HIV patients. METHODS: A historical cohort study was conducted between January 2010 and December 2014 with 23 patients, assessing the quality of their lives using the Nottingham Health Profile. A statistical analysis was performed using the McNemar test for related samples. RESULTS: There was a significant difference between preoperative and postoperative response in 19 of the 38 questions. CONCLUSION: We may say that gluteal reconstruction plays a role in improving quality of life for HIV patients who have been affected by antiretroviral related gluteal lipodystrophy.

Correção cirúrgica da lipodistrofia relacionada ao uso da terapia antirretroviral: uma análise sobre os procedimentos realizados e o impacto sobre os pacientes / Surgical lipodystrophy correction associated with the use of antiretroviral therapy: an analysis of procedures performed and impact on the patients

Introdução: O tratamento de pacientes portadores da síndrome da imunodeficiência adquirida deve ser integral e se basear no controle da doença e das complicações relacionadas ao uso de medicações antirretrovirais, como a lipodistrofia. Esse estudo tem como objetivo avaliar as principais queixas, os aspectos epidemiológicos e os procedimentos cirúrgicos realizados para corrigir a lipodistrofia em pacientes em uso crônico de antirretrovirais. Método: Estudo retrospectivo, no qual foram coletados dados dos prontuários de 27 pacientes submetidos a 36 procedimentos cirúrgicos relacionados à correção de lipodistrofia no período de março de 2010 a junho de 2014 no serviço de Cirurgia Plástica do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto. Resultados: A idade média dos pacientes foi 47,2 anos, 22,2% homens e 77,8% mulheres. O tempo médio de uso da terapia antirretroviral (TARV) foi de 12,1 anos. As queixas mais encontradas foram: giba dorsal (44,4%), lipodistrofia abdominal (44,4%) e lipoatrofia glútea (37,04%). Na maioria dos pacientes (70,4%), foi realizada uma cirurgia. Quanto às cirurgias, a lipoaspiração de giba foi realizada em 48,1% dos pacientes, seguida da lipoaspiração de abdome, dorso ou flancos (44,4%) e gluteoplastia (22,2%). Entre todos os 36 procedimentos realizados, apenas dois apresentaram complicações. O tempo médio de seguimento pós-operatório foi de 11,2 meses. Do total, 70,4% dos pacientes mostraram-se satisfeitos após os procedimentos. Conclusões: O sucesso do tratamento cirúrgico da lipodistrofia causada pelo uso da TARV baseia-se na seleção pré-operatória adequada e em seguimento constante e prolongado. A melhoria da autoestima facilita a adesão ao tratamento com antirretrovirais.

Introduction: Treatment of patients with acquired immunodeficiency syndrome should be complete and based on controlling the disease and the complications related to the use of antiretroviral medications, such as lipodystrophy. This study aimed to evaluate the main complaints, epidemiological aspects, and surgical procedures performed for lipodystrophy correction among patients receiving long-term antiretroviral therapy. Method: In this retrospective study, data were collected from the medical records of 27 patients who underwent 36 surgical procedures associated with lipodystrophy correction, from March 2010 to June 2014, at the Plastic Surgery Service of the Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto. Results: The average age of the patients was 47.2 years; 22.2% were men and 77.8% were women. The average duration of antiretroviral therapy (HAAR ) was 12.1 years. The most frequent complaints were dorsal hump (44.4%), abdominal lipodystrophy (44.4%), and gluteal lipoatrophy (37.04%). The majority of patients (70.4%) had undergone surgery . The most common type of surgery performed was hump liposuction (carried out in 48.1% of the patients), followed by abdominal, back, or flank liposuction (44.4%) and gluteoplasty (22.2%). Among all 36 procedures performed, only 2 resulted in complications. The average postoperative follow-up period was 11.2 months. In total, 70.4% of patients were satisfied with the results of their procedure. Conclusions: The success of surgical treatment of HAARinduced lipodystrophy is based on proper preoperative selection as well as constant and prolonged follow-up. Improved selfesteem facilitates the adherence to antiretroviral drug treatment.

Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a meta-analysis into the effects of leptin on metabolic and hepatic endpoints / Terapia de reposição de leptina para o tratamento de síndromes lipodistróficas não associadas ao uso de antirretrovirais: uma metanálise dos efeitos da leptina em parâmetros metabólicos e hepáticos

The clinical manifestations of lipodystrophy syndromes (LS) are hypoleptinemia, hyperglycemia, insulin resistance, dyslipidemia and hepatic steatosis. Leptin replacement therapy (LRT) is effective at improving these pathologies. Currently, there are no data compiling the evidence from the literature, and demonstrating the effect of LRT in LS patients. A systematic review of the MEDLINE and Cochrane Library databases was conducted to identify studies assessing the effect of LRT on metabolic and hepatic endpoints in patients with LS not associated with highly active antiretroviral therapy (HAART) use. Standardized mean differences (SMD) and 95% confidence intervals of pooled results were calculated for overall changes in glucose homeostasis, lipid profile, and hepatic physiology, using an inverse-variance random-effects model. After screening, 12 studies were included for review. Meta-analysis of results from 226 patients showed that LRT decreased fasting glucose [0.75 SMD units (range 0.36‐1.13), p=0.0001], HbA1c [0.49 (0.17‐0.81), p=0.003], triglycerides [1.00 (0.69‐1.31), p<0.00001], total cholesterol [0.62 (0.21‐1.02), p=0.003], liver volume [1.06 (0.51‐1.61), p=0.0002] and AST [0.41 (0.10‐0.73) p=0.01]. In patients with non-HAART LS, LRT improves the outcome of several metabolic and hepatic parameters. Studies were limited by small populations and therefore large prospective trials are needed to validate these findings.

As manifestações clínicas das síndromes lipodistróficas (SL) incluem hipoleptinemia, hiperglicemia, resistência insulínica, dislipidemia e esteatose hepática. A terapia de reposição de leptina (TRL) melhora tais parâmetros, mas atualmente não há dados compilados demonstrando tal efeito. Uma revisão sistemática dos bancos de dados MEDLINE e Cochrane Library identificou estudos avaliando os efeitos da TRL sobre parâmetros metabólicos e hepáticos em pacientes com SL não associadas ao uso de antirretrovirais. Diferenças médias padronizadas (DMP) e intervalos de confiança de 95% foram calculados a partir dos resultados, para os efeitos da TRL sobre a homeostase da glicose, perfil lipídico, e morfologia/função hepática, usando um modelo de variação inversa e efeitos randômicos. Após a triagem, 12 estudos foram incluídos para revisão. A metanálise dos resultados de 226 pacientes mostrou que a TRL reduziu a glicemia de jejum [0,75 DMP (amplitude 0,36‐1,13), p=0,0001], HbA1c [0,49 (0,17‐0,81), p=0,003], triglicerídeos [1,00 (0,69‐1,31), p<0,00001], colesterol total [0,62 (0,21‐1,02), p=0,003], volume hepático [1,06 (0,51‐1,61), p=0,0002] e AST [0,41 (0,10‐0,73), p=0,001]. Em pacientes com SL não associada ao uso de antirretrovirais, a TRL melhora vários parâmetros metabólicos e hepáticos. Os estudos avaliados foram limitados pelo pequeno número de pacientes. Maiores estudos clínicos prospectivos são necessários para validar tais achados.

Bioplastia na lipodistrofia de pacientes com HIV/AIDS / Bioplasty for lipodystrophy in patients with HIV/AIDS

INTRODUÇÃO: O início do tratamento da síndrome da imunodeficiência adquirida (AIDS) com a terapia antirretroviral de alta atividade (HAART), na década de 1990, aumentou, consideravelmente, a longevidade e a qualidade de vida dos portadores da doença. A redução da morbidade e da mortalidade associadas a doenças infecciosas e neoplásicas oportunistas, porém, tem sido acompanhada pelo aumento da prevalência de outras doenças, entre elas a lipodistrofia associada ao vírus da imunodeficiência humana (HIV). A lipodistrofia decorre da toxicidade de drogas utilizadas na terapia antirretroviral, sendo atribuída aos inibidores de protease e aos inibidores da transcriptase reversa análogos do nucleosídeo. Este trabalho aborda a lipoatrofia facial, que confere um aspecto de envelhecimento precoce e traz de volta o velho estigma da "facies da AIDS", podendo impactar negativamente na qualidade de vida dos portadores de HIV. MÉTODO: Neste estudo foram incluídos 41 pacientes apresentando lipoatrofia facial, que foram submetidos a preenchimento com polimetilmetacrilato (PMMA) no Hospital Universitário da Universidade Federal de Juiz de Fora (HU-UFJF) e na clínica Plastic Center, Clínica de Cirurgia Plástica em Juiz de Fora, no período entre janeiro de 2010 e fevereiro de 2012. RESULTADOS: O número de procedimentos realizados em cada paciente variou de 1 a 4, sendo respeitado um intervalo mínimo de 90 dias entre eles. A quantidade de PMMA utilizado variou de acordo com o grau e a região a serem corrigidos, ficando entre 3 ml e 18 ml por procedimento. Em todos os pacientes, o resultado obtido foi favorável esteticamente. CONCLUSÕES: Os resultados obtidos pela bioplastia com PMMA foram considerados satisfatórios pelos pacientes. O material utilizado possui alta adaptabilidade às áreas receptoras, necessitando apenas da modelagem e da quantidade adequada para que apresente bom padrão estético.

BACKGROUND: When the treatment of acquired immunodeficiency syndrome (AIDS) with highly active antiretroviral therapy (HAART) began in the 1990s, it considerably increased the life expectancy and quality of life of AIDS patients. However, the decrease in morbidity and mortality associated with opportunistic infectious and neoplastic diseases was accompanied by an increase in the prevalence of other diseases, including HIV-associated lipodystrophy. Lipodystrophy is due to the toxicity of drugs used in antiretroviral therapy, including protease inhibitors and nucleoside analog reverse transcriptase inhibitors. This article discusses the treatment of facial lipodystrophy, which confers an appearance of premature aging and brings back the old stigma of the "AIDS face," which negatively impacts the quality of life of HIV carriers. METHODS: Forty-one patients with facial lipoatrophy received filling with polymethylmethacrylate (PMMA) at the Hospital Universitário da Universidade Federal de Juiz de Fora (HU-UFJF) and at the Plastic Center Clinic, Plastic Surgery Clinic in Juiz de Fora between January 2010 and February 2012. RESULTS: Patients received 1 to 4 procedures with a minimum interval of 90 days between procedures. The amount of PMMA used ranged from 3 to 18 mL per procedure according to the degree and region to be corrected. The results were aesthetically favorable in all patients. CONCLUSIONS: The results obtained through bioplasty with PMMA are considered satisfactory by patients. The material used is highly adaptable to the receiving areas, requiring only modeling and an adequate amount in order to obtain good aesthetic results.

Lipodistrofia secundaria al uso de antirretrovirales inhibidores de proteasas / Lipodistrophy secondary to the use of antiretrovirals pretease inhibitors

El uso de inhibidores de proteasas en el tratamiento de la infección por HIV-1, ha revolucionado la sobrevida de éstos enfermos. Pero también se lo ha asociado a diabetes mellitus de nuevo comienzo, hiperlipidemia y lipodistrofia. Presentamos tres pacientes con lipodistrofia secundaria y comentamos la fisiopatogenia y tratamiento