The cross-talk between leptin and circadian rhythm signaling proteins in physiological processes: a systematic review.

BACKGROUND: Today, modern lifestyles and disrupted sleep patterns cause circadian clock rhythm impairments that are associated with altered leptin levels, which subsequently affect a wide range of physiological processes and have significant health burdens on societies. Nevertheless, there has been no systematic review of circadian clock genes and proteins, leptin, and related signaling pathways. METHODS: Accordingly, we systematically reviewed circadian clock proteins, leptin, and molecular mechanisms between them by searching Pubmed, Scopus, ProQuest, Web of Sciences, and Google Scholar until September 2022. After considering the inclusion and exclusion criteria, 20 animal studies were selected. The risk of bias was assessed in each study. RESULTS: The results clarified the reciprocal interconnected relationship between circadian clock genes and leptin. Circadian clock genes regulate leptin expression and signaling via different mechanisms, such as CLOCK-BMAL1 heterodimers, which increase the expression of PPARs. PPARs induce the expression of C/EBPα, a key factor in upregulating leptin expression. CLOCK-BMAL1 also induces the expression of Per1 and Rev-erb genes. PER1 activates mTORC1 and mTORC1 enhances the expression of C/EBPα. In addition, REV-ERBs activate the leptin signaling pathway. Also, leptin controls the expression of circadian clock genes by triggering the AMPK and ERK/MAPK signaling pathways, which regulate the activity of PPARs. Moreover, the roles of these molecular mechanisms are elucidated in different physiological processes and organs. CONCLUSIONS: Crosstalk between circadian clock genes and leptin and their affecting elements should be considered in the selection of new therapeutic targets for related disorders, especially obesity and metabolic impairments.

Validity and reliability of the BODI for assessing damage in Behcet's disease.

OBJECTIVE: In the present study, we aimed to validate the Behçet's syndrome Overall Damage Index (BODI) and compare its performance with that of vasculitis damage index (VDI) in Iranian patients with BD. METHODS: This study included 274 patients with a diagnosis of BD and median follow-up of 40 months. The medical records of the patients were reviewed and the demographic characteristics, disease activity status, clinical manifestations, and data on organs damage were collected from all patients. RESULTS: To evaluate the construct/convergent validity, BODI and VDI were applied to all participants. We found a good correlation between BODI score and VDI score. There was a significant and strong correlation between physician global assessment with BODI (r = 0.869, P = 0.001) and VDI (r = 0.817, P = 0.001). The ability of BODI to determine the accumulation of damage over time was assessed by analyzing the changes in BODI score over time. The increase in BODI score was occurred in 53 (19.3%) patients. In comparison, the increase in VDI score occurred in 36 (13.1%) patients. The increase in median BODI was significantly more than median VDI (P < 0.001). Multiple linear regression analysis showed that age at disease onset, disease duration, and disease severity were independent predictors of BODI scores. Reliability of BODI was examined by comparing the BODI scores as determined by two independent assessors in 100 patients. Cronbach's α was 0.942. CONCLUSION: The BODI demonstrated acceptable validity and reliability in assessing BD-related damage in Iranian patients with BD.

Effects of melatonin supplementation on disease activity, oxidative stress, inflammatory, and metabolic parameters in patients with rheumatoid arthritis: a randomized double-blind placebo-controlled trial.

OBJECTIVE: Considering the pathologic significance of inflammation and oxidative stress in rheumatoid arthritis (RA) as well as the antioxidant, anti-inflammatory and hypolipidemic effects of melatonin, the current research is designed to investigate the effect of melatonin supplementation on disease activity, oxidative stress, inflammatory, and metabolic parameters in RA patients. METHODS: In this randomized double-blind, placebo-controlled trial, 64 RA cases were selected and randomly assigned into 2 groups to take 6 mg/day melatonin or placebo for 12 weeks. Before and after trial, serum malondialdehyde (MDA), total antioxidant capacity (TAC), erythrocyte sedimentation rate (ESR), lipid profile, fasting blood sugar (FBS), and insulin levels were measured and disease activity was determined by disease activity score-28 (DAS-28). RESULTS: Compared to the baseline, melatonin significantly decreased DAS-28, ESR, MDA, and LDL-C by 50.5%, 59%, 97%, and 13%, respectively (P<0.001) and significantly increased TAC by 89% (P=0.013) and HDL-C by 22% (P<0.001). After treatment, considerable differences were only seen between the two groups in serum MDA (P<0.001) and LDL-C (P=0.007) concentrations, adjusted for baseline measures. Moreover, there were no significant changes in DAS-28, ESR, TAC, triglyceride, total cholesterol, HDL-C, FBS, and insulin levels compared to placebo group (P>0.05). CONCLUSIONS: Although melatonin supplementation had no beneficial effects on DAS-28, it could lower serum MDA and LDL-C levels. It seems that melatonin supplementation should not be used as a replace for routine drugs prescribed in RA treatment. Further investigations should be conducted to fully understand the effects of melatonin in RA. Key Points • Compared to baseline, melatonin significantly decreased DAS-28, ESR, MDA, and LDL-C and significantly increased TAC and HDL-C. • After treatment, considerable differences were only seen between melatonin and placebo groups in serum MDA and LDL-C concentrations. • After treatment, there were no significant changes in DAS-28, ESR, TAC, triglyceride, total cholesterol, HDL-C, FBS, and insulin levels compared to the placebo group.

Quality of Life in Patients With Behçet Disease and Its Relation With Clinical Symptoms and Disease Activity / Calidad de vida en pacientes con enfermedad de Behçet y su relación con los síntomas clínicos y la actividad de la enfermedad

Background: Behçet's disease(BD) is a systemic vasculitis which may affect the quality of life (QoL).AimsThis study aimed to assess the QoL in Iranian Azeri BD patients as well as evaluating the association between QoL and disease characteristics including disease activity and clinical symptoms. Methods: In this cross-sectional study, a total of 123 BD patients aged 15–65 years fulfilling International Criteria for BD and 123 healthy controls matched with regard to gender were included. Patients aged 15–18 years had the informed consent and consent of their parents for participation. Short Form-36 Quality of Life Scale (SF-36) was used to evaluate QoL. Disease activity was measured by Behcet's Disease Current Activity Form and the Iranian Behcet's Disease Dynamic Activity Measure and Vasculitis Damage Index (VDI) was used for the clinical assessment of damage. Results: The mean±SD age of BD patients and control group was 38.19±10.99 and 33.65±7.29 years, respectively. The Physical Health score as well as most of SF-36 domains including Role Physical, Bodily Pain, General Health, Vitality, and Mental Health were significantly lower in BD patients compared with the control group (P<0.05). There was significant correlation between the Physical and Mental Health scores and most of SF-36 domains with disease activity and clinical symptoms including genital ulcers, ophthalmic and central nervous system (CNS) involvement (P<0.05). Significant correlation was only observed between VDI and Bodily Pain domain (P<0.05). Conclusion: Quality of life is impaired in BD patients, and this impairment is related with disease severity. It seems that presence of genital ulcers, eye and CNS involvement lead to the impairment of QoL in BD patients. These results highlight the importance of nursing interventions in managing clinical symptoms in these patients.(AU)

Antecedentes: La enfermedad de Behçet (BD) es una vasculitis sistémica que puede afectar la calidad de vida (QoL).ObjetivosEste estudio tuvo como objetivo evaluar la QoL en pacientes con BD azerí iraní, así como evaluar la asociación entre la QoL y las características de la enfermedad, incluida la actividad de la enfermedad y los síntomas clínicos. Métodos: En este estudio transversal, un total de 123 pacientes con BD de 15 a 65 años de edad cumplieron con los criterios internacionales para BD y 123 controles sanos que fueron emparejados por género. Los pacientes de 15 a 18 años de edad tenían el consentimiento informado y el consentimiento de sus padres para participar en el estudio. Se usó la escala de calidad de vida corta-36 (SF-36) para evaluar la calidad de vida. La actividad de la enfermedad se midió mediante el formulario de actividad actual de la BD y la medida de la actividad dinámica de la BD iraní y el índice de daño de la vasculitis (VDI) se usaron para la evaluación clínica del daño. Resultados: La media±DE de los pacientes con BD y el grupo control fue de 38,19±10,99 y 33,65±7,29 años, respectivamente. La puntuación de Salud física, así como la mayoría de los dominios SF-36, incluyendo Rol físico, Dolor corporal, Salud general, Vitalidad y Salud mental, fueron significativamente más bajos en los pacientes con BD en comparación con el grupo control (p<0,05). Hubo una correlación significativa entre los puntajes de Salud física y mental y la mayoría de los dominios SF-36 con actividad de la enfermedad y síntomas clínicos, como úlceras genitales, compromiso del sistema oftálmico y del sistema nervioso central (SNC) (p<0,05). Solo se observó una correlación significativa entre el VDI y el dominio del dolor corporal (p<0,05). Conclusión: La calidad de vida se ve afectada en los pacientes con BD, y este deterioro está relacionado con la gravedad de la enfermedad.(AU)

Is Palindromic Rheumatism a Pre-rheumatoid Arthritis Condition? Low Incidence of Rheumatoid Arthritis in Palindromic Rheumatism Patients Treated with Tight Control Strategy.

OBJECTIVES: Palindromic rheumatism (PR) is characterized by repetitive, afebrile episodes of acute arthritis and peri-arthritis. The aim of this study was considering the long-term outcomes of patients with PR who were treated with tight control strategy using Disease-modifying anti-rheumatic drugs (DMARDs). METHODS: We reviewed the charts of 106 patients diagnosed with PR who were referred to the Connective Tissue Diseases Research Center (CTDRC). We recruited all the patients diagnosed with PR according to the criteria of Hannonen. They visited the CTDRC clinic regularly and were treated with hydroxychloroquine and low dose prednisolone because of active episodes of PR. In cases that the attacks did not come under control in 3-6 months, methotrexate was added or replaced and the dose was increased up to 25mg/week. In resistant cases, sulfasalazine was added, followed by the addition of leflunomide and then azathioprine. Disease outcome was evaluated by getting complete or partial remission and prevention of disease evolution to rheumatoid arthritis (RA) or other inflammatory connective tissue diseases. RESULTS: This study included 92 patients with PR who were treated with DMARDs. Attacks were controlled completely or partially in 76 (82.6%) patients. Medications free remission was obtained in 16.3% of the patients. RA developed in 8.7% of the patients. By multivariate logistic regression analysis, age ≤40 at disease presentation, non-adherence to therapy and PIP joints involvement were the only factors which independently predicted the risk of treatment failure. CONCLUSIONS: Tight control strategy by using DMARDs may control PR and prevent disease progression to RA.

Evaluation of DNA methylation status of toll-like receptors 2 and 4 promoters in Behcet's disease.

BACKGROUND: Altered innate immune function plays an important role in the initiation of inflammatory response in Behcet's disease (BD). Toll-like receptors (TLRs) are the master regulators of the innate immune system. Because the role of TLRs remains unknown in the pathogenesis of BD, the present study aimed to evaluate the expression levels and methylation status of the TLR2 and TLR4 promoters in patients with BD. METHODS: In the present study, Iranian Azeri BD patients (n = 47) with an active (n = 22) and inactive (n = 25) period, and healthy controls (n = 61), were matched according to age, sex and ethnicity. TLR2 and TLR4 genes promoter CpG islands were predicted with the Eukaryotic Promoter Database (https://epd.vital-it.ch). Methylated DNA immunoprecipitation (MeDIP) was conducted. RESULTS: The results showed that mRNA of TLR4 was significantly increased in the peripheral blood mononuclear cells (PBMCs) of BD patients with an active phase compared to the control group. Differences in mRNA of TLR4 between the inactive BD and control groups were not significant. Differences in TLR2 mRNA levels in the PBMCs of the active and inactive phase BD and control groups were not significant. The methylation rate of TLR4 gene promoter was significantly lower in the active and inactive BD groups compared to the control group. The difference between the active and inactive BD groups was not significant. There was no significant difference in the methylation rates of the TLR2 gene between studied groups. CONCLUSIONS: Our preliminary findings suggest that the hypomethylation of TLR4 gene may be involved in the pathogenesis of BD via increasing TLR4 expression.

Effects of coenzyme Q10 supplementation on matrix metalloproteinases and DAS-28 in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVES: This study aimed to assess the effect of CoQ10 supplementation on serum matrix metalloproteinases (MMPs) and clinical parameters in rheumatoid arthritis (RA) patients. METHOD: In this randomized, double-blind, placebo-controlled trial, 54 RA patients who fulfilled the eligibility criteria (18-56 years, diagnosed at least 6 months ago, with DAS-28 > 3.2) were randomly assigned into two groups to receive 100 mg/day CoQ10 (n = 27) or placebo (n = 27) for 2 months. Serum MMP-1 and MMP-3 levels and clinical status using disease activity score in 28 joints (DAS-28) were assessed before and after supplementation. Data were analyzed using χ2, independent sample t test, paired t test, Wilcoxon, Mann-Whitney, and analysis of covariance. RESULTS: A significant reduction was observed in both CoQ10 and placebo groups in the medians of serum MMP-1 (0.2 to 0.16, P < 0.001), (0.18 to 0.15, P = 0.001); swollen joint count (2 to 0, P < 0.001), (2 to 0, P = 0.009); and the means of DAS-28 (5.01 ± 1.21 to 2.34 ± 0.68, P < 0.001), (4.88 ± 0.96 to 4.04 ± 1.36, P = 0.009) respectively. Serum MMP-3 level increased significantly in placebo group (2.26 to 2.57, P = 0.020), and the MMP-3 changes between groups were significant (P = 0.027). Furthermore, significant reductions were only observed in ESR, pain score, and tender joint count in CoQ10 group compared with baseline (P = 0.001, P < 0.001, and P < 0.001, respectively). Significant differences were observed between two groups in DAS-28, pain score, and swollen and tender joint count after the intervention (P < 0.001, P < 0.001, and P = 0.012 and P < 0.001, respectively). CONCLUSIONS: It seems that CoQ10 may provide a new complementary approach for RA patients.Key Points• CoQ10 supplementation in RA patients attenuated serum MMP-3 level.• CoQ10 supplementation in RA patients improved clinical outcomes and ameliorated disease severity.• CoQ10 may provide a new complementary approach for patients with RA.

Subjective global assessment of nutritional status in children.

This study was aimed to compare the subjective and objective nutritional assessments and to analyse the performance of subjective global assessment (SGA) of nutritional status in diagnosing undernutrition in paediatric patients. One hundred and forty children (aged 2-12 years) hospitalized consecutively in Tabriz Paediatric Hospital from June 2008 to August 2008 underwent subjective assessment using the SGA questionnaire and objective assessment, including anthropometric and biochemical measurements. Agreement between two assessment methods was analysed by the kappa (κ) statistic. Statistical indicators including (sensitivity, specificity, predictive values, error rates, accuracy, powers, likelihood ratios and odds ratio) between SGA and objective assessment method were determined. The overall prevalence of undernutrition according to the SGA (70.7%) was higher than that by objective assessment of nutritional status (48.5%). Agreement between the two evaluation methods was only fair to moderate (κ = 0.336, P < 0.001). The sensitivity, specificity, positive and negative predictive value of the SGA method for screening undernutrition in this population were 88.235%, 45.833%, 60.606% and 80.487%, respectively. Accuracy, positive and negative power of the SGA method were 66.428%, 56.074% and 41.25%, respectively. Likelihood ratio positive, likelihood ratio negative and odds ratio of the SGA method were 1.628, 0.256 and 6.359, respectively. Our findings indicated that in assessing nutritional status of children, there is not a good level of agreement between SGA and objective nutritional assessment. In addition, SGA is a highly sensitive tool for assessing nutritional status and could identify children at risk of developing undernutrition.

Subjective vs objective nutritional assessment study in children: a cross-sectional study in the northwest of Iran.

Different methods have been used to assess nutritional status in hospitalized pediatric patients, and there is no agreement on the finest index which reflects nutritional status. The aim of this study was to compare the subjective global assessment (SGA) and objective assessment of nutritional status in hospitalized pediatric patients. One hundred forty children with mean age of 6.43 +/- 0.23 years hospitalized consecutively in Tabriz Pediatric Hospital from June to August in 2008 underwent a subjective assessment using the SGA questionnaire and objective assessment (anthropometric and biochemical measurements). An agreement between 2 assessment methods were analyzed by the kappa statistic. According to the result of SGA method, the overall prevalence of malnutrition was higher than the objective assessment method. The agreement between the 2 methods were merely fair to moderate (kappa = 0.336, P = .000). The linear relationship between 2 methods was also fair to moderate (r = 0.374, P < .05). Our findings indicated that the differences between two evaluated methods in assessing nutritional status of pediatric patients, and it can also detect the changing trend of nutritional status, which may be missed by one-time anthropometry and biochemical methods.