Can HDL cholesterol be replaced by paraoxonase 1 activity in the prediction of severe coronary artery disease in patients with type 2 diabetes?

BACKGROUND AND AIMS: Novel biomarkers are required to improve cardiovascular disease prediction in patients with type 2 diabetes (T2D) as a high-risk population. This study was conducted to examine whether coronary artery disease (CAD) risk assessment can be improved by substituting high-density lipoprotein (HDL)-bound paraoxonase 1 (PON1) activity for HDL cholesterol (HDL-C) concentration in patients with T2D. METHODS AND RESULTS: In this study, we studied 139 patients with T2D (mean age 64.12 ± 8.17 years) who underwent coronary angiographic examination. The initial rate of substrate hydrolysis was spectrophotometrically assayed in kinetic mode for measuring PON1 activity. Receiver operating characteristic (ROC) graphs are created by plotting true positivity versus false positivity. In patients with HbA1c ≥ 7%, PON1 (AUC = 0.7, p = 0.029) and nonHDL-C/PON1 (AUC = 0.75, p = 0.013) were significantly more capable of differentiating patients with CAD from those without CAD compared to HDL-C and nonHDL-C/HDL-C. Also, the predictive power of PON1 (AUC = 0.64, p = 0.029) and nonHDL-C/PON1 (AUC = 0.71, p = 0.004) were significantly higher in comparison with HDL-C and nonHDL-C/HDL-C for CAD characterization in patients aged ≥50 years. Moreover, PON1 and nonHDL-C/PON1 are associated with the incidence of CAD with an AUC of 0.7 (p = 0.026) and AUC of 0.64 (p = 0.087), respectively, among subjects with low HDL-C. CONCLUSION: PON1 and the ratio of nonHDL-C/PON1 significantly improve the prediction of severe CAD in T2D patients and in patients with HbA1c ≥ 7%, age ≥50 years, or low HDL-C. PON1 activity and lipid ratios using this enzyme may be valuable as substitutes of HDL-C for increasing clinical efficacies in cardiovascular risk assessment.

Oxidized LDL-regulated microRNAs for evaluating vascular endothelial function: molecular mechanisms and potential biomarker roles in atherosclerosis.

As a simple monolayer, vascular endothelial cells can respond to physicochemical stimuli. In addition to promoting the formation of foam cells, oxidized low-density lipoprotein (ox-LDL) contributes to the atherosclerotic process through different mechanisms, including endothelial cell dysfunction. As conserved noncoding RNAs, microRNAs (miRNAs) naturally lie in different genomic positions and post-transcriptionally regulate the expression of many genes. They participate in integrated networks formed under stress to maintain cellular homeostasis, vascular inflammation, and metabolism. These small RNAs constitute therapeutic targets in different diseases, including atherosclerosis, and their role as biomarkers is crucial given their detectability even years before the emergence of diseases. This review was performed to investigate the role of ox-LDL-regulated miRNAs in atherosclerosis, their molecular mechanisms, and their application as biomarkers of vascular endothelial cell dysfunction.

Epigenetic alterations and genetic variations of angiotensin-converting enzyme 2 (ACE2) as a functional receptor for SARS-CoV-2: potential clinical implications.

Receptor recognition is a crucial step in viral infection and is a critical factor for cell entry and tissue tropism. In several recent studies, angiotensin-converting enzyme 2 (ACE2) has been demonstrated to be the cellular receptor of SARS-CoV-2 as it was previously well known as the receptor of SARS-CoV. SARS-CoV-2 can bind with high affinity to human ACE2 and engages it as an entry receptor. It seems that the genetic, notably epigenetic variations of ACE2 are less known in different populations, indicating the need for its further investigation. These variations have the potential to affect its contribution to the pathogenicity of COVID-19. The contribution of epigenetics in the interindividual variability of ACE2 merits more attention because epigenetic processes can play important roles in ACE2 alterations in various tissues and different people and populations. Analyzing different DNA methylation patterns and microRNAs, contributing to the ACE2 modulation in the lungs will have a high priority. The epigenetic and genetic variations of ACE2 become even more important when considering that some people have mild clinical symptoms despite having COVID-19. The pathogenicity of SARS-CoV-2 infection is complex; therefore, a better understanding of the underlying pathobiology, especially binding the virus to its receptors, could help improve therapeutic and preventive approaches. This review aims to highlight the importance of evaluating both the epigenetic and genetic variations of ACE2 as a receptor for the deadly SARS-CoV-2.

Improved risk assessment of coronary artery disease by substituting paraoxonase 1 activity for HDL-C: Novel cardiometabolic biomarkers based on HDL functionality.

BACKGROUND AND AIMS: Developing laboratory assays to evaluate HDL functions and improve cardiovascular disease (CVD) risk assessment has recently emerged as a challenge. The present study was conducted to help predict the risk of coronary artery disease (CAD) by investigating new cardiometabolic risk factors based on substituting paraoxonase 1 (PON1) as a critical enzyme in the functionality of HDL for that of HDL-C. METHODS AND RESULTS: The present study recruited 274 subjects undergoing diagnostic coronary angiography, 92 without significant CAD (non-CAD), and 182 with a severe CAD. The diagnostic accuracy of the new biomarkers in non-CAD versus multi-vessel disease was obtained in descending order of AUC as 0.72 (P < 0.001) for log (TG/PON1), 0.70 (P < 0.001) for nonHDL-C/PON1, and 0.67 (P < 0.001) for LDL-C/PON1. After performing a multivariate adjustment for age, gender, BMI, statin therapy, and diabetes mellitus, the increased odds of CAD remained significant for the new cardiometabolic ratios as independent variables [adjusted OR = 1.47 (1.15-1.88), p = 0.002 for LDL-C/PON1; adjusted OR = 2.15 (1.41-3.5), p = 0.009 for nonHDL-C/PON1; adjusted OR = 5.03 (2.14-13.02), p = 0.004 for log (TG/PON1)]. CAD was diagnosed with an optimal discriminating cutoff of 1.84 for LDL-C/PON1, 2.8 for nonHDL-C/PON1, and 0.48 for log (TG/PON1). CONCLUSIONS: To improve CAD's risk assessment, the PON1 activity was proposed as an alternative to HDL-C in the commonly used atherogenic lipid ratios. Substituting the PON1 activity for the HDL-C concentration can provide an index of the HDL activity. The present study sought to exploit the lipoprotein-related risk factors of CAD from a more effective perspective.

Functional mechanisms of miR-192 family in cancer.

By growing research on the mechanisms and functions of microRNAs (miRNAs, miRs), the role of these noncoding RNAs gained more attention in healthcare. Due to the remarkable regulatory role of miRNAs, any dysregulation in their expression causes cellular functional impairment. In recent years, it has become increasingly apparent that these small molecules contribute to development, cell differentiation, proliferation, apoptosis, and tumor growth. In many studies, the miR-192 family has been suggested as a potential prognostic and diagnostic biomarker and even as a possible therapeutic target for several cancers. However, the mechanistic effects of the miR-192 family on cancer cells are still controversial. Here, we have reviewed each family member of the miR-192 including miR-192, miR-194, and miR-215, and discussed their mechanistic roles in various cancers.

Epigenetics of paraoxonases.

PURPOSE OF REVIEW: Studies have shown the three-member paraoxonase (PON) multigene family to be involved in the development of a large variety of diseases with an inflammatory component. Environmental factors such as lifestyle-related factors differ widely between populations and it is important to consider that their impacts may be exerted through the epigenetic mechanisms, which connect genes, the environment and disease development and are a potential therapeutic avenue. RECENT FINDINGS: In the review period, very little was published on epigenetics of PON2 or PON3, mostly on their diagnostic value in cancer by measuring methylation levels of these genes. However, the picture is more promising with PON1. Here, several studies have linked the epigenetic regulation of PON1 to various metabolic processes and particularly to the development of several diseases, including stroke, heart disease, aortic valve stenosis and chronic obstructive pulmonary disease. SUMMARY: Studies into the epigenetic regulation of the PON family are in their infancy. However, recent studies linking epigenetic regulation of PON1 to disease development will encourage further research and open up the possibility for new potential therapeutic interventions.

Enzymatic characterization of a NADH-dependent diaphorase from Lysinibacillus sp. strain PAD-91.

Diaphorases are flavin-containing enzymes with potential applications in biotransfomation reactions, biosensor design and in vitro diagnostic tests. In this paper, we present recombinant expression, characterization and medium optimization of a lipoamide dehydrogenase (DLD) with NADH-dependent diaphorase activity from a Lysinibacillus sp. strain. DLD encoding sequence showed an open reading frame of 1413-bp encoding a 470 amino acid chain. Lysinibacillus sp. DLD catalyzed the NADH-dependent reduction of electron acceptors and exhibited diaphorase activity. The molecular mass of the isolated enzyme was found to be about 50 kDa, and determined to be a monomeric protein. The optimum pH and temperature for the catalytic activity of the enzyme was about pH 7.5 and 30 °C. The Km and Vmax values were estimated to be 0.025 mM and 1.33 µmol/min, respectively. Recombinant enzyme was optimally produced in fermentation medium containing 10 g/L sucrose, 25 g/L yeast extract, 5 g/L NaCl and 0.25 g/L MgSO4. By Scaling up fermentation from flask to bioreactor, enzyme activity was increased to 487.5 U/ml. This study provides data on the identification, characterization and medium optimization of a NADH-dependent diaphorase from a newly isolated Lysinibacillus sp. PAD-91.

Paraoxonase-2 variants potentially influence insulin resistance, beta-cell function, and their interrelationships with alanine aminotransferase in type 2 diabetes.

BACKGROUND: The aim of this study was to determine whether insulin resistance, beta-cell function, and their associations with alanine aminotransferase (ALT) are affected by the functional variants of paraoxonase-2 (PON2) as an intracellular antioxidant in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: Quantitative insulin sensitivity check index (QUICKI) and homeostasis model assessment for beta-cell function (HOMA-BCF) were assessed in T2D patients. Insulin levels were determined using ELISA. The variants PON2-A148G and PON2-S311C were genotyped using polymerase chain reaction-based restriction fragment length polymorphism. RESULTS: According to the PON2-G148A variant, ALT was found to be significantly correlated with QUICKI (r = -0.616, P = 0.005) and HOMA-BCF (r = 0.573, P = 0.01) in the GA + GG group; however, the correlations were not statistically significant in the AA genotypes. Based on the genotypes of PON2-S311C, there was a significant correlation between ALT with QUICKI (r = -0.540, P = 0.031) and HOMA-BCF (r = 0.567, P = 0.022) in the SC + CC group. In the multiple adjusted logistic regression analyses, considering the variants PON2-G148A and PON2-C311S as independent variables and QUICKI and HOMA-BCF as the dependent variables, both variants were significantly associated with the QUICKI (P = 0.019 for PON2-G148A and P = 0.041 for PON2-C311S). Furthermore, PON2-C311S remained significantly associated with HOMA-BCF (P = 0.03). CONCLUSION: These data implicate a role for the functional variants of PON2 in insulin resistance and beta-cell function as well as underscore the effective role of these variants in the associations between them and ALT. Our data contribute to our understanding of the important physiologic functions of PON2 in glucose metabolism and its related metabolic diseases.

Cloning and expression of codon-optimized recombinant darbepoetin alfa in Leishmania tarentolae T7-TR.

Darbepoetin alfa is an engineered and hyperglycosylated analog of recombinant human erythropoietin (EPO) which is used as a drug in treating anemia in patients with chronic kidney failure and cancer. This study desribes the secretory expression of a codon-optimized recombinant form of darbepoetin alfa in Leishmania tarentolae T7-TR. Synthetic codon-optimized gene was amplified by PCR and cloned into the pLEXSY-I-blecherry3 vector. The resultant expression vector, pLEXSYDarbo, was purified, digested, and electroporated into the L. tarentolae. Expression of recombinant darbepoetin alfa was evaluated by ELISA, reverse-transcription PCR (RT-PCR), Western blotting, and biological activity. After codon optimization, codon adaptation index (CAI) of the gene raised from 0.50 to 0.99 and its GC% content changed from 56% to 58%. Expression analysis confirmed the presence of a protein band at 40 kDa. Furthermore, reticulocyte experiment results revealed that the activity of expressed darbepoetin alfa was similar to that of its equivalent expressed in Chinese hamster ovary (CHO) cells. These data suggested that the codon optimization and expression in L. tarentolae host provided an efficient approach for high level expression of darbepoetin alfa.

Allele frequency and genotype distribution of a common variant in the 3´-untranslated region of the SLC22A3 gene in patients with type 2 diabetes: Association with response to metformin.

BACKGROUND: Organic cation transporter 3 (OCT3) is an excellent transporter for metformin, which is used as first-line therapy for type 2 diabetes (T2D). OCT3 genetic variants may influence the clinical response to metformin. This study aimed to determine the genotype and allele frequency of OCT3-564G>A (rs3088442) variant and its role in the glycemic response to metformin in patients with newly diagnosed T2D. MATERIALS AND METHODS: Based on the response to metformin, 150 patients were classified into two groups: Sixty-nine responders (decrease in glycated hemoglobin [HbA1c] values by more than 1% from the baseline) and 81 nonresponders (decrease in HbA1c values <1% from the baseline). HbA1c levels were determined by chromatography. The variant OCT3-564G>A was genotyped using polymerase chain reaction - based restriction fragment length polymorphism. RESULTS: The genotypes frequencies were 51.3% GG, 36% AG, and 12.7% AA. Allele frequency of major allele (G) and minor allele (A) in OCT3-564G>A variant was found to be 0.69 and 0.31, respectively. Fasting glucose, HbA1c, body mass index, and lipid profile in both GG genotypes and GA + AA group decreased significantly after 3 months of metformin therapy compared with baseline (P < 0.05). In both responders and nonresponders, HbA1c and fasting glucose levels were lower in patients with the GA + AA genotype than in those with the GG genotype; however, the differences were not statistically significant (P > 0.05). CONCLUSION: The A allele frequency (which may be a protective allele against coronary heart disease) in the Iranian diabetic patients was lower than Iranian, Caucasian and Japanese healthy populations. Metformin is useful in improving the lipid profile, in addition to its impacts in glycemic control, and these effects are regardless of OCT3-564G>A variant.

Pleiotropic functions and clinical importance of circulating HDL-PON1 complex.

High density lipoprotein (HDL) functions are mostly mediated through a complex proteome, particularly its enzymes. HDL can provide a scaffold for the assembly of several proteins that affect each other's function. HDL particles, particularly small, dense HDL3, are rich in paraoxonase 1 (PON1), which is an important enzyme in the functionality of HDL, so the antioxidant and antiatherogenic properties of HDL are largely attributed to this enzyme. There is an increasing need to represent a valid, reproducible, and reliable method to assay HDL function in routine clinical laboratories. In this context, HDL-associated proteins may be key players; notably PON1 activity (its arylesterase activity) may be a proper candidate because its decreased activity can be considered an important risk factor for HDL dysfunctionality. Of note, automated methods have been developed for the measurement of serum PON1 activity that facilitates its assay in large sample numbers. Arylesterase activity is proposed as a preferred activity among the different activities of PON1 for its assay in epidemiological studies. The binding of PON1 to HDL is critical for the maintenance of its activity and it appears apolipoprotein A-I plays an important role in HDL-PON1 interaction as well as in the biochemical and enzymatic properties of PON1. The interrelationships between HDL, PON1, and HDL's other components are complex and incompletely understood. The purpose of this review is to discuss biochemical and clinical evidence considering the interactions of PON1 with HDL and the role of this enzyme as an appropriate biomarker for HDL function as well as a potential therapeutic target.

Altered expression of miR-375 and miR-541 in type 2 diabetes patients with and without coronary artery disease (CAD): the potential of miR-375 as a CAD biomarker.

Background: MicroRNAs (miRNAs, miRs) have been linked to beta-cell pathologies and have also shown potential as biomarkers for cardiovascular disease. This study aimed to evaluate the expression of miR-375 and miR-541 in T2D patients with and without CAD, in order to determine the potential of these miRNAs as biomarkers for assessing CAD risk. Methods: This study was conducted on 106 patients with T2D who underwent coronary angiographic examination. Reverse transcription was performed using the cDNA synthesis kit. Real-time PCR was performed using the SYBR Green method and specific primers. The ability to predict which person had developed CAD was evaluated by calculating the area under the receiver-operating characteristic (ROC) curve (AUC). Results: The expression of miR-375 was significantly higher in samples from CAD patients compared to those without CAD (p = 0.009). While the expression of miR-541 was also higher in CAD patients, the difference was not statistically significant. In terms of predicting CAD, miR-375 was found to be a suitable predictor with an AUC of 0.74 (p = 0.01), while miR-541 was not. With a cut-off value of 0.016 for miR-375, the sensitivity was 67% and the specificity was 80%. Conclusion: Our results indicated that circulating levels of miR-375 and miR-541 were elevated in T2D patients with CAD compared to those without CAD. This suggests that miR-375 could potentially be used as a non-invasive biomarker for the diagnosis of CAD in T2D patients.

Paraoxonase 1 Activity is Associated with Interleukin-6 Levels in Type 2 Diabetes: Effects of Age and Gender.

Background: A further understanding of the mechanisms linking inflammation to T2D and related complications can help prevent or control this silent but dangerous disease. This study was conducted to determine the association between paraoxonase 1 (PON1) activity and interleukin-6 (IL-6) in type 2 diabetes (T2D). Furthermore, we have evaluated the role of age and gender in the relationship between the PON1 activity and IL-6. Methods: A total of 105 people with T2D were enrolled in this study. IL-6 levels were determined using ELISA. For the PON1 activity assay, the hydrolysis rate of the substrate phenylacetate was spectrophotometrically assayed in serum at 270 nm. The determined velocities were the initial velocities of substrate hydrolysis. Results: PON1 activity was negatively correlated with IL-6 in total data (r = -0.34, P = 0.001). In both groups with age ≥50 and <50 years, PON1 activity was negatively correlated with IL-6, but the correlation was significant in patients aged 50 years and above (r = -0.358, P = 0.005) compared with patients with age <50 years. In both women and men, PON1 activity was negatively correlated with IL-6, but the correlation was significant in women (r = -0.318, P = 0.006) in comparison with men. Conclusions: Inverse association between PON1 activity and IL-6 in T2D may represent the oxidative-inflammatory interaction in this disease. Our findings highlight that at older ages and in women, the associations between lower PON1 activity and higher IL-6 concentrations are more evident, and this should be considered in patients with T2D.

R-carrying genotypes of serum paraoxonase (PON1) 192 polymorphism and higher activity ratio are related to susceptibility against ischemic stroke.

The polymorphic gene of serum paraoxonase (PON1) and its activity involved in atherosclerosis. The purpose of the study was to analyze PON1 192 Q/R polymorphism and the enzyme activities in ischemic stroke. The polymorphism as the most common polymorphism in PON1 gene coding sequence is associated with variation in the enzyme activity and vascular disease. The study included 85 stroke patients and 71 control subjects. PON1 192 polymorphism was genotyped using PCR protocol. Paraoxonase activity (Para) and arylesterase activity (Aryl) were determined spectrophotometrically using paraoxon and phenylacetate as the substrates. The QR and RR genotypes were more frequent in stroke population compared to controls, resulting in a higher frequency of the R allele in patients (0.24 vs 0.18, OR = 1.41). Patients had significantly higher Para/Aryl ratio than that of controls (P = 0.016). In stroke patients, Para/Aryl and Para/HDL ratios increased with this order: QQ < QR < RR. Hypertension significantly increased the risk of ischemic stroke by 15-fold among R-containing people, while this was significantly increased 4-fold for QQ homozygotes. Smoking increased the risk of having ischemic stroke in both QQ homozygote and QR + RR group (OR = 2.84 and OR = 2.33, respectively). In conclusion, these data highlight the importance of PON1 192 R allele and high Para/Aryl ratio in susceptibility to ischemic stroke in the population. The presence of the 192 R allele potentiates the risk of stroke especially in hypertensive people. Decreased Aryl and increased Para/Aryl, Para/HDL and Aryl/HDL ratios may be markers indicated the increased susceptibility to ischemic stroke in the population.

Increased oxidized-LDL levels and arylesterase activity/HDL ratio in ESRD patients treated with hemodialysis.

PURPOSE: Investigations, in which oxidized-low density lipoprotein (ox-LDL), serum paraoxonase (PON1) and homocysteine (Hcy) are considered together as important agents involved in the development of oxidative and atherogenic events in non-diabetic hemodialysis (HD) population, are limited. This case-control study was designed to evaluate these parameters in the patients and control subjects and to determine the correlations among the factors. METHODS: Forty-nine age- and sex- matched subjects, including 28 non-diabetic HD patients (paired pre-and post-dialysis samples) and 21 control subjects, were enrolled. Ox-LDL and Hcy levels were measured with ELISA and EIA methods, respectively. Arylesterase activity of PON1 was measured by spectrophotometric assay. RESULTS: Compared with the control group, ox-LDL levels were significantly increased both before (p=0.001) and after HD (p=0.036). Arylesterase activity-to-HDL ratio in HD patients was significantly higher than control subjects (p=0.003). Homocysteine levels in the ESRD patients were higher than control subjects both in pre-dialysis and post-dialysis. There was a significant positive correlation (r= 0.25, p= 0.026) between ox-LDL and homocysteine in samples obtained before HD. Logistic regression analysis revealed ox-LDL levels (OR=3.02, p < 0.001) and arylesterase activity/HDL ratio (OR=2.43, p=0.01) to be associated with the increased risk of ESRD. CONCLUSIONS: Ox-LDL levels and arylesterase activity/HDL ratio indicated the strongest association with ESRD risk. These factors, especially ox-LDL as an indicator of oxidative stress, may be biomarkers in evaluating the status of non-diabetic ESRD patients. Because of the pathogenic relationship between ox-LDL and homocysteine as nontraditional risk factors of atherosclerosis, therapeutic strategies adopted to reduce them may be useful in decrease of high prevalence of cardiovascular mortality in dialysis patients. In addition, measurement of PON1 activity to HDL ratio is possibly a more valuable biomarker than arylesterase activity alone in non-diabetic ESRD.

Association between vitamin D receptor gene polymorphism (rs731236) and aggrecan gene VNTR polymorphism with the risk of lumbar intervertebral disc degeneration.

Background: Low back pain is one of the most common causes of referral to physicians. Lumbar disc degeneration (LDD) is the main cause of back pain in different countries. It seems that genetic factors are more effective than environmental factors in the developing of degenerative phenomena. The aim of this investigation, therefore, was to study the association of the aggrecan gene (ACAN) variable number tandem repeat (VNTR) and the vitamin D receptor (VDR) rs731236 (TaqI) polymorphisms, with lumbar intervertebral disc degeneration in a population in the North of Iran. Methods: In this study, 55 patients with symptomatic intervertebral disk degeneration and 55 control subjects were included. VDR gene polymorphism was genotyped by PCR-based RFLP. The isolated DNA was used to genotype the VNTR of ACAN gene via conventional PCR. Results: For VDR gene polymorphism, the CC genotype (OR=5.337, P=0.019) was significantly higher among the patients compared with the controls, revealing a higher frequency of the C allele in patients compared with controls (OR=2.707, P=0.005). The lower number of frequent repetitions in the VNTR aggrecan gene was associated with a six-time increase of lumbar disc degeneration. Also, high BMI can be considered as an independent factor in the incidence of this disease. Conclusion: Aggrecan gene VNTR polymorphism had an association with degeneration of lumbar intervertebral discs that the shorter VNTR repeats increasing the chance of the disc degeneration in this population in the North of Iran. Moreover, an association between the mutant allele (C) of VDR gene TaqI polymorphism and disc degeneration is found.

Naringenin is an inhibitor of human serum paraoxonase (PON1): an in vitro study.

BACKGROUND: Inhibition studies on PON1 as an organophosphate-hydrolyzing and atheroprotective enzyme could be useful in elucidating the function of PON1. This study is aimed at examining the in vitro effects of the flavonoid naringenin on PON1 activity in human serum and purified enzyme. METHODS: The inhibition kinetics of the interaction of naringenin with human PON1 in serum and purified enzyme was determined spectrophotometrically using paraoxon and phenylacetate as the substrates. RESULTS: Naringenin could be introduced as an effective inhibitor on purified human PON1 activity for phenylacetate as the substrate with an IC(50) value of 10 µM. Paraoxonase and arylesterase activities of PON1, in the serum assay, were also inhibited by naringenin with IC(50) values of 37.9 and 34.6 µM, respectively. PON1, according to acompetitive-type inhibition pattern, was inhibited by naringenin with K(i) constant of 14.5 µM for serum paraoxonase activity. The results were compared with a known inhibitor of PON1, 2-hydroxyquinoline. We believe (to our knowledge) that this is the first reported study for kinetic parameters of PON1 inhibition by naringenin. CONCLUSIONS: Lipophilic property appears to be an important feature of the structure in evaluating the inhibitor potential. Comparison of our findings and other authors showed that the induction of PON1 gene by naringenin and its inhibitory effects on the enzyme protein are probably two different mechanisms by which the flavonoid affects PON1. The in vitro data reported in this study could be useful in the development of structure-activity relationship for PON1 inhibition.

The complex combination of COVID-19 and diabetes: pleiotropic changes in glucose metabolism.

PURPOSE: Angiotensin converting enzyme 2 (ACE2) is the door for SARS-CoV-2, expressed in critical metabolic tissues. So, it is rational that the new virus causes pleiotropic alterations in glucose metabolism, resulting in the complication of pre-existing diabetes's pathophysiology or creating new disease mechanisms. However, it seems that less attention has been paid to this issue. This review aimed to highlight the importance of long-term consequences and pleiotropic alterations in glucose metabolism following COVID-19 and emphasize the need for basic and clinical research in metabolism and endocrinology. RESULTS: SARS-CoV-2 shifts cellular metabolism from oxidative phosphorylation to glycolysis, which leads to a decrease in ATP generation. Together with metabolic imbalance, the impaired immune system elevates the susceptibility of patients with diabetes to this deadly virus. SARS-CoV-2-induced metabolic alterations in immune cells can result in hyper inflammation and a cytokine storm. Metabolic dysfunction may affect therapies against SARS-CoV-2 infection. The effective control of metabolic complications could prove useful therapeutic targets for combating COVID-19. It is also necessary to understand the long-term consequences that will affect patients with diabetes who survived COVID-19. CONCLUSIONS: Since the pathophysiology of COVID-19 is still mostly unknown, identifying the metabolic mechanisms contributing to its progression is essential to provide specific ways to prevent and improve this dangerous virus's detrimental effects. The findings show that the new virus may induce new-onset diabetes with uncertain metabolic and clinical features, supporting a potential role of COVID-19 in the development of diabetes.

The Atherogenic Index Log (Triglyceride/HDL-Cholesterol) as a Biomarker to Identify Type 2 Diabetes Patients with Poor Glycemic Control.

BACKGROUND: Identifying appropriate biomarkers for predicting type 2 diabetes (T2D) patients with increased HbA1c may prove helpful in preventing increased risk of cardiovascular disease (CVD). The present study was conducted to analyze the diagnostic performance of the atherogenic index log (TG/HDL-C) in T2D patients with increased HbA1c. METHODS: Patients with T2D were classified into two groups according to having an HbA1c <8% or ≥8%. Atherogenic index was calculated from the logarithmic transformation of TG/HDL-C. Receiver operating characteristic curve was used to evaluate the diagnostic performance of log (TG/HDL-C). Insulin and fasting glucose concentrations were used to determine homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: Compared with the patients with HbA1c <8%, log (TG/HDL-C) was significantly higher in the patients with HbA1c ≥8% (p = 0.025). The atherogenic index was a biomarker for the prediction of T2D patients with HbA1c ≥8% versus patients with HbA1c <8%, as shown in the area under the curve (AUC = 0.61, P = 0.013). The best cut-off point of log (TG/HDL-C) for the discrimination between patients with HbA1c ≥8% versus patients with HbA1c <8% determined to be 0.44. Atherogenic index was significantly and positively correlated with HOMA-IR in female patients (r = 0.313, P = 0.003) and in patients with an age ≥5o (r = 0.253, P = 0.021). CONCLUSION: The log (TG/HDL-C) in addition to its known association with enhanced CVD risk could be considered as a biomarker to predict T2D patients with poor glycemic control. Therefore, the increased ratio may provide a simple and useful way of identifying poor glycemic T2D patients who are possibly to be at elevated risk of CVD.