ACE I/D gene polymorphisms and polycystic ovary syndrome manifestations.

Objective: Polycystic ovary syndrome (PCOS) is a common multifactorial endocrine disorder affecting women of reproductive age. ACE enzyme is involved in the physiopathology of the ovarian system, and there are inconsistencies between studies regarding the association between ACE gene variants and PCOS. The objective of this study is to evaluate the association between ACE I/D gene polymorphisms and PCOS, as well as its clinical manifestations, in Iranian women with PCOS. Design: This study included 140 patients with PCOS and 153 controls without the disease. Samples were collected from Yas Hospital Complex in Tehran-Iran during 2018 to 2022. Genomic DNA was obtained from whole blood samples using salt extraction, and genotyping was carried out using polymerase chain reaction (PCR). Results: Variants of DD, ID, and II were observed in 31.4, 44.3, and 24.3% of PCOS, and 38.6, 44.1, and 17.2% of control group, respectively. The frequency of ACE gene variants did not differ between PCOS patients and control group. A significant difference was observed between the frequency of elevated LH to FSH ratio > 2 and ACE gene polymorphisms in patients with PCOS (OR: 0.32 (0.12-0.88), P value 0.024) with lower frequency observed in D allele carriers. Conclusion: This study indicate that although ACE I/D variants frequency in PCOS women is similar to non-PCOS women, it may be involved in the pathogenesis of the disease through mechanisms regulating steroidogenesis in the ovary and suggests that ACE might be related to exacerbated clinical manifestations of PCOS which requires further investigations.

Association analysis between the VDR gene variants and type 2 diabetes.

Background: Type 2 diabetes mellitus (T2DM) is recognized as a complex metabolic which has affected the lives of millions of people around the world. Vitamin D receptor (VDR) gene polymorphisms have been suggested to be a vital contributor to the development of T2DM. However, the association between VDR gene polymorphisms and T2DM remains controversial. We have investigated the association between two VDR gene polymorphisms (rs731236 and rs1544410) and T2DM in an Iranian population. Methods: A total of 148 T2DM patients and 100 normal controls were recruited in this study. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis to perform genotyping. Results: The results of the present research revealed that the frequency of the rs731236 C allele was significantly higher in T2DM patients than in normal controls (p = 0.044). The CC genotype of rs731236 was connected with an increased risk of T2DM (OR = 2.85, 95% CI = 1.06-7.69, p = 0.039). However, no significant difference in the frequency of the rs1544410 C allele between T2DM patients and normal controls was observed (p = 0.918). Conclusion: Our findings were suggestive of the rs731236 polymorphism of the VDR as a risk factor for developing T2DM in the Iranian population, while rs1544410 polymorphism may not be associated with T2DM susceptibility. Further research is needed to approve these findings in other populations and to clarify the underlying mechanisms involved in such an association. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01323-0.

Investigating the relationship between the VNTR variant of the interleukin-1 receptor antagonist gene and coronary in-stent restenosis.

OBJECTIVE: This study aimed to examine the association between the interleukin-1 receptor antagonist gene (IL-1RN) and coronary in-stent restenosis (ISR) through the analysis of the VNTR variant based on the previously reported results. MATERIALS AND METHODS: The samples were classified into two clearly defined groups: the case group, which comprised 45 patients diagnosed with in-stent restenosis (ISR+), and the control group, which included 60 patients without ISR (ISR-). Polymerase chain reaction (PCR) was performed to examine the 86-bp VNTR variant of the IL-1RN gene. RESULTS: In the analysis of six identified groups consisting of variant alleles of 86 base pairs of VNTR of the IL-1RN gene statistically significant difference was observed for the presence of IL1RN*2 allele between cases and controls (p = 0.04, OR; 0.045). CONCLUSION: Individuals with allele 2 of the IL-1Ra gene may be more predisposed to ISR. This could be due to an imbalance between IL-1Ra and IL-1ß which is crucial in preventing the initiation or advancement of inflammatory diseases in specific organs. The observed phenomenon can be characterized by increased production of IL-1ß and potential reduction of IL-1Ra as a result of functional VNTR variation in IL-RN gene.

PTEN promoter methylation and expression in endometrial cancer tissues.

Introduction: Some gene expression regulation in cancers can be controlled by epigenetic change like methylation. PTEN promoter methylation and expression were evaluated in endometrial cancer. Methods: The study was run on 39 tumor tissues of endometrial cancer patients and 41 normal endometrial tissues. After total RNA extraction, cDNA synthesis was done by reverse transcription of the total (real-time PCR) using SYBER Green master mix. DNA extraction and bisulfite treatment were conducted and methylation was semiquantified by the methylation-sensitive high-resolution melting method. Finally, promoter methylation quantification of the total number of 25 tumors and 22 non-neoplastic tissues was done. Results: PTEN gene expression showed a significant decrease in endometrial cancer tissues. Promoter methylation was significantly lower in the non-neoplastic group (7.2; p < 0.001). In addition, PTEN promoter methylation was observed in 52.0% of tumor tissues compared with 13.6% in the non-neoplastic group (p = 0.06). There were no significant correlations between PTEN expression and methylation and clinicopathological features in endometrial cancer patients (p > 0.05). Conclusion: PTEN gene expression in endometrial cancer tissues decreased because of its promoter hypermethylation.

Association of ACE gene polymorphisms with in-stent restenosis by stent type (biomime, supraflex, xience).

INTRODUCTION: Angiotensin Converting Enzyme or ACE is an exo-peptidase that causes the conversion of angiotensin I to angiotensin II, vasoconstriction, and aldosterone production. ACE gene polymorphism (I/D) affects enzyme activity and the risk of coronary artery disease or CAD. AIMS: To examine the role of ACE (I/D) Gene Polymorphisms by Stent Types (Biomime, Supraflex, Xience) the Ace gene allele and genotype frequencies were determined in patients who underwent angioplasty. MATERIAL & METHODS: Patients with in-stent restenosis (ISR+) (N = 53) and patients as non-ISR group (ISR-) (N = 68) have been enrolled in this study based on follow-up angiography > 1 year after PCI. Frequencies of allele and genotypes of the ACE (I/D) variant were determined using polymerase chain reaction (PCR). RESULTS: The genotypes and allele frequencies were not significantly different between the studied populations (p-Values > 0.05). However, there was a significant difference between people with a history of Clopidogrel use in the ISR- and ISR + groups observed (p-Values > 0.005). CONCLUSION: In the present study, there was no statistically significant relationship between ACE (I/D) gene polymorphism and the incidence of restenosis in patients who underwent repeat angiography. The results showed that the number of patients who received Clopidogrel in the ISR + group was significantly less than the ISR- group. This issue can indicate the inhibitory effect of Clopidogrel in the recurrence of stenosis.

Zinc supplementation ameliorates type 2 diabetes markers through the enhancement of total antioxidant capacity in overweight patients.

BACKGROUND: Evidence show that the recommended dose of zinc may not be sufficient for controlling pathological conditions such as type 2 diabetes mellitus (T2DM). AIM: This study aimed to evaluate the effects of zinc supplementation on the oxidative status in overweight T2DM. In addition, the routine glycaemic parameters were determined and compared in zinc-treated and placebo groups. METHODS: In this randomised, double-blind, placebo-controlled trial, 70 patients with T2DM were selected. They were divided into two groups for supplementation of 50 mg zinc gluconate or placebo (zinc group, n=35; placebo group, n=35) per day for 8 weeks. Blood samples were collected from all the individuals in the zinc group and controls for analysis. RESULTS: The results showed that zinc supplementation to patients with T2DM for 8 weeks significantly inhibited serum levels of lipid peroxidation (25%), nitrotyrosine (30%) and total oxidant status levels (25%, p<0.05). Nevertheless, the total antioxidant capacity was significantly elevated (16%) following zinc intake by patients with T2DM. CONCLUSIONS: These data, together with our previous report, may suggest that the control in the glycaemic condition in overweight patients with T2DM is correlated with the antioxidative/oxidative balance following intake of 50 mg zinc supplementation for 8 weeks. Under these circumstances, the clinical and glycaemic indices, including fasting blood glucose, insulin, haemoglobin A1c and homeostasis model of assessment-insulin resistance, were controlled. TRIAL REGISTRATION NUMBER: IRCT2015083102.

The association between acylcarnitine and amino acids profile and metabolic syndrome and its components in Iranian adults: Data from STEPs 2016.

Background: Evidence, albeit with conflicting results, has suggested that cardiometabolic risk factors, including obesity, type 2 diabetes (T2D), dyslipidemia, and hypertension, are highly associated with changes in metabolic signature, especially plasma amino acids and acylcarnitines levels. Here, we aimed to evaluate the association of circulating levels of amino acids and acylcarnitines with metabolic syndrome (MetS) and its components in Iranian adults. Methods: This cross-sectional study was performed on 1192 participants from the large-scale cross-sectional study of Surveillance of Risk Factors of non-communicable diseases (NCDs) in Iran (STEP 2016). The circulating levels of amino acids and acylcarnitines were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in individuals with MetS (n=529) and without MetS (n=663). Results: The higher plasma levels of branched-chain amino acids (Val, Leu), aromatic amino acids (Phe, Tyr), Pro, Ala, Glu, and the ratio of Asp to Asn were significantly associated with MetS, whereas lower circulating levels of Gly, Ser, His, Asn, and citrulline were significantly associated with MetS. As for plasma levels of free carnitine and acylcarnitines, higher levels of short-chain acylcarnitines (C2, C3, C4DC), free carnitine (C0), and long-chain acylcarnitines (C16, C18OH) were significantly associated with MetS. Principal component analysis (PCA) showed that factor 3 (Tyr, Leu, Val, Met, Trp, Phe, Thr) [OR:1.165, 95% CI: 1.121-1.210, P<0.001], factor 7 (C0, C3, C4) [OR:1.257, 95% CI: 1.150-1.374, P<0.001], factor 8 (Gly, Ser) [OR:0.718, 95% CI: 0.651-0.793, P< 0.001], factor 9 (Ala, Pro, C4DC) [OR:1.883, 95% CI: 1.669-2.124, P<0.001], factor 10 (Glu, Asp, C18:2OH) [OR:1.132, 95% CI: 1.032-1.242, P= 0.009], factor 11 (citrulline, ornithine) [OR:0.862, 95% CI: 0.778-0.955, P= 0.004] and 13 (C18OH, C18:1 OH) [OR: 1.242, 95% CI: 1.042-1.480, P= 0.016] were independently correlated with metabolic syndrome. Conclusion: Change in amino acid, and acylcarnitines profiles were seen in patients with MetS. Moreover, the alteration in the circulating levels of amino acids and acylcarnitines is along with an increase in MetS component number. It also seems that amino acid and acylcarnitines profiles can provide valuable information on evaluating and monitoring MetS risk. However, further studies are needed to establish this concept.

Metformin and long non-coding RNAs in breast cancer.

Breast cancer (BC) is the second most common cancer and cause of death in women. In recent years many studies investigated the association of long non-coding RNAs (lncRNAs), as novel genetic factors, on BC risk, survival, clinical and pathological features. Recent studies also investigated the roles of metformin treatment as the firstline treatment for type 2 diabetes (T2D) played in lncRNAs expression/regulation or BC incidence, outcome, mortality and survival, separately. This comprehensive study aimed to review lncRNAs associated with BC features and identify metformin-regulated lncRNAs and their mechanisms of action on BC or other types of cancers. Finally, metformin affects BC by regulating five BC-associated lncRNAs including GAS5, HOTAIR, MALAT1, and H19, by several molecular mechanisms have been described in this review. In addition, metformin action on other types of cancers by regulating ten lncRNAs including AC006160.1, Loc100506691, lncRNA-AF085935, SNHG7, HULC, UCA1, H19, MALAT1, AFAP1-AS1, AC026904.1 is described.

Analyzing the Reaction of Orotidine 5'-Phosphate Decarboxylase as a Way to Examine Some Key Catalytic Proposals.

This study analyzes the origin of enzyme catalysis by focusing on the reaction of orotidine 5'-phosphate decarboxylase (ODCase). This reaction involves an enormous catalytic effect of 23 kcal/mol that has been attributed to reactant state destabilization associated with the use of binding energy through the so-called Circe effect. However, our early studies and subsequent key experiments have shown that the presumed effect of the binding energy (namely, the strain exerted by a bond to a phosphate group) does not contribute to the catalysis. In this study, we perform quantitative empirical valence bond calculations that reproduce the catalytic effect of ODCase and the effect of removing the phosphate side chain. The calculations demonstrate that the effect of the phosphate is due to a change in reorganization energy and should not be described as an induced fit effect. Similarly, we show that the overall catalytic effect is due to electrostatic transition state stabilization, which again reflects the smaller reorganization energy in the enzyme than in water. We also elaborate on the problems with the induced fit proposal, including the fact that it does not serve to tell us what the actual origin of the action of the catalytic effect is. In addition to the above points, we use this paper to discuss misconceptions about the meaning of the preorganization effect, as well as other misunderstandings of what is being done in consistent calculations of enzyme catalysis.

The Association of Coronary Artery Calcium Score and Osteoporosis in Postmenopausal Women: A Cross-Sectional Study.

BACKGROUND: The association between osteoporosis, a common metabolic bone disorder, and atherosclerosis has been reported in different studies. In this study, we aimed to investigate the association between the coronary artery calcium score (CACS) and bone mineral density (BMD) at different sites and bone biomarkers in postmenopausal women. METHODS: A total of 184 participants were enrolled in this study. The CACS and BMD at different sites, including the spinal, total hip, and femoral neck, were measured using computed tomography angiography and dual energy X-ray absorptiometry, respectively. Serum levels of osteocalcin, ß-C-terminal telopeptide (ß-CTX), parathyroid hormone, and 25-hydroxy-vitamin D were measured. RESULTS: A negative association between CACS and bone biomarker levels (osteocalcin, P=0.021; ß-CTX, P=0.013) was noted. The univariable model showed an association between CACS and osteoporosis of the femoral neck (P=0.03). It was found that with an increase of 10 U in CACS, the odds of osteoporosis at the femoral neck escalates by 2% (odds ratio=1.02, 95% confidence interval, 1.002-1.03) using the multivariate logistic regression model, while such an association with osteoporosis could not be found at the spinal site. The best cutoff point of the calcium score was estimated to be 127. CONCLUSIONS: The results suggest that in postmenopausal women, coronary atherosclerosis is independently associated with osteoporosis of the femoral neck, but such an association could not be detected with spinal osteoporosis. The importance of screening for osteoporosis in patients with cardiovascular disease and the implications of preventive measures in the primary care setting were highlighted considering the common risk factors.

Relationship between a near Melanocortin-4 receptor gene variant and puberty timing in children is vague unlike obesity.

Background: Obesity is a complicated phenomenon which is a combination of genetic, environmental, and psychological factors. Genetic factors of obesity play an important role in individual risk. It is well known that obese children have disturbed puberty timing. To the best of our knowledge, no study has been performed to investigate the association between MC4R gene mutation and puberty timing. Methods: This study was performed as a cross-sectional study evaluating the near MC4R rs17782313 variation in 60 obese children and 98 healthy non obese children. Weight, height, BMI ( Body Mass Index ), BMI z-score (BMIz), family history of diabetes mellitus and obesity, the age of the obesity onset, overeating behavior, type of obesity (central or general) and puberty stage were evaluated in 60 obese children. Results: The average age of the participants was 14.87 (+/- 1.3) years, with average weight and BMI of 90.77 (+/-12.2) Kg and 31.72 (+/-4.35) Kg/m2, respectively. Compared to healthy non obese patients, those with C-T genotype (C-T Vs. T-T and C-C) had higher odds of obesity than those with T-T and C-C genotype (p < 0.0001) while genotype TT showed significant protective effect (p = 0.0007). The heterozygote individuals (CT) have a higher BMIz than homozygote ones (CC and TT) (2.8 vs. 2.5 Kg/m2, p = 0.04). Conclusions: children with CT genotype have 5.1 increased risk of obesity. While genotype TT showed significant obesity protective effect. We did not find association of this polymorphism with either childhood eating disorders or puberty. It is recommended to perform a cohort study in a larger sample. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-022-01011-5.

Study of the frequency and clinical features of maturity-onset diabetes in the young in the pediatric and adolescent diabetes population in Iran.

OBJECTIVES: Maturity-onset diabetes of the young (MODY), an autosomal dominant disease, is frequently misdiagnosed as type 1 or 2 diabetes. Molecular diagnosis is essential to distinguish them. This study was done to investigate the prevalence of MODY subtypes and patients' clinical characteristics. METHODS: A total of 43 out of 230 individuals with diabetes were selected based on the age of diagnosis >6 months, family history of diabetes, absence of marked obesity, and measurable C-peptide. Next-generation and direct SANGER sequencing was performed to screen MODY-related mutations. The variants were interpreted using the Genome Aggregation Database (genomAD), Clinical Variation (ClinVar), and pathogenicity prediction tools. RESULTS: There were 23 males (53.5%), and the mean age at diabetes diagnosis was 6.7 ± 3.6 years. Sixteen heterozygote single nucleotide variations (SNVs) from 14 patients (14/230, 6%) were detected, frequently GCK (37.5%) and BLK (18.7%). Two novel variants were identified in HNF4A and ABCC8. Half of the detected variants were categorized as likely pathogenic. Most prediction tools predicted Ser28Cys in HNF4A as benign and Tyr123Phe in ABCC8 as a pathogenic SNV. Six cases (42.8%) with positive MODY SNVs had islet autoantibodies. At diagnosis, age, HbA1c, and C-peptide level were similar between SNV-positive and negative patients. CONCLUSIONS: This is the first study investigating 14 variants of MODY in Iran. The results recommend genetic screening for MODY in individuals with unusual type 1 or 2 diabetes even without family history. Treatment modifies depending on the type of patients' MODY and is associated with the quality of life.

Exploring the Role of Chemical Reactions in the Selectivity of Tyrosine Kinase Inhibitors.

A variety of diseases are associated with tyrosine kinase enzymes that activate many proteins via signal transduction cascades. The similar ATP-binding pockets of these tyrosine kinases make it extremely difficult to design selective covalent inhibitors. The present study explores the contribution of the chemical reaction steps to the selectivity of the commercialized inhibitor acalabrutinib over the Bruton's tyrosine kinase (BTK) and the interleukin-2-inducible T-cell kinase (ITK). Ab initio and empirical valence bond (EVB) simulations of the two kinases indicate that the most favorable reaction path involves a water-assisted mechanism of the 2-butynamide reactive group of acalabrutinib. BTK reacts with acalabrutinib with a substantially lower barrier than ITK, according to our calculated free-energy profile and kinetic simulations. Such a difference is due to the microenvironment of the active site, as further supported by a sequence-based analysis of specificity determinants for several commercialized inhibitors. Our study involves a new approach of simulating directly the IC50 and inactivation efficiency keff, instead of using the standard formulas. This new strategy is particularly important in studies of covalent inhibitors with a very exothermic bonding step. Overall, our results demonstrate the importance of understanding the chemical reaction steps in designing selective covalent inhibitors for tyrosine kinases.

Circulating amino acids and acylcarnitines correlated with different CAC score ranges in diabetic postmenopausal women using LC-MS/MS based metabolomics approach.

BACKGROUND: Diabetes mellitus (DM) and its cardiovascular disease (CVD) complication are among the most frequent causes of death worldwide. However, the metabolites linking up diabetes and CVD are less understood. In this study, we aimed to evaluate serum acylcarnitines and amino acids in postmenopausal women suffering from diabetes with different severity of CVD and compared them with healthy controls. METHODS: Through a cross-sectional study, samples were collected from postmenopausal women without diabetes and CVD as controls (n = 20), patients with diabetes and without CVD (n = 16), diabetes with low risk of CVD (n = 11), and diabetes with a high risk of CVD (n = 21) referred for CT angiography for any reason. Metabolites were detected by a targeted approach using LC-MS/MS and metabolic -alterations were assessed by applying multivariate statistical analysis. The diagnostic ability of discovered metabolites based on multivariate statistical analysis was evaluated by ROC curve analysis. RESULTS: The study included women aged from 50-80 years with 5-30 years of menopause. The relative concentration of C14:1, C14:2, C16:1, C18:1, and C18:2OH acylcarnitines decreased and C18 acylcarnitine and serine increased in diabetic patients compared to control. Besides, C16:1 and C18:2OH acylcarnitines increased in high-risk CVD diabetic patients compared to no CVD risk diabetic patients. CONCLUSION: Dysregulation of serum acylcarnitines and amino acids profile correlated with different CAC score ranges in diabetic postmenopausal women. (Ethic approval No: IR.TUMS.EMRI.REC.1399.062).

The vitamin D receptor gene variants, ApaI, TaqI, BsmI, and FokI in diabetic foot ulcer and their association with oxidative stress.

INTRODUCTION: To date, numerous disorders have been linked to vitamin D deficiency. Several lines of evidence indicate a relationship between vitamin D deficiency and the risk of developing type 2 diabetes. It has been postulated that vitamin D may influence insulin activity, which can predispose individuals to develop type 2 diabetes. MATERIALS AND METHODS: In this case-control study, 262 patients with definite type 2 diabetes were enrolled, considering whether they were being affected by diabetic foot ulcers or not. The plasma levels of vitamin D and homocysteine were measured using ELISA, and the PCR-RFLP technique was utilized to determine allele and genotype frequencies. The antioxidant capacity of plasma samples of diabetic patients was analyzed using the thiobarbituric acid reactive substance (TBARS) and ferric reducing ability of plasma (FRAP) assays. RESULTS: The obtained results demonstrated no significant difference in the frequency of TaqI and BsmI polymorphisms between the case and control groups. However, the frequency of genotypes and alleles of the ApaI polymorphism in the VDR gene significantly differed between the case and control groups. A significant correlation was found between ApaI polymorphism and oxidative stress, as patients with the GG genotype had lower levels of TBARS than those with other genotypes. Furthermore, in the case group, patients with the CC genotype of BsmI showed a significant decrease in TBARS levels. DISCUSSION: It seems that the plasma levels of vitamin D do not differ between patients with or without diabetic foot ulcers; however, the presence of some VDR gene polymorphisms is thought to be involved in the development of diabetic foot ulcers via increasing oxidative stress.

Adenosine deaminase gene variant in diabetes and obesity.

Purpose: Personal medicine is a new notion for individualizing treatment in the future. Studying pathogenic markers including genetic variants would be beneficial in better diagnosis and management of complex diseases such as diabetes and obesity. Adenosine deaminase (ADA) is a purine metabolic enzyme and modulates insulin activity in various tissues through several different mechanisms. Increased ADA activity is associated with decreased glucose uptake. A significant increase in serum deaminase activity has been reported in patients with T2DM and obesity. ADA gene polymorphisms seem to affect ADA enzymatic activity and a polymorphism at the position 4223 in the first intron of ADA gene (ADA 4223 A/C) has been previously associated with obesity. The aim of this study was to explore ADA gene 4223 A/C polymorphism and its association with obesity in patients with Type 2 diabetes. Methods: Obese patients (N = 133: 64 diabetic +69 non-diabetic) with BMI ≥ 30 and subjects with BMI < 30 (N = 152: 83 diabetics +69 non-diabetic) were recruited into a case-control association study. Blood samples were collected and after DNA extraction, the allele and genotype frequency for ADA gene polymorphism was determined using PCR-RFLP technique. Results: We observed a significant increase for the frequency of AA+CA genotype in non-obese patients with diabetes compared to obese patients with diabetes (P = 0.04, OR = 2.1, 95%CI; 0.93-4.9). Conclusion: The higher frequency of AA+CA genotype in none obese diabetes individuals and lower frequency of this genotype in obese diabetes subjects indicates an important role for ADA gene polymorphism in diabetes subjects without obesity.

Enhancing computational enzyme design by a maximum entropy strategy.

Although computational enzyme design is of great importance, the advances utilizing physics-based approaches have been slow, and further progress is urgently needed. One promising direction is using machine learning, but such strategies have not been established as effective tools for predicting the catalytic power of enzymes. Here, we show that the statistical energy inferred from homologous sequences with the maximum entropy (MaxEnt) principle significantly correlates with enzyme catalysis and stability at the active site region and the more distant region, respectively. This finding decodes enzyme architecture and offers a connection between enzyme evolution and the physical chemistry of enzyme catalysis, and it deepens our understanding of the stability-activity trade-off hypothesis for enzymes. Overall, the strong correlations found here provide a powerful way of guiding enzyme design.

Effect of Environmental Factors on the Catalytic Activity of Intramembrane Serine Protease.

The cleavage of protein inside cell membranes regulates pathological pathways and is a subject of major interest. Thus, the nature of the coupling between the physical environment and the function of such proteins has recently attracted significant experimental and theoretical efforts. However, it is difficult to determine the nature of this coupling uniquely by experimental and theoretical studies unless one can separate the chemical and the environmental factors. This work describes calculations of the activation barriers of the intramembrane rhomboid protease in neutral and charged lipid bilayers and in detergent micelle, trying to explore the environmental effect. The calculations of the chemical barrier are done using the empirical valence bond (EVB) method. Additionally, the renormalization method captures the energetics and dynamical effects of the conformational change. The simulations indicate that the physical environment around the rhomboid protease is not a major factor in changing the chemical catalysis and that the conformational and substrate dynamics do not exhibit long-time coupling. General issues about the action of membrane-embedded enzymes are also considered.

Vascular Endothelial Growth Factor Genetic Variant Is Associated with in-Stent Restenosis after Percutaneous Coronary Intervention.

Background: In-stent restenosis (ISR) is an inevitable complication of percutaneous coronary intervention, with genetic factors thought to play a role in its pathogenesis. The vascular endothelial growth factor (VEGF) gene can have an inhibitory effect on ISR development. Accordingly, in the present study, we investigated the role of -2549 VEGF (insertion/deletion [I/D]) variants in ISR formation. Methods: Patients with ISR (ISR+) (n=53) and patients without ISR (ISR-) (n=67) were enrolled in this case-control study based on follow-up angiography 1 year after percutaneous coronary intervention between 2019 and 2020. The clinical characteristics of the patients were evaluated, and the frequencies of the alleles and genotypes of -2549 VEGF (I/D) variants were determined using polymerase chain reaction. The χ2 test was performed for the calculation of genotypes and alleles. A P value of less than 0.05 was considered the level of significance. Results: This study recruited 120 individuals at a mean age of 61.43±8.91 years in the ISR+ group and 62.09±7.94 years in the ISR- group. Women and men, respectively, comprised 26.4% and 73.6% of the ISR+ group and 43.3% and 56.7% of the ISR- group. A significant association was observed between the VEGF -2549 genotype frequency and ISR. The frequency of the insertion/insertion (I/I) allele was significantly higher in the ISR+ group than in the ISR- group, while the frequency of the D/D allele was higher in the latter group. Conclusion: Regarding ISR development, the I/I allele may be a risk allele and the D/D allele a protective allele.