Radical SAM enzyme QueE defines a new minimal core fold and metal-dependent mechanism

7-carboxy-7-deazaguanine synthase (QueE) catalyzes a key S-adenosyl-L-methionine (AdoMet)- and Mg[superscript 2+]-dependent radical-mediated ring contraction step, which is common to the biosynthetic pathways of all deazapurine-containing compounds. QueE is a member of the AdoMet radical superfamily, which employs the 5′-deoxyadenosyl radical from reductive cleavage of AdoMet to initiate chemistry. To provide a mechanistic rationale for this elaborate transformation, we present the crystal structure of a QueE along with structures of pre- and post-turnover states. We find that substrate binds perpendicular to the [4Fe-4S]-bound AdoMet, exposing its C6 hydrogen atom for abstraction and generating the binding site for Mg[superscript 2+], which coordinates directly to the substrate. The Burkholderia multivorans structure reported here varies from all other previously characterized members of the AdoMet radical superfamily in that it contains a hypermodified ([β [subscript 6] over α [subscript 3]]) protein core and an expanded cluster-binding motif, CX[subscript 14]CX[subscript 2]C.United States. Dept. of Energy. Office of Biological and Environmental ResearchUnited States. Dept. of Energy. Office of Basic Energy SciencesNational Center for Research Resources (U.S.) (P41RR012408)National Institute of General Medical Sciences (U.S.) (P41GM103473)National Center for Research Resources (U.S.) (5P41RR015301-10)National Institute of General Medical Sciences (U.S.) (8 P41 GM 103403-10)United States. Dept. of Energy (Contract DE-AC02-06CH11357

AGTR1 rs5186 variants in patients with type 2 diabetes mellitus and nephropathy

Diabetic nephropathy (DN) is one of the leading causes of death in patients with type 2 diabetes mellitus (DM) and genetic factor can influence development of this complication. Association of Angiotensin II receptor type 1 (AGTR1) gene and DN has been evaluated in recent years. This study aim was to assess the association of AGTR1 gene polymorphisms with DN in a group of Iranian diabetic patients. In the present study, 97 patients with DM, 94 patients with DN and 100 healthy controls were included. Allele and genotype frequencies of AGTR1A1166C (rs5186) were determined by ARMS PCR technique. In all groups, blood glucose concentration, creatinine, urea and HbA1c were measured and urine albumin to creatinine ratio (ACR) as well as glomerular filtration rate (GFR) was calculated. A statistically significant association was found between C allele of rs5186 and DN (odds ratio (OR) = 1.84 95% CI: 1.10�3.08; p_value = 0.03). Among patients with DM, carriers of C allele (AC + CC) had significantly higher ACR (p_value = 0.04) compared to AA homozygote patients. This study showed the association of AGTR1 gene polymorphisms (rs5186) with increased urinary albumin excretion in a group of Iranian patients with DM. Also, C allele can be introduced as a risk allele for DN. © 201

The Influence of Adipokines on Fetal Bone Turnover

"nBackground: A relation between adiponectin and bone homeostasis has been illustrated through studying adiponectin se­cretion and its receptor presentation in bone forming cells. The aim of our study was to investigate the relationship between fetal bone turnover and adipokines."nMethods: In a cross-sectional study performed in Tehran University of medical sciences related hospitals, 77 samples (39 males, 38 females) of umbilical cord blood immediately after delivery were gathered. Clinical characteristics such as gen­der, weight, length, weight to length ratio were recorded. Measurements of leptin, adiponectin, osteocalcin and crosslaps were done by ELISA methods in biochemistry and hormone laboratory of endocrinology and metabolism research center. The amounts of crosslaps and osteocalcin were expressed as t-scores, and then t-scores of crosslaps was subtracted from osteocalcin t-scores to establish estimation for bone formation, which we named Bone Formation Index."nResults: In Univariate Analysis, after entrance sex, birth weight and birth length as fixed factors, leptin and adiponectin displayed an independent effect on Bone Formation Index."nConclusion: Our data suggest that both leptin and adiponectin have a remarkable impact on bone turnover in fetus

High intensity interval training improves diabetic cardiomyopathy via miR-1 dependent suppression of cardiomyocyte apoptosis in diabetic rats

Purpose: Diabetes and its complications such as diabetic cardiomyopathy still account for significant morbidity and mortality. High-quality evidence was shown the importance of exercise in controlling diabetes complications, but the molecular mechanism on diabetic cardiomyopathy is not yet fully understood. This study aimed to compare and investigate the effect of high intensity interval training (HIIT) and continuous endurance training (CET) on the signaling pathway of diabetic cardiomyopathy. Methods: Hence, 21 Wistar rats with an average weight of 260 ± 10 g, after induction of diabetes (STZ 50 mg/kg BW) were randomly divided into three groups (control, CET and HIIT; n = 7). Training programs were conducted 5 days a week for 5 weeks. CET program was defined as running at 60 vVO2max for 30 min in each session and the HIIT program was defined as running at 85�90 vVO2max for 3 min followed by 1 min recovery (30�35 vVO2max), that was repeated four times in each session. The cardiac performance was analyzed via determination of end systolic and diastolic dimensions and the ejection fraction by echocardiography. To elucidate the responsible molecular mechanism of miR-1, IGF-1 and IGF-1R mRNA and apoptosis marker protein expression were investigated. Results: Both training programs specifically HIIT, significantly reduced the blood glucose, enhanced heart performance, reduced miR-1 expression, induced IGF-1 and IGF-1R expression and reduced apoptotic protein expression. Conclusion: We showed that HIIT is more effective than CET for reduction of diabetic cardiomyopathy as a complication of diabetes in animal models through suppressing miR-1 and its downstream apoptosis pathway. © 2020, Springer Nature Switzerland AG