Exploring effects of Simvastatin on coagulation mediators to alleviate the advancement of high cholesterol diet triggered neurodegeneration

The objectives of our study were to investigate the possible effect of Simvastatin in ameliorating high cholesterol diet (HCD)-induced neurodegeneration and to also investigate its possible action on coagulation mediators. In silico and in vitro studies were performed to evaluate the impact of Simvastatin on prime coagulation mediators. HCD was used to induce neuropathology in wistar rats and histopathological and immunohistochemical studies were performed to evaluate the efficacy of Simvastatin in preventing the advancement of neurodegeneration in obese rats. Biochemical analyses were used to estimate changes in lipid profile, oxidative stress, inflammatory and coagulation markers. Simvastatin showed good theoretical affinity to coagulation proteins, significantly reversed changes in inflammatory and coagulation biomarkers which were induced by HCD. Enhanced fibrinolytic activity of Simvastatin was revealed through in vitro analysis. Immunohistoanalysis showed raised level of Nrf2. Histopathological studies also supported neuroprotective potential of Simvastatin in HCD fed rats. Simvastatin demonstrated reduced hypercoagulation, enhanced fibrinolysis and reversed neurodegeneration in HCD exposed rats suggesting its potential role in preventing the progression of neurodegeneration in obesity.     

Determination of Heavy Metal Concentrations and Their Potential Sources in Selected Plants: Xanthium strumarium L. (Asteraceae), Ficus exasperata Vahl (Moraceae), Persicaria attenuata (R.Br) Sojak (Polygonaceae), and Kanahia laniflora (Forssk.) R.Br. (Asclepiadaceae) from Awash River Basin,Ethiopia

The objective of this study was to determine the concentrations, potential sources and evaluate the risks of heavy metals in selected plants from Awash River Basin, Ethiopia. A total of 57 samples were analyzed from four different plant species. Microwave-assisted digestion was applied to digest the samples and the concentration of nine elements namely: Al, Cr, Ni, Cu, Zn, As, Cd, Hg, and Pb were analyzed using Inductively Coupled Plasma-Mass Spectrometry (ICP- MS) (Thermos X SERIES2). The obtained data were analyzed using Statistical Package for Social Sciences (SPSS IBM version 20). The recorded mean concentration of heavy metals in the plants were 1.934, 0.023, 0.023, 0.045, 0.129, ND, 0.025, ND, and 0.009 mg/kg in Xanthium strumarium L.(Asteraceae); 0.834, 0.036, 0.024, 0.021, 0.090, ND, 0.002, 0.001, and 0.006 mg/kg in Ficus exasperata Vahl (Moraceae); 1.603, 0.018, 0.019, 0.025, 0.133, 0.005, 0.006, 0.002, and 0.012 mg/kg in Persicaria attenuata (R.Br) Sojak (Polygonaceae); and 0.557, 0.010, 0.010, 0.024, 0.098, ND, 0.012, 0.020, and 0.004 mg/kg in Kanahia laniflora (Forssk.) R.Br. (Asclepiadaceae) for Al, Cr, Ni, Cu, Zn, As, Cd, Hg, and Pb, respectively. Pearson’s correlation analysis indicated that there was a strong positive correlation between Al–Ni (r = 0.927^**) and Zn–Cu (r = 0.764^**) at α = 0.01 significant level. Principal component analysis (PCA) indicated that the sources of heavy metals in the plants were associated with anthropogenic factors. The mean concentrations of all elements except Cd in Xanthium strumarium L. (Asteraceae) and Pb in Ficus exasperata Vahl (Moraceae) were below the permissible limit of FAO/WHO (2001 /2005).

     

Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: A meta-analysis and meta-regression

BackgroundSodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a meta-analysis and meta-regression of randomized controlled trials (RCTs) evaluating SGLT2i in T1DM to assess moderators of the relative risk (RR) of DKA, of glycemic (HbA1c, fasting plasma glucose, continuous glucose monitoring parameters, insulin dose, and insulin sensitivity indices) and non-glycemic (body mass index (BMI), systolic BP, renal function, albuminuria, and diabetic eye disorders) efficacy, and of other safety outcomes (including hypoglycemia, infections, major adverse cardiovascular events, and death).Methods and findingsWe searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (β = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (β = −0.766 [−1.276, −0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R² = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R² = 86%). The association of DKA with a BMI >27 kg/m² and with an eGDR <8.3 mg/kg/min was confirmed also in subgroup analyses. Among efficacy outcomes, the novel findings were a reduction in albuminuria (WMD: −9.91, 95% CI: −16.26, −3.55 mg/g, p = 0.002), and in RR of diabetic eye disorders (RR: 0.27[0.11, 0.67], p = 0.005) associated with SGLT2i. A SGLT2i dose-response gradient was consistently observed for main efficacy outcomes, but not for adverse events (AEs). Overall, predictors of DKA and of other AEs differed substantially from those of glycemic and non-glycemic efficacy. A limitation of our analysis was the relatively short (≤52 weeks) duration of included RCTs. The potential relevance for clinical practice needs also to be confirmed by real-world prospective studies.ConclusionsIn T1DM, the risk of DKA and main therapeutic responses to SGLT2i are modified by baseline BMI and insulin resistance, by total insulin dose reduction-to-baseline insulin sensitivity ratio, and by volume depletion, which may enable the targeted use of these drugs in patients with the greatest benefit and the lowest risk of DKA.

Giovanni Musso and colleagues conduct a meta-analysis to identify risk factors of diabetic ketoacidosis in patients with Type 1 diabetes taking SGLT2 inhibitors.     

Chromosomal location and molecular mapping of a tan spot resistance gene in the winter wheat cultivar Red Chief

The winter wheat cultivar Red Chief has been identified as the wheat cultivar most resistant toPyrenophora tritici-repentis (Ptr). This study was undertaken to determine the inheritance, chromosomal location and molecular mapping of a tan spot resistance gene in Red Chief. χ² analysis of the F₂ segregation data of the hybrids between 21 monosomic lines of the susceptible wheat cultivar Chinese Spring and the resistant cultivar Red Chief revealed that tan spot resistance in cv. Red Chief is controlled by a single recessive gene located on chromosome 3A. Linkage analysis using SSR markers in the Red Chief/Chinese Spring F2 population showed that thetsr4 gene is clustered in the region aroundXgwm2a, on the short arm of chromosome 3A. This marker has also been identified as the closest marker to thetsr3 locus on chromosome 3D in synthetic wheat lines. Validation analysis of this marker for thetsr3 andtsr4 genes using 28 resistant and 6 susceptible genotypes indicated that the 120 bp allele (thetsr3 gene) specific fragment was observed in 11 resistant genotypes, including the three synthetic lines XX41, XX45 and XX110, while the 130 bp allele was amplified only in cv. Red Chief and Dashen.Xgwm2a can be used to trace the presence of the target gene in successive backcross generations and pyramiding of thetsr3 &tsr4 genes into a commonly grown and adaptable cultivar.     

S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism

The injurious consequences of ionizing radiation (IR) to normal human cells and the acquired radioresistance of cancer cells represent limitations to cancer radiotherapy. IR induces DNA damage response pathways that orchestrate cell cycle arrest, DNA repair or apoptosis such that irradiated cells are either repaired or eliminated. Concomitantly and independent of DNA damage, IR activates acid sphingomyelinase (ASMase), which generates ceramide, thereby promoting radiation-induced apoptosis. However, ceramide can also be metabolized to sphingosine-1-phosphate (S1P), which acts paradoxically as a radioprotectant. Thus, sphingolipid metabolism represents a radiosensitivity pivot point, a notion supported by genetic evidence in IR-resistant cancer cells. S1P lyase (SPL) catalyzes the irreversible degradation of S1P in the final step of sphingolipid metabolism. We show that SPL modulates the kinetics of DNA repair, speed of recovery from G2 cell cycle arrest and the extent of apoptosis after IR. SPL acts through a novel feedback mechanism that amplifies stress-induced ceramide accumulation, and downregulation/inhibition of either SPL or ASMase prevents premature cell cycle progression and mitotic death. Further, oral administration of an SPL inhibitor to mice prolonged their survival after exposure to a lethal dose of total body IR. Our findings reveal SPL to be a regulator of ASMase, the G2 checkpoint and DNA repair and a novel target for radioprotection.     

Two New Records of Genus Lepiota (Agaricaceae) from Pakistan

Biology Bulletin - In our ongoing efforts to inventory the lepiotaceous fungi of Pakistan, we here report on two species, new to Pakistan: Lepiota cingulum is also new to Asia, and L. oreadiformis....     

The taxonomic position and derivation of Cerastium adnivale Chiov. (Caryophyllaceae)

Detailed studies of comprehensive herbarium material confirmed that the afroalpine Cerastium adnivale Chiov. is too indistinctly delimited from the earlier described C. octandrum Hochst. ex A. Rich, to be given more than varietal rank. The restricted distribution of var. adnivale on only some of the high mountains harbouring C. octandrum s. lat. as well as results of experimental cultivation show that the reduced pubescence of the former cannot be due to environmental influence alone but must result from genetic differences. The derivation of var. adnivale from C. octandrum s. lat. is discussed.     

Pressure and Temperature Effects on the Activity and Structure of the Catalytic Domain of Human MT1-MMP

Membrane type 1-matrix metalloproteinase (MT1-MMP or MMP-14) is a zinc-transmembrane metalloprotease involved in the degradation of extracellular matrix and tumor invasion. While changes in solvation of MT1-MMP have been recently studied, little is known about the structural and energetic changes associated with MT1-MMP while interacting with substrates. Steady-state kinetic and thermodynamic data (including activation energies and activation volumes) were measured over a wide range of temperatures and pressures by means of a stopped-flow fluorescence technique. Complementary temperature- and pressure-dependent Fourier-transform infrared measurements provided corresponding structural information of the protein. MT1-MMP is stable and active over a wide range of temperatures (10–55°C). A small conformational change was detected at 37°C, which is responsible for the change in activity observed at the same temperature. Pressure decreases the enzymatic activity until complete inactivation occurs at 2 kbar. The inactivation is associated with changes in the rate-limiting step of the reaction caused by additional hydration of the active site upon compression and/or minor conformational changes in the active site region. Based on these data, an energy and volume diagram could be established for the various steps of the enzymatic reaction.     

A novel SMC-like protein,SbcE (YhaN), is involved in DNA double-strand break repair and competence in Bacillus subtilis

Bacillus subtilis and most Gram positive bacteria possess four SMC like proteins: SMC, SbcC, RecN and the product of the yhaN gene, termed SbcE. SbcE is most similar to SbcC but contains a unique central domain. We show that SbcE plays a role during transformation in competent cells and in DNA double-strand break (DSB) repair. The phenotypes were strongly exacerbated by the additional deletion of recN or of sbcC, suggesting that all three proteins act upstream of RecA and provide distinct avenues for presynapsis. SbcE accumulated at the cell poles in competent cells, and localized as a discrete focus on the nucleoids in 10% of growing cells. This number moderately increased after treatment with DNA damaging agents and in the absence of RecN or of SbcC. Damage-induced foci of SbcE arose early after induction of DNA damage and rarely colocalized with the replication machinery. Our work shows that SMC-like proteins in B. subtilis play roles at different subcellular sites during DNA repair. SbcC operates at breaks occurring at the replication machinery, whereas RecN and SbcE function mainly, but not exclusively, at DSBs arising elsewhere on the chromosome. In agreement with this idea, we found that RecN-YFP damage-induced assemblies also arise in the absence of ongoing replication.