Sulfonylureas (SUs) are a class of antidiabetic drugs widely used in the management of diabetes mellitus type 2. They promote insulin secretion by inhibiting the ATP-sensitive potassium channel in pancreatic β-cells. Recently, the exchange protein directly activated by cAMP (Epac) was identified as a new class of target proteins of SUs that might contribute to their antidiabetic effect, through the activation of the Ras-like guanosine triphosphatase Rap1, which has been controversially discussed. We used human embryonic kidney (HEK) 293 cells expressing genetic constructs of various Förster resonance energy transfer (FRET)-based biosensors containing different versions of Epac1 and Epac2 isoforms, alone or fused to different phosphodiesterases (PDEs), to monitor SU-induced conformational changes in Epac or direct PDE inhibition in real time. We show that SUs can both induce conformational changes in the Epac2 protein but not in Epac1, and directly inhibit the PDE3 and PDE4 families, thereby increasing cAMP levels in the direct vicinity of these PDEs. Furthermore, we demonstrate that the binding site of SUs in Epac2 is distinct from that of cAMP and is located between the amino acids E443 and E460. Using biochemical assays, we could also show that tolbutamide can inhibit PDE activity through an allosteric mechanism. Therefore, the cAMP-elevating capacity due to allosteric PDE inhibition in addition to direct Epac activation may contribute to the therapeutic effects of SU drugs.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials.
OBJECTIVE: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM.
METHODS: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis.
RESULTS: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]).
CONCLUSIONS: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.

BACKGROUND: How a person\'s Parkinson disease (PD) risk is affected by dipeptidyl peptidase-4 (DPP-4) inhibitors remains unclear. We evaluated the association of PD risk with use of these inhibitors in individuals diagnosed as having diabetes mellitus (DM).
METHODS: Individuals diagnosed as having new-onset DM were enrolled into the case group and comparison group, comprising patients who received a DPP-4 inhibitor and a sulfonylurea, respectively. These groups were matched through propensity score matching on the basis of income level, gender, urbanization level, enrollment year, age, and diabetes complications severity index score. The case group was divided into subgroups on the basis of whether they had a cumulative defined daily dose (cDDD) of <75, 75-150, or >150. The DPP-4 inhibitor-PD risk association was evaluated through a Cox proportional hazards model. The Bonferroni adjustment test was employed to adjust P-values and reduce the false positive rate.
RESULTS: Compared with those in the comparison group (treatment with a sulfonylurea), patients with a DPP-4 inhibitor cDDD of >150 had a hazard ratio (HR) of 1.30 for PD development (95% confidence interval [CI]: 0.97-1.73; adjusted P = .263); the HRs for patients with a cDDD of <75 or 75-150 were 0.95 (95% CI: 0.71-1.27; adjusted P = .886) and 1.06 (95% CI: 0.75-1.50; adjusted P = .886), respectively. We noted nonsignificant differences regarding the associations between the use of the various DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin) and PD risk after adjustment for any individual inhibitor (adjusted P > .05).
CONCLUSIONS: DPP-4 inhibitors were discovered in this study to not be associated with increased PD risk. This result was confirmed when the analysis was conducted individually for the 4 investigated DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and vildagliptin).

OBJECTIVE: To construct an efficient bacterial complex to degrade nicosulfuron and clarify its degradative characteristics, promote the growth of maize (Zea mays), and provide a theoretical foundation for the efficient remediation of soil contaminated with nicosulfuron.
RESULTS: Biocompatibility was determined by the filter paper sheet method by mixing Serratia marcescens A1 and Bacillus cereus A2 in a 1:1 ratio, yielding A12. The optimum culture conditions for the bacterial composite were obtained based on a three-factor, three-level analysis using response surface methodology, with 29.25 g l-1 for maltodextrin, 10.04 g l-1 for yeast extract, and 19.93 g l-1 for NaCl, which resulted in 92.42% degradation at 4 d. The degradation characteristics of A12 were clarified as follows: temperature 30°C, pH 7, initial concentration of nicosulfuron 20 mg l-1, and 4% inoculum. The ability to promote growth was determined by measuring the ratio of the lysosphere diameter (D) to the colony diameter (d), and the ability of the complex A12 to promote growth was higher than that of the two single strains.
CONCLUSIONS: Nicosulfuron degradation in sterilized and unsterilized soils reached 85.4% and 91.2% within 28 d, respectively. The ability of the strains to colonize the soil was determined by extraction of total soil DNA, primer design, and gel electrophoresis. The bioremediation effect of A12 was confirmed by the maximum recovery of fresh weight (124.35%) of nicosulfuron-sensitive crop plants and the significant recovery of soil enzyme activities, as measured by the physiological indices in the sensitive plants.

This study aimed to compare the impact of iodosulfuron-methyl-sodium and an iodosulfuron-based herbicidal ionic liquid (HIL) on the microbiomes constituting the epiphytes and endophytes of cornflower (Centaurea cyanus L.). The experiment involved biotypes of cornflower susceptible and resistant to acetolactate synthase inhibition, examining potential bacterial involvement in sulfonylurea herbicide detoxification. We focused on microbial communities present on the surface and in the plant tissues of roots and shoots. The research included the synthesis and physicochemical analysis of a novel HIL, evaluation of shifts in bacterial community composition, analysis of the presence of catabolic genes associated with sulfonylurea herbicide degradation and determination of their abundance in all experimental variants. Overall, for the susceptible biotype, the biodiversity of the root microbiome was higher compared to shoot microbiome; however, both decreased notably after herbicide or HIL applications. The herbicide-resistant biotype showed lower degree of biodiversity changes, but shifts in community composition occurred, particularly in case of HIL treatment.

Several new classes of medications for diabetes have recently become available newer medication classes have been increasing in use. It is unclear how their utilization varied across provinces and how the COVID-19 pandemic may have affected these trends. Our objective was to investigate Canada-wide and province-specific trends in diabetes medication dispensed by drug class over time, while also examining the impact of the COVID-19 pandemic and related restrictions on diabetes medication dispensing. We conducted a repeated cross-sectional analysis study. Data were obtained from IQVIA\'s CompuScript database for Canada-wide prescription dispensing patterns in primary care from January 2018 to December 2021. Drug classes of interest were biguanides dipeptidyl peptidase 4 inhibitors, sulfonylurea\'s, insulins, sodium-glucose co-transporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists. We examined trends before and after the onset of the pandemic with special attention to changes during periods of high COVID-19 activity. Most drug classes displayed a stable number of prescriptions each month throughout, except for glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors, which demonstrated a consistent pattern of increased dispensing. Sodium-glucose co-transporter inhibitors and glucagon-like peptide-1 receptor agonists exhibited the greatest growth over the examined period, of 7.9% and 5.0% increases, respectively. For sodium-glucose co-transporter 2 inhibitors, Prince Edward Island (4.0%) displayed the greatest growth while Ontario showed the least (2.5%). For glucagon-like peptide-1 receptor analogs, Saskatchewan (11.3%) displayed the greatest growth and Newfoundland the least (4.5%). The pandemic did not impact overall dispensing trends. However, spikes in COVID-19 cases corresponded to changes in dispensing for most drug classes. Important variations across Canada in guideline-recommended medication classes seems to be increasing over time. This is likely due to differing formulary listing and access to drug coverages. If so, future research could explore national formulary harmonization across Canada and health outcomes for patients with diabetes.

This study evaluated the impact of differential sowing windows and improved weed management strategies on weed dynamics, productivity, and economic viability of direct drum seeded rice (Oryza sativa L.) in the temperate agro-ecosystem of Kashmir. A two-year field experiment was conducted utilizing a split-plot design with two sowing dates (May 10 and June 3) as main plots and six weed management practices as sub-plots. The earlier sowing date (May 10) resulted in significantly enhanced leaf area index, crop growth rate, relative growth rate, net assimilation rate, and grain and straw yields compared to the later sowing (June 3). Among weed management treatments, four mechanized conoweedings (equivalent to weed-free conditions) and sequential application of bensulfuron methyl + pretilachlor (60 and 600 g a.i. ha-1) as pre-emergence followed by 2,4-D (0.75 kg a.i. ha-1) as post-emergence demonstrated superior efficacy in weed suppression and augmentation of crop growth parameters and yield attributes. These treatments also exhibited the lowest weed index and highest benefit-cost ratio. The May 10 sowing, coupled with efficacious weed control measures, significantly reduced weed density and biomass while concomitantly improving nutrient uptake and economic returns. The results indicate that adopting a May 10 sowing date for direct seeded rice, in conjunction with either four conoweedings or the aforementioned sequential herbicide application, can optimize agronomic productivity and economic profitability under the temperate conditions of Kashmir. The study aided in choosing the best sowing window and efficient weed management strategy for attaining higher productivity and profitability of direct seeded rice in temperate conditions.

Nicosulfuron and Cd are common pollutants that pose significant threats to the environment and human health, particularly under combined stress. This study is the first to remediate environmental nicosulfuron and Cd under combined stress using microbiological techniques. Enterobacter ludwigii ES2 was isolated, characterized, and demonstrated to degrade 93.80 % of nicosulfuron and remove 59.64 % of Cd within 4 d. Potential functional genes, including nicosulfuron degradation genes gstA, gstB, glnQ, glnP, mreB, and sixA, and Cd tolerance/removal-related genes mntA, mntB, mntH, dnaK, znuA, and zupt, were predicted by sequencing the whole genome of strain ES2, and their expression was verified by qRT-PCR. Strain ES2 managed oxidative stress induced by Cd through superoxide dismutase, glutathione, catalase, peroxidase, and malondialdehyde. Furthermore, to repair compound stress, up to 90.48 % of nicosulfuron and 67.74 % of Cd were removed. The community structure analysis indicated that Enterobacteriaceae, Sphingomonadaceae, and Gemmatimonadaceae were dominant populations, with ES2 stably colonizing and becoming the dominant bacterium. In summary, ES2 demonstrated significant potential in remediating nicosulfuron and Cd pollution from various perspectives, providing a solid theoretical foundation.

Nicosulfuron-resistant biotype (R) and -sensitive biotype (S) Amaranthus retroflexus L. seeds were subjected to different temperature, light, salt, osmotic potential, pH value and burial depth treatments. The difference in germination response of two populations to the above abiotic environmental factors was used to study the fitness cost of nicosulfuron-resistance evolution in A. retroflexus. The aim is to find a powerful tool for weed control in the presence of evolutionary resistance selection. The results of this experiment showed that the germination rate and germination index in S population were generally higher than that in R population. When the salt stress was 80 mM, the water potential was -0.1 Mpa ~ -0.4 Mpa, and under strong acid and alkali conditions, the germination index in S population was prominently higher than that in R population (p<0.05). The delayed seed germination in R population indicated that its nicosulfuron resistance may be linked to seed biochemical compositions that altered seed germination dynamics. The resistant and sensitive biotype of A. retroflexus had differently favourable adaptability in diverse environments. Salt, osmotic potential and pH value are not the major constraints for A. retroflexus germination, however, A. retroflexus are strongly responsive to temperature, light and burial depth. Considering that seeds of A. retroflexus are unable to reach the soil surface beyond the depth of 6 cm, deep inversion tillage before sowing may be an effective and economical weed management tool for the control of nicosulfuron resistant A. retroflexus.

Pesticides are crucial for crop protection and have seen a 50 % increase in use in the last decade. Besides preventing significant crop losses their use has raised health concerns due to consumer exposure through residues in food and water. The toxicity data from individual components is often used to assess overall mixture toxicity, but uncertainty persists in understanding the behaviors of individual chemicals within these mixtures. Assessing the risk of pesticide mixture exposure remains challenging, potentially leading to overestimation or underestimation of toxicity. This study aims to establish a possible link between exposure to a herbicide mixture and genotoxic effects, focusing on cancer development. Our analysis was focused on four herbicides glyphosate, nicosulfuron, S-metolachlor and terbuthylazine. To determine the link between genes associated with cancer development due to exposure to herbicide mixture, a CTD database tools were used. Through the ToppFun tool molecular function and biological process associated with genes common to the disease of interest and selected herbicides were evaluated. And finally, GeneMANIA was used in order to analyze the function and interaction between common genes of herbicide mixture. Among the 7 common genes for herbicide mixture and cancer development coexpression characteristics were dominant at 65.41 %, 22.14 % of annotated genes shared the same pathway and 7.88 % showed co-localization. Among six target genes involved in genetic disease development co-expression was dominant at 87.34 %, colocalization at 8.03 % and shared protein domains at 4.52 %. Comprehensive molecular analyses, encompassing genomics, proteomics, and pathway analysis, are essential to unravel the specific mechanisms involved in the context of the studied mixture and its potential carcinogenic effects.