Treatment switch from multiple daily insulin injections to sulphonylureas in an African young adult diagnosed with HNF1A MODY: a case report.

BACKGROUND: Maturity onset diabetes of the young is one of the commonest causes of monogenic diabetes and can easily be mistaken for type 1 diabetes. A diagnosis of maturity onset diabetes of the young can have direct implications for genetic counseling, family screening, and precision diabetes treatment. However, the cost of genetic testing and identifying individuals to test are the main challenges for diagnosis and management in sub-Saharan Africa. We report the very first documented case of HNF1A maturity onset diabetes of the young in the sub-Saharan African region. CASE PRESENTATION: A 20-year-old female Black African young adult diagnosed with type 1 diabetes aged 14 presented for routine out-patient diabetes consultation. She was on multiple daily insulin injections; total combined dose 0.79 IU/kg/day with an HbA1c of 7.7%. The rest of her laboratory examinations were normal. On extended laboratory analysis, she had good residual insulin secretion with post-meal plasma C-peptide levels at 1150 pmol/L. She tested negative for glutamic acid decarboxylase (GAD65), islet antigen-2 (IA-2), and zinc transporter 8 (ZnT8) islet autoantibodies. Targeted next-generation sequencing (t-NGS) for monogenic diabetes was performed using DNA extracted from a buccal sample. She was diagnosed with HNF1A maturity onset diabetes of the young, with the c.607C > T; p.(Arg203Cys) pathogenic variant, which has never been reported in sub-Saharan Africa. Her clinical practitioners provided genetic and therapeutic counseling. Within 10 months following the diagnosis of maturity onset diabetes of the young, she was successfully switched from multiple daily insulin injections to oral antidiabetic tablets (sulphonylurea) while maintaining stable glycemic control (HBA1c of 7.0%) and reducing hypoglycemia. She expressed a huge relief from the daily finger pricks for blood glucose monitoring. CONCLUSION: This case reveals that HNF1A maturity onset diabetes of the young (and probably other causes of monogenic diabetes) can present in sub-Saharan Africa. A diagnosis of maturity onset diabetes of the young can have significant life-changing therapeutic implications.

The Prevalent New-User Design to Study Drug-Drug Interactions: The Example of Sulfonylureas and Warfarin Interaction on the Risk of Severe Hypoglycemia.

PURPOSE: The optimal design for pharmacoepidemiologic drug-drug interactions (DDIs) studies is unclear. Using the association between concomitant use of sulfonylureas and warfarin and the risk of severe hypoglycemia as a case study, a DDI with little or no clinical impact, we tested whether the prevalent new-user design can be applied in the area. METHODS: Among all patients initiating sulfonylureas in the UK's Clinical Practice Research Datalink (1998-2020), we identified those adding-on warfarin while on a sulfonylurea. For each co-exposed patient, we defined a prescription-based exposure set including other sulfonylurea users not adding-on warfarin (comparators). Within each exposure set, we matched each co-exposed patient to five comparators on time-conditional propensity scores (TCPS) and followed them using an as-treated approach. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of severe hypoglycemia associated with concomitant use of sulfonylureas and warfarin compared to use of sulfonylureas alone. Sensitivity analyses addressed the impact of different potential sources of bias. RESULTS: The study cohort included 17 890 patients co-exposed to sulfonylureas and warfarin and 88 749 matched comparators. After TCPS matching, patient characteristics were well-balanced between groups. Compared to use of sulfonylureas alone, concomitant use of sulfonylureas and warfarin was not associated with the risk of severe hypoglycemia (HR, 1.04; 95% CI, 0.92-1.17). Sensitivity analyses were consistent with the primary analysis (HRs ranging from 1.01 to 1.15, all not statistically significant). CONCLUSIONS: Our study suggests that the prevalent new-user design could be used for the assessment of clinical effects of DDIs.

Effect of diabetes mellitus type 2 and sulfonylurea on colorectal cancer development: a case-control study.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is a significant global health concern, with studies estimating a rise in new cases to 2.5 million by 2035. Type 2 diabetes (T2D) is also a growing issue, with an estimated 642 million adults affected by 2040. However, the relationship between T2D, its medications, and CRC remains unclear. MATERIALS AND METHODS: This case-control study includes 810 controls without CRC and 684 cases with CRC admitted to Rasoul-Akram and Firouzgar Hospitals from September 2019 to 2023. Adjusted and unadjusted odds ratios (OR) were calculated to investigate the effect of T2D and sulfonylurea consumption on the chance of CRC development, using univariate and multivariate logistic regression analyses. The relationship between T2D and the clinicopathological features of the tumor was investigated. RESULTS: The results show that the effect of T2D on CRC is significant based on unadjusted OR (OR = 1.39, CI = 1.07, 1.81) and insignificant in adjusted OR (OR = 0.67, CI = 0.37, 1.20). The effect of sulfonylurea consumption on CRC was significant in both unadjusted (OR = 2.39, CI = 1.40, 4.09) and adjusted ORs (OR = 2.35, CI = 1.12, 4.91). All analyses related to the relationship between T2D and tumor clinicopathological characteristics were insignificant. CONCLUSION: This study found an insignificant association between type 2 diabetes and the chance of CRC development in an adjusted state. Sulfonylurea consumption was also associated with a higher chance of CRC development among patients with T2D. These findings have implications for clinical practice and public health strategies in CRC prevention for patients with T2D.

Removal of chlorimuron-ethyl from the environment: The significance of microbial degradation and its molecular mechanism.

Chlorimuron-ethyl is a selective pre- and post-emergence herbicide, which is widely used to control broad-leaved weeds in soybean fields. However, herbicide residues have also increased as a result of the pervasive use of chlorimuron-ethyl, which has become a significant environmental concern. Consequently, the removal of chlorimuron-ethyl residues from the environment has garnered significant attention in recent decades. A variety of technologies have been developed to address this issue, including adsorption, aqueous chlorination, photodegradation, Fenton, photo-Fenton, ozonation, and biodegradation. After extensive studies, the biodegradation of chlorimuron-ethyl by microorganisms has now been recognized as an efficient and environmentally friendly degradation process. As research has progressed, a number of microbial strains associated with chlorimuron-ethyl degradation have been identified, such as Pseudomonas sp., Klebsiella sp., Rhodococcus sp., Stenotrophomonas sp., Aspergillus sp., Hansschlegelia sp., and Enterobacter sp. In addition, the enzymes and genes responsible for chlorimuron-ethyl biodegradation are also being investigated. These degradation genes include sulE, pnbA, carE, gst, Kj-CysJ, Kj-eitD-2267, Kj-kdpD-226, Kj-dxs-398, Kj-mhpC-2096, and Kj-mhpC-2289, among others. The degradation enzymes associated with chlorimuron-ethyl biodegradation includes esterases (SulE, PnbA, and E3), carboxylesterase (CarE), Cytochrome P450, flavin monooxygenase (FMO), and glutathione-S-transferase (GST). Regrettably, few reviews have focused on the microbial degradation and molecular mechanisms of chlorimuron-ethyl. Therefore, this review covers the microbial degradation of chlorimuron-ethyl and its degradation pathways, the molecular mechanism of the microbial degradation of chlorimuron-ethyl, and the outlook on the practical application of the microbial degradation of sulfonylurea herbicides are all covered in this review's overview of previous studies into the degradation of chlorimuron-ethyl.

Pharmacometabolomics of sulfonylureas in patients with type 2 diabetes: a cross-sectional study.

Background: Sulfonylureas have been a longstanding pharmacotherapy in the management of type 2 diabetes, with potential benefits beyond glycemic control. Although sulfonylureas are effective, interindividual variability exists in drug response. Pharmacometabolomics is a potent method for elucidating variations in individual drug response. Identifying unique metabolites associated with treatment response can improve our ability to predict outcomes and optimize treatment strategies for individual patients. Our objective is to identify metabolic signatures associated with good and poor response to sulfonylureas, which could enhance our capability to anticipate treatment outcome. Methods: In this cross-sectional study, clinical and metabolomics data for 137 patients with type 2 diabetes who are taking sulfonylurea as a monotherapy or a combination therapy were obtained from Qatar Biobank. Patients were empirically categorized according to their glycosylated hemoglobin levels into poor and good responders to sulfonylureas. To examine variations in metabolic signatures between the two distinct groups, we have employed orthogonal partial least squares discriminant analysis and linear models while correcting for demographic confounders and metformin usage. Results: Good responders showed increased levels of acylcholines, gamma glutamyl amino acids, sphingomyelins, methionine, and a novel metabolite 6-bromotryptophan. Conversely, poor responders showed increased levels of metabolites of glucose metabolism and branched chain amino acid metabolites. Conclusion: The results of this study have the potential to empower our knowledge of variability in patient response to sulfonylureas, and carry significant implications for advancing precision medicine in type 2 diabetes management.

Sulfonylurea prescription patterns in elderly patients with type 2 diabetes mellitus: A comprehensive analysis of real-world data from pharmacies in Japan.

AIMS/INTRODUCTION: The study aim was to investigate sulfonylurea prescription patterns in elderly patients (age ≥65 years) with type 2 diabetes mellitus in Japan. Sulfonylurea use among older adults has been insufficiently examined, despite the associated risks of hypoglycemia. MATERIALS AND METHODS: This retrospective cross-sectional survey entailed analysis of Japanese pharmacy data, extracted from the Musubi database, for patients (age 20-100 years) prescribed sulfonylureas between November 2022 and October 2023. Dose distribution, adherence to the Diabetes Treatment Guidelines for the Elderly 2023 and coprescription of other diabetes medications were investigated. RESULTS: Of the total 91,229 patients, 80.1% were prescribed glimepiride, 16.3% gliclazide and 3.6% glibenclamide. In patients aged ≥65 years, exceeding the recommended dose (>1 mg/day for glimepiride, >40 mg/day for gliclazide) was numerically higher for glimepiride (25.0%) than for gliclazide (7.8%). The most common prescribing patterns were quadruple therapy with a sulfonylurea, a dipeptidyl peptidase-4 inhibitor, an sodium-glucose transporter 2 inhibitor and a biguanide in patients aged 65 to <75 years, and dual therapy with a sulfonylurea and a dipeptidyl peptidase-4 inhibitor in patients aged ≥75 years. Unfortunately, glinide was coprescribed for 338 (0.5%) of elderly patients. Insulin was coprescribed for 3,682 (5.6%) of elderly patients. CONCLUSIONS: Analysis of real-world sulfonylurea prescription data found guideline non-adherence, namely, excessive prescription of glimepiride, use of glibenclamide in elderly patients, and common coprescription with dipeptidyl peptidase-4 inhibitors. These findings might provide an opportunity to reconsider the treatment of patients with type 2 diabetes mellitus who are over-prescribed sulfonylureas to reduce residual risks, such as hypoglycemia.

GO promotes detoxification of nicosulfuron in sweet corn by enhancing photosynthesis, chlorophyll fluorescence parameters, and antioxidant enzyme activity.

Although graphene oxide (GO) has extensive recognized application prospects in slow-release fertilizer, plant pest control, and plant growth regulation, the incorporation of GO into nano herbicides is still in its early stages of development. This study selected a pair of sweet corn sister lines, nicosulfuron (NIF)-resistant HK301 and NIF-sensitive HK320, and sprayed them both with 80 mg kg-1 of GO-NIF, with clean water as a control, to study the effect of GO-NIF on sweet corn seedling growth, photosynthesis, chlorophyll fluorescence, and antioxidant system enzyme activity. Compared to spraying water and GO alone, spraying GO-NIF was able to effectively reduce the toxic effect of NIF on sweet corn seedlings. Compared with NIF treatment, 10 days after of spraying GO-NIF, the net photosynthetic rate (A), stomatal conductance (Gs), transpiration rate (E), photosystem II photochemical maximum quantum yield (Fv/Fm), photochemical quenching coefficient (qP), and photosynthetic electron transfer rate (ETR) of GO-NIF treatment were significantly increased by 328.31%, 132.44%, 574.39%, 73.53%, 152.41%, and 140.72%, respectively, compared to HK320. Compared to the imbalance of redox reactions continuously induced by NIF in HK320, GO-NIF effectively alleviated the observed oxidative pressure. Furthermore, compared to NIF treatment alone, GO-NIF treatment effectively increased the activities of superoxide dismutase (SOD), guaiacol peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) in both lines, indicating GO induced resistance to the damage caused by NIF to sweet corn seedlings. This study will provides an empirical basis for understanding the detoxification promoting effect of GO in NIF and analyzing the mechanism of GO induced allogeneic detoxification in cells.

Diverse mechanisms confer bensulfuron-methyl resistance in Schoenoplectiella juncoides (Roxb.) lye.

The effectiveness of bensulfuron-methyl in controlling Schoenoplectiella juncoides (Roxb.) Lye has significantly decreased in rice fields in China. Hence, a bensulfuron-methyl-resistant S. juncoides population (W15) was collected from Dandong City, Liaoning Province, China, to investigate the underlying resistance mechanisms. Whole-plant dose-response experiments and ALS activity assay confirmed that W15 has evolved high-level resistance to bensulfuron-methyl compared with the susceptible S. juncoides population (W4). Molecular analysis revealed a Pro-197-Ser mutation in ALS1, while there was no significant difference in the relative ALS gene expression between W15 and W4. LC-MS/MS analysis showed W15 metabolized bensulfuron-methyl more rapidly than W4. Furthermore, bensulfuron-methyl resistance in W15 was significantly alleviated by malathion and 4-chloro-7-nitrobenzoxadiazole (NBD-Cl). Glutathione S-transferase activity was higher in W15 than in W4. Meanwhile, W15 displayed cross-resistance to halosulfuron-methyl and multi-resistance to MCPA-Na. In summary, these findings demonstrated for the first time that both target- and non-target-site resistance are relevant in the resistance of S. juncoides to bensulfuron-methyl.

Involvement of P450s in the metabolic resistance of Digitaria sanguinalis (L.) Scop. To ALS-inhibiting herbicides.

Weed resistance to a range of herbicides has rapidly evolved, often with different mechanisms of action. The resulting uninhibited growth of weeds poses demonstrable threats to crop production and sustainable agriculture. Digitaria sanguinalis (L.) Scop., a troublesome weed in corn and other agricultural fields, has developed resistance to herbicides that inhibiting ALS (Acetolactate Synthase), such as nicosulfuron. Understanding the weed's resistance patterns and mechanisms is crucial. However, little is known of the non-target site resistance (NTSR) mechanisms of D. sanguinalis owing to a lack of relevant genome sequences and other materials. Therefore, in this study, a population of D.sanguinalis presenting multiple resistance was tested and found that its high level of resistance to ALS-inhibiting herbicides was not associated with target-related alterations.Administration of P450 inhibitors reversed the resistance to ALS-inhibiting herbicides. Following the application of ALS-inhibiting herbicides, the activities of NADPH-P450 reductase and p-nitroanisole O-demethylase (PNOD) were notably greater in the resistant population of D. sanguinalis than those in the susceptible population. The results suggested P450 enzyme familyplays a major role in the metabolic resistance mechanism, that increased P450 enzyme activity promote cross-resistance in D. sanguinalis to ALS-inhibiting herbicides. RNA-seq analysis showed that five genes from the P450 family (CYP709B2, CYP714C2, CYP71A1, CYP76C2, and CYP81E8) were upregulated in resistant D. sanguinalis. In conclusion, the upregulation of several P450 genes is responsible for establishing resistance to ALS-inhibiting herbicides in D. sanguinalis.

Association between dipeptidyl peptidase-4 inhibitor use and risk of Parkinson's disease among patients with diabetes mellitus: a retrospective cohort study.

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).

Diabetes treatment satisfaction among a multi-ethnic Aotearoa New Zealand population with uncontrolled type 2 diabetes mellitus.

AIMS: To assess whether diabetes treatment satisfaction differs by ethnicity among participants with insufficient glycaemic control of type 2 diabetes mellitus in a clinical trial involving additional oral diabetes medications. Patient satisfaction is used as an indicator of healthcare quality. However, data on patients' diabetes treatment satisfaction in the context of insufficient glycaemic control is limited. METHODS: Individuals with type 2 diabetes and an HbA1c of 58-110mmol/mol (7.5-12.5%) were recruited across Aotearoa New Zealand to participate in an 8-month randomised crossover study of vildagliptin and pioglitazone as add-on therapy to metformin and/or sulfonylurea. Participants completed the Diabetes Treatment Satisfaction Questionnaire (DTSQ) at baseline pre-randomisation. Treatment satisfaction scores were compared between ethnic groups and other characteristics using the analysis of variance and linear regression. Perceived hyper- and hypoglycaemia were summarised separately. RESULTS: Between February 2019 and March 2020, 346 participants (41% women, 32% Pacific peoples, 23% Maori, 26% European) completed the DTSQ. Mean (SD) age was 57.5 (10.9) years, diabetes duration was 9 (6.3) years and HbA1c was 75 (12)mmol/mol (9.0[3.2]%). At study entry, 40% were receiving monotherapy for diabetes. Treatment satisfaction was rated highly, with a score of 29(6) (interquartile range 25-33). Pacific peoples and older people reported greater treatment satisfaction than other groups (p<0.001). CONCLUSIONS: Diabetes treatment satisfaction was high, particularly among Pacific peoples, despite suboptimal glycaemic control and insufficient glucose-lowering therapy.

Influence of sowing dates and weed management practices on weed dynamics, productivity and profitability of direct seeded rice.

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.

Trends in diabetes medication prescribing from 2018 to 2021: A cross-sectional analysis.

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.

Germination characteristics associated with nicosulfuron resistance in Amaranthus retroflexus L.

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.

The mutation Asp-376-Glu in the ALS gene confers resistance to mesosulfuron-methyl in Beckmannia syzigachne.

Understanding the mechanisms by which weeds develop herbicide resistance is crucial for managing resistance effectively and optimizing herbicide use. Beckmannia syzigachne, a harmful grass weed prevalent in wheat and rice-wheat rotation areas, poses a significant threat to crop productivity. A field herbicide resistance survey identified a resistant population with a new ALS mutation (Asp-376-Glu). The Glu-376-Asp population displayed varying resistance levels to seven ALS herbicides, verified using the dCAPS method. qRT-PCR analysis showed that no significant difference existed in the ALS gene expression between the Asp-376-Glu and S populations. P450 and GST inhibitors failed to reverse resistance to mesosulfuron-methyl, suggesting no involvement of P450- and GST-based metabolic resistance. Molecular docking indicated that the Asp-376-Glu mutation reduces the binding affinity between ALS-inhibitors and BsALS. The findings provide valuable insights into herbicide resistance mechanisms for weed resistance control.

Enhanced bioremediation of soils contaminated with nicosulfuron using the bacterial complex A12.

AIMS: 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. METHODS AND 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.

Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM.

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. OBJECTIVES: 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.

Live Cell Monitoring of Phosphodiesterase Inhibition by Sulfonylurea Drugs.

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 ß-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.

Strengthening bioremediation potential: Enterobacter ludwigii ES2 for combined nicosulfuron and Cd contamination through whole genome and microbial diversity community analysis.

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.

Comparative analysis of bacterial populations in sulfonylurea-sensitive and -resistant weeds: insights into community composition and catabolic gene dynamics.

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.