Search Results (177)

False cleavers (Galium spurium L.) is a broadleaf weed species that affects wheat productivity because of its strong competition for resources. It has developed resistance to acetolactate synthase (ALS) inhibitors, such as sulfonylureas and triazolopyrimidines, which are herbicides widely used in durum wheat. Integrated weed management programs can contribute to the control of this species and delay the evolution of herbicide resistance. Thus, a two-year field experiment was conducted to evaluate the effects of sowing time, variety, and herbicides on crop yield, density, and dry weight of a false cleavers population with resistance to ALS inhibitors. In both growing seasons, a split-split-plot design was used with three replicates. The sowing date was chosen as the main plot factor, durum wheat varieties as the subplot factor, and herbicides as the sub-subplot factor. The herbicide treatments were: (1) metsulfuron-methyl/bensulfuron-methyl (4/50 g a.i. ha⁻¹), (2) aminopyralid/florasulam (9.9/4.95 g a.i. ha⁻¹), (3) pyroxsulam and florasulam/2,4-D (18.75 + 4.725/225 g a.i. ha⁻¹), (4) 2,4-D/bromoxynil (633.15/601.2 g a.i. ha⁻¹), non-treated control, and hand-weeded control for the first season, while in the second season one more herbicide treatment (halauxifen-methyl/florasulam, 5.6/5.15 g a.i. ha⁻¹) was added. Herbicide application was performed on 10 March 2021 and 28 March 2022, when the crop was at the end of tillering and the beginning of stem elongation. The results showed that the density of false cleavers was not affected by the variety or sowing time. However, its dry weight was 17.3–23.4% higher in early sowing (16 November in 2020 and 8 November 2021) than in late sowing (24 December 2020 and 2 December 2021). Among the herbicides tested, 2,4-D/bromoxynil and halauxifen-methyl/florasulam effectively controlled false cleavers, showing greater efficacy in late sowing (>88%), which ultimately led to a higher yield. In conclusion, our two-year findings demonstrate that delayed sowing as part of an integrated weed management strategy can contribute to controlling resistant populations of false cleavers to ALS-inhibiting herbicides without affecting the quantity and quality of durum wheat yield in areas with a Mediterranean climate. Full article

Background/Objectives: In the context of diabetes, a multifactorial metabolic disorder with significant clinical implications, the present study investigates the hypoglycemic effects of a synthetic sulfonamide (S) administered individually and in combination with Salvia officinalis extract, compared to metformin as a standard therapeutic agent. Methods: An in vivo model of experimentally induced diabetes using alloxan was applied to Wistar female rats, divided into six experimental groups, including a healthy control group and a diabetes-induced, untreated group. Plasma concentrations of metformin and sulfonamide were quantified by high-performance liquid chromatography. The plasma steady-state concentrations of the pharmaceutical agents and their correlation with hypoglycemic effect were evaluated. Results: The combination of the synthetic sulfonamide (S) with Salvia officinalis extract resulted in the greatest reduction in blood glucose level (average value of 50.2%) compared to S (40.6%) or metformin (36.4%). All treatments demonstrated statistically significant differences in blood glucose levels compared to the diabetes-induced untreated group (p < 0.05). Pharmacokinetic analysis revealed a larger volume of distribution for the synthetic sulfonamide S (23.92 ± 8.40 L) compared to metformin (16.07 ± 5.60 L), consistent with its physicochemical properties. No significant correlation was found between plasma drug levels and glycemic response (p > 0.05). Conclusions: Our findings support the potential of combining standard therapeutic agents with natural alternatives such as Salvia officinalis to achieve improved glycemic control through complementary mechanisms. To the best of our knowledge, this is the first in vivo study to evaluate the combined effects of a sulfonylurea-type compound and Salvia officinalis extract in a diabetic animal model. Full article

Background/Objectives: We sought to determine if glibenclamide, a sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel blocker, reduces cerebral edema and improves neurological functioning in aneurysmal subarachnoid hemorrhage (aSAH). Methods: Following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, a systematic search was conducted in PubMed, Cochrane Library, Web of Science, and SCOPUS for studies evaluating glibenclamide in aSAH patients. Primary outcomes included scores on the modified Rankin Scale (mRS) at discharge and the Subarachnoid Hemorrhage Early Brain Edema Score (SEBES) at ten days post-intervention. Secondary outcomes included adverse events, and safety and efficacy endpoints. Random-effects models were employed for meta-analyses. Results: Three studies utilizing oral glibenclamide (n = 245) met inclusion criteria. Oral glibenclamide demonstrated no significant improvements in mRS scores [MD −0.19 with 95% CI (−2.05, 1.66)] at discharge, [MD 0.06, (−0.60, 0.71)] at 3 months, and [MD 0.4, (−0.67, 0.87)] at 6 months; functional independence [risk ratio (RR) 1.05, (0.81, 1.36)]; independent ambulation [RR 1.07, (0.77, 1.48)]; mortality [RR 0.79, (0.42, 1.50)]; or delayed cerebral ischemia [RR 0.58, (0.31, 1.09]). Hypoglycemia risk was significantly higher in the glibenclamide group [RR 3.92, (1.14, 13.49)]. Conclusions: Oral glibenclamide offers a novel approach to addressing cerebral edema in aSAH but shows limited clinical efficacy in improving functional and neurological outcomes in subtherapeutic doses. Its safety profile is acceptable, though hypoglycemia risk necessitates careful monitoring. Further research is required to optimize dosing, timing of intervention, and patient selection to enhance therapeutic outcomes. By contrast, intravenous administration of therapeutic doses of glibenclamide offers a promising avenue for future studies in the management of aSAH by taking advantage of the favorable pharmacokinetics of this route of administration. Full article

Aim: Myricetin, a natural bioflavonoid, is reported as an anti-diabetic agent since it possesses the ability to inhibit α-glucosidase activity, stimulate insulin action and secretion, manage ROS, and prevent diabetes complications. Myricetin was identified as a new insulin secretagogue that enhances glucose-stimulated insulin secretion and seems like a better antidiabetic drug candidate. Here, we explored the insulinotropic mechanism(s) of myricetin in vitro in mice islets and in silico. Methods: Size-matched pancreatic islets were divided into groups and incubated in the presence or absence of myricetin and agonists/antagonists of major insulin signaling pathways. The secreted insulin was measured by ELISA. Molecular docking studies were performed with the key player of insulin secretory pathways. Results: Myricetin dose-dependently enhanced insulin secretion in isolated mice islets, and its insulinotropic effect was exerted at high glucose concentrations distinctly different from glibenclamide. Myricetin-induced insulin secretion was significantly inhibited using the diazoxide. Furthermore, myricetin amplified glucose-induced insulin secretion in depolarized and glibenclamide-treated islets. Myricetin showed an additive effect with forskolin- and IBMX-induced insulin secretion. Interestingly, H89, a PKA inhibitor, and MAY0132, an Epac-2 inhibitor, significantly inhibited myricetin-induced insulin secretion. The in silico molecular docking studies further validated these in vitro findings in isolated pancreatic islets. Conclusions: Myricetin, a potential natural insulin secretagogue, amplifies glucose-induced insulin secretion via the cAMP-PKA-Epac-2 signaling pathway. Full article

Background: Oral semaglutide, a GLP1-receptor agonist (GLP1-RA), shows promise in efficacy and compliance, especially amid the global shortage of injectable GLP-1 RAs. Its short-term effectiveness remains unexplored. Objective: This real-world observational study assessed the short-term effectiveness of oral semaglutide after three months of therapy. Methods: Patients with type 2 diabetes from four Italian diabetes centers, who received an initial prescription of oral semaglutide, were reassessed after three months. Primary outcomes included glycated hemoglobin (HbA1c) and body weight reduction; secondary outcomes involved changes in lipid parameters and cardiovascular risk. Results: Among 167 participants (mean age 66.5 years, mostly obese, baseline HbA1c 8.4% ± 1.5), 83.2% received a 7 mg dose. After three months, HbA1c significantly declined (8.4% to 7.1%, −1.3%, p < 0.001), alongside body mass index (BMI) (30.9 kg/m² to 29.6 kg/m², p < 0.0001). The target HbA1c ≤ 7% was achieved by 54.5%, and 34.7% reached ≤6.5%. Patients losing >5% of their initial weight (30.5%) saw the largest HbA1c drop (−1.9%). Those with newly diagnosed diabetes or a duration < 5 years showed superior responses (p = 0.001), while no significant differences were found based on the timing of drug administration. Oral semaglutide replaced or supplemented prior therapies, allowing discontinuation of dipeptidyl peptidase 4 inhibitors (DPP4i), sulfonylureas, glinides, and acarbose, and deprescription of thiazolidinediones. A significant reduction in cardiovascular risk was observed (p = 0.04), together with a significant reduction in lipid parameters. Conclusions: Oral semaglutide showed significant short-term efficacy, reducing HbA1c, body weight, and cardiovascular risk in three months, making it a valuable therapeutic option. Full article

Optimized glycemic management is crucial for controlling atherosclerosis and consequent cardiovascular morbidity in patients with diabetes. Due to the continuous glucose burden from glucose-containing peritoneal dialysis (PD) solutions, PD patients with diabetes experience difficulties in glucose level regulation with glucose hypervariability and worsening dyslipidemia. Even in non-diabetic PD patients, glucose-containing PD solutions aggravate insulin resistance and cause overweight. Additionally, glucose degradation products (GDP) from glucose-based PD solutions provoke oxidative stress and complex inflammatory processes, leading to chronic deleterious and fibrotic peritoneal membrane changes. In this narrative review, we searched the literature using PubMed, MEDLINE, and Google Scholar over the last three decades to summarize the most important facts relevant to the presented issues, aiming to inform both endocrinologists and nephrologists in providing the best currently available care for people with diabetes on PD. We not only focus on adequate tailoring of insulin therapy adapted at the time of PD exchange with hypertonic glucose solution., but also emphasize the use of continuous glucose monitoring (CGM) that allows assessment of mean glucose values and time spent in normal, hypo, and hyperglycemia. However, the routine use of CGM in PD patients is limited due to high cost, and hemoglobin A1c (HbA1c) analysis is still recommended as a basic clinical tool for the assessment of glycemic control. Possible choices of antidiabetic drugs were considered given the narrowed choice due to contraindications for metformin and sulfonylurea. The other important therapeutic approach in PD patients with diabetes is using glucose-sparing PD regimens based on icodextrin and amino acid PD solutions with the addition of just one or two bags of low glucose concentration PD solution daily. This glucose-sparing approach not only reduces the glucose load and improves glycoregulation with correction of the lipid profile but also maintains the viability of the peritoneal membrane by reducing the harmful effects of GDPs. Full article

Background: The antidiabetic drug gliclazide is often taken with antacids due to its gastrointestinal side effects. However, patients rarely report antacid use, making drug–drug interactions a potential cause of therapy failure. Therefore, this study aimed to investigate the in vitro effects of various antacids on gliclazide permeability and to explore the underlying mechanisms. Methods: The permeability of gliclazide alone and in the presence of antacids (sodium bicarbonate, calcium carbonate, aluminum hydroxide, hydrotalcite and calcium carbonate/magnesium carbonate) was investigated using the parallel artificial membrane permeability assay (PAMPA) in four media (buffers pH 1.2, pH 4.5, pH 6.8 and water). The permeability coefficients were calculated, and the effect of pH on gliclazide permeability was also evaluated. Results: At simulated fasting gastric conditions (pH 1.2), groups with calcium carbonate, hydrotalcite and the combination of calcium carbonate/magnesium carbonate showed significantly higher permeability of gliclazide than the control group. At fed-state gastric conditions (pH 4.5), only hydrotalcite did not significantly change the permeability of gliclazide. Sodium bicarbonate, aluminum hydroxide and hydrotalcite significantly reduced the gliclazide permeability in comparison to the control group at pH 6.8 as a representative of fasted-state intestinal fluid. Conclusions: Antacids significantly impact the permeability of gliclazide at different pH values, potentially influencing its bioavailability. Gliclazide permeability is mainly influenced by pH-dependent ionization, though complex or salt formation may also play a role. Since both gliclazide and antacids are taken with food, and gliclazide is primarily absorbed in the small intestine, calcium- and magnesium-based antacids can be considered the most suitable choice. Full article

Aims: Despite its high prevalence, studies on glucocorticoid-induced hyperglycemia are lacking. We examined the glucose profiles of patients with type 2 diabetes undergoing dexamethasone-containing chemotherapy using continuous glucose monitoring (CGM). We also investigated the effects of gliclazide on the management of hyperglycemia in these patients. Materials and Methods: Seventeen patients with type 2 diabetes who received cyclic chemotherapy with dexamethasone were enrolled in this study. During the first cycle, iPro2, a blinded CGM device, was applied for 7 days. If a patient’s CGM data exhibited an increase of 20% or more in the mean glucose level after dexamethasone administration, they received the second cycle, unless they had already received sulfonylurea or their chemotherapy regimen had changed. During the second cycle, the patients were treated with gliclazide as an add-on to their routine diabetic medication. Results: Dexamethasone treatment significantly increased glucose levels, especially in patients with a longer diabetes duration (8.4 years vs. 1.2 years, p = 0.009). For the nine patients who proceeded to the second cycle, gliclazide treatment significantly ameliorated hyperglycemia. Time in range increased from 33.11% to 45.22% (p = 0.020), and time above range significantly decreased from 66.89% to 52.78% (p = 0.003). The glucose management indicators were 9.52% and 8.40% for pre- and post-gliclazide treatment, respectively. One patient visited the emergency department because of symptomatic hypoglycemia. Conclusions: Chemotherapy regimens containing dexamethasone result in high blood glucose levels even after the last dexamethasone dose in patients with pre-existing diabetes. Adding gliclazide could be beneficial in managing hyperglycemia during dexamethasone-containing chemotherapy. Full article

Background/Objectives: α-carbonic anhydrase (α-TcCA) has emerged as a promising drug target in T. cruzi, the causative agent of Chagas disease in the Americas. Sulfonamides, known inhibitors of CAs, bind to the zinc ion on the enzyme’s active site. This study proposes the repositioning of sulfonamide-based drugs to identify new trypanocidal agents. Method: Ligand-based virtual screening and molecular docking analysis were performed on FDA-approved drugs targeting α-TcCA. These compounds were evaluated in vitro and ex vivo against the A1 and NINOA strains, followed by enzymatic assays. Results: Four sulfonylureas were selected: glimepiride (Glim), acetohexamide (Ace), gliclazide (Glic), and tolbutamide (Tol). Ace and Tol had half-maximal inhibitory concentration (IC₅₀) values similar or better than reference drugs against the NINOA strain in the epimastigote and trypomastigote stages, while Glic and Glim had the highest activity against the A1 strain (epimastigotes and amastigotes). Notably, Ace had the highest trypanocidal activity against all stages in NINOA, with IC₅₀ values of 6.5, 46.5, and 46 μM for epimastigotes, trypomastigotes, and amastigotes, respectively. Additionally, Ace inhibited α-TcCA with K_I = 5.6 μM, suggesting that its trypanocidal effect is associated to the enzyme inhibition. Conclusions: This study supports the repositioning of FDA-approved sulfonamide-based hypoglycaemic agents as trypanocidal compounds. Future studies should focus on structural modifications to improve selectivity. Integrating docking, parasitological, and enzymatic data is crucial for optimizing drug candidates for Chagas disease. Full article

Background: Weed herbicide resistance is a serious problem in crop protection globally. Giant foxtail (Setaria faberi R.A.N. Herrm.) populations cannot be controlled by acetolactate synthase (ALS)-inhibiting herbicides in a few corn (Zea mays L.) monoculture fields. Methods: Five putative resistant giant foxtail populations, originating from corn monoculture fields in northeastern Greece, were evaluated for possible evolution of ALS-inhibitor resistance (nicosulfuron, rimsulfuron). The resistance ratio, the underlying resistance mechanism, and its impact on competitive ability against corn were studied. Results: The whole-plant rate-response assays showed that these populations were resistant (R) to the sulfonylureas nicosulfuron and rimsulfuron, but susceptible (S) to imidazolinone imazamox, triketone 4-hydroxyphenylpyruvate dioxygenase inhibitor tembotrione, and acetyl-CoA carboxylase inhibitor cycloxydim. The sequencing of the ALS gene did not reveal the presence of resistance-associated point mutations, indicating that the resistance was probably not target-site mediated. This was confirmed by the application of piperonyl butoxide two hours before nicosulfuron application, which reversed the resistance in all R giant foxtail populations, supporting the evidence of enhanced metabolism-mediated resistance. The competition study between corn and R or S giant foxtail populations indicated no stable trend reduction in corn traits, suggesting that the resistance mechanism was not associated with the competitive ability of the R populations. The novel ALS genotype in S. faberi, characterized for the first time and submitted to the GenBank database with accession number PV016837, indicated a closer genetic relationship with the S. viridis ALS gene than with S. italica. Conclusions: Five giant foxtail populations have evolved metabolism-based resistance to the ALS-inhibiting herbicides nicosulfuron and rimsulfuron. Full article

Integration of old and recent experimental data consequences is needed to correct and help improve the hypothetical mechanism responsible for the stimulus–secretion coupling mechanism of glucose-induced insulin secretion. The main purpose of this review is to supply biochemical considerations about some of the metabolic pathways implicated in the process of insulin secretion. It is emphasized that glucose β-cells’ threshold to activate secretion (5 mM) might depend on the predominance of anaerobic glycolysis at this basal glucose concentration. This argues against the predominance of phosphoenolpyruvate (PEP) over mitochondrial pyruvate oxidation for the initiation of insulin secretion. Full quantitative and qualitative reproduction, except the threshold effect, of glucose-induced insulin release by a permeable methylated analog of succinic acid indicates that mitochondrial metabolism is enough for sustained insulin secretion. Mitochondrial PEP generation is skipped if the GABA-shunt pathway is exclusively coupled to the citric acid cycle, as proposed in the “GABA-shunt” model of stimulus–secretion coupling. Strong or maintained depolarization by KCl or sulfonylureas might induce the opening of β-cells Cx36 hemichannels, allowing the loss of adenine nucleotides and other metabolites, mimicking the effect of an excessive mitochondrial ATP demand. A few alterations of OxPhos (Oxidative Phosphorylation) regulation in human T2D islets have been described, but the responsible mechanism(s) is (are) not yet known. Finally, some experimental data arguing as proof of the relative irrelevance of the mitochondrial function in the insulin secretion coupling mechanism for the initiation and/or sustained stimulation of hormone release are discussed. Full article

Background: Diabetic autonomic neuropathy (DAN) is a severe complication of diabetes that affects the autonomic nervous system, impacting cardiovascular, gastrointestinal, genitourinary, and other systems. This study examines the levels of three potential biomarkers—DEFA1, progranulin, and NRG4—to assess their diagnostic and prognostic value in DAN patients. Methods: This observational, single-center study included 80 patients with type 2 diabetes. Clinical data and laboratory results were collected, and serum levels of DEFA1, progranulin, and NRG4 were measured using ELISA. The presence of DAN was assessed using Ewing’s tests. Statistical analyses included t-tests, Pearson’s correlations, and ROC analysis to explore associations and the predictive values of the biomarkers. Results: Progranulin levels were significantly elevated in patients with DAN compared to those without (p < 0.05), showing a positive correlation with diabetes duration (r = 0.375; p = 0.01) and a significant predictive value for DAN (AUC = 0.666; p = 0.013). DEFA1 and NRG4 levels did not differ significantly between the groups. Progranulin was also higher in patients who were treated with sulfonylureas and GLP-1 receptor agonists and in those with coronary artery disease. Conclusions: Progranulin emerges as a potential biomarker for the presence and severity of DAN, correlating with disease duration and autonomic dysfunction. While DEFA1 and NRG4 showed no significant association, the findings underscore the importance of further exploring the inflammatory pathways in DAN. Progranulin measurement could enhance early diagnosis and personalized management of autonomic neuropathy in diabetes. Full article

Maize hybrids exhibit varying levels of tolerance to the herbicide nicosulfuron, influenced by the environment, plant developmental stage, and herbicide rate. The objective of this study was to determine the sensitivity of maize hybrids to nicosulfuron through biochemical markers. Eight hybrids were treated with 120 g ha⁻¹ of nicosulfuron at the V2 and V6 growth stages in a greenhouse experiment. The plants were collected at one day after the application of the herbicide to determine the contents of nicosulfuron, aminobutyric and quinic acids and valine, leucine, and isoleucine amino acids. Plant height and phytotoxicity were evaluated at 7, 14, 21, and 28 DAA. The plants were collected at 28 DAA to determine the shoot dry weight. The results indicated that sensitivity to nicosulfuron varied among the eight hybrids studied, with the V2 stage exhibiting higher herbicide accumulation, greater height reduction, and increased phytotoxicity. Aminobutyric acid levels increased in all hybrids after herbicide application, with a stronger correlation between its accumulation and growth inhibition at the V2 stage. These findings suggest that V2 is the most suitable stage for distinguishing hybrid sensitivity to nicosulfuron. Full article

Diabetes-related cognitive impairment (DCI) is a severe complication of type 2 diabetes mellitus (T2DM), with limited understanding of its molecular mechanisms hindering effective therapeutic development. This study identified SERPINA3 as a potential therapeutic target for DCI through integrated machine learning and molecular docking analyses. Transcriptomic data from cortical neuronal samples of T2DM patients were analysed using support vector machine recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression, revealing SERPINA3 as a significantly upregulated gene in DCI. Experimental validation via Western blot confirmed elevated SERPINA3 protein levels in DCI patient plasma. Molecular docking demonstrated the stable binding of sulfonylurea hypoglycaemic agents, such as gliclazide and glimepiride, to SERPINA3, with binding energies of −6.8 and −6.6 kcal/mol, respectively. These findings suggest that SERPINA3 plays a pivotal role in DCI pathogenesis and that sulfonylurea drugs may exert neuroprotective effects through SERPINA3-mediated pathways. This study provides novel insights into the molecular mechanisms of DCI and highlights the potential of SERPINA3-targeted therapies for early intervention and treatment. Further research is warranted to validate these findings in larger cohorts and explore their clinical applicability. Full article

Background/Objectives: Limited evidence is available regarding insulin total daily dose (TDD), or the factors associated with TDD, among adults with type 2 diabetes (T2D) using multiple daily injections of insulin (MDI). Our aim was to determine the percentage of adults in the United States (US) with T2D who are prescribed MDI, their prescribed insulin TDD, and potential factors associated with TDD. Methods: This retrospective cohort study used deidentified data from the US IQVIA ambulatory electronic medical record database to study adults (≥18 years) with T2D initiating MDI (≥3 daily basal-plus-prandial insulin injections) from 1 January 2017 to 1 July 2022. The TDD was calculated from first evidence of MDI (index date). We used a generalized linear model regression analysis to model the relationship between TDD and clinically relevant factors associated with TDD. Results: During the study period, of 3,339,663 adults with T2D, 451,769 (13.5%) had ≥1 basal insulin prescriptions, 206,000 (6.2%) had both basal and prandial insulin prescriptions, and 41,215 (1.2%) were prescribed MDI (mean age, 58 years; 52% women; 62% White/Caucasian, 14% African American; mean body mass index [BMI], 34 kg/m²). Mean TDD was 96 units (1.0 units/kg/day); median TDD was 80 units (interquartile range, 54–124). In the regression analysis (model R², 0.14), factors predicting lower TDD included female sex, African American race, and prior 6-month (pre-index) prescriptions of sulfonylurea, metformin, or 2–3 noninsulin glucose-lowering medications. Predictors of greater TDD included increasing BMI, age 30–64 years, and pre-index SGLT2 inhibitor or GLP-1 RA prescription. Conclusions: Among US adults with T2D, 1.2% were prescribed MDI, with a wide range of TDD and median TDD of 80 units. Further research in other populations and using other data sources is warranted to explore prescribed insulin TDD for T2D and to examine other potentially relevant predictors of TDD. Full article