Research on phytotoxicity assessment and photosynthetic characteristics of nicosulfuron residues on Beta vulgaris L.

Nicosulfuron is a common herbicide used to control weeds in maize fields. In northeast China, sugar beet is often grown as a subsequent crop after maize, and its frequently suffers from soil nicosulfuron residue damage, but the related toxicity evaluation and photosynthetic physiological mechanisms are not clear. Therefore, we experimented to evaluate the impacts of nicosulfuron residues on beet growth, photochemical properties, and antioxidant defense system. The results showed that when the nicosulfuron residue content reached 0.3 µg kg-1, it inhibited the growth of sugar beet. When it reached 36 µg kg-1 (GR50), the growth stagnated. Compared to the control group, a nicosulfuron residue of 36 µg kg-1 significantly decreased beet plant height (70.93 %), leaf area (91.85 %), dry weights of shoot (70.34 %) and root (32.70 %). It also notably reduced the potential photochemical activity (Fv/Fo) by 12.41 %, the light energy absorption performance index (PIabs) by 46.09 %, and light energy absorption (ABS/CSm) by 6.56 %. It decreased the capture (TRo/CSm) by 9.30 % and transferred energy (ETo/CSm) by 16.13 % per unit leaf cross-section while increasing the energy flux of heat dissipation (DIo/CSm) by 22.85 %. This ultimately impaired the photochemical capabilities of PSI and PSII, leading to a reduction in photosynthetic performance. Furthermore, nicosulfuron increased malondialdehyde (MDA) content while decreasing superoxide dismutase (SOD) and catalase (CAT) activities. In conclusion, this research clarified the toxicity risk level, lethal dose, and harm mechanism of the herbicide nicosulfuron residue. It provides a theoretical foundation for the rational use of herbicides in agricultural production and sugar beet planting management.

Factors Affecting Prescribing of Type 2 Diabetes Medications in Older Adults within an Integrated Healthcare System.

BACKGROUND: Despite type 2 diabetes guidelines recommending against the use of sulfonylureas in older adults and for the use of sodium-glucose cotransporter-2 inhibitors (SGLT2) and glucagon-like peptide-1 agonists (GLP1s) in patients with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and heart failure (HF), real-world guideline-concordant prescribing remains low. While some factors such as cost have been suggested, an in-depth analysis of the factors associated with guideline-concordant prescribing is warranted. OBJECTIVE: To quantify the extent of guideline-concordant prescribing in an integrated health care delivery system and examine provider and patient level factors that influence guideline-concordant prescribing. DESIGN: We performed a cross-sectional study. PARTICIPANTS: Participants were included if they had a diagnosis of type 2 diabetes, were prescribed a second-line diabetes medication between January 1, 2018 and December 31, 2020 and were at least 65 years old at the time of this second-line prescription. MAIN MEASURES: Our outcome of interest was guideline-concordant prescribing. The definition of guideline-concordant prescribing was based on American Diabetes Association and American Geriatric Society recommendations as well as expert consensus. Factors affecting guideline concordant prescribing included patient demographics and provider characteristics among others. KEY RESULTS: We included 1,693 patients of which only 50% were prescribed guideline-concordant medications. In a subgroup of 843 patients with cardiorenal conditions, only 30% of prescriptions were guideline concordant. Prescribing of guideline-concordant prescriptions was more likely among pharmacists than physicians (RR 1.34, 95% CI 1.19-1.51, p<0.001) and in endocrinology practices compared to primary care practices (RR 1.41 95% CI 1.16-1.72, p=0.007). Additionally, guideline concordant prescribing increased over time (42% in 2018 vs 53% in 2019 vs 53% in 2020, p<0.001). CONCLUSIONS: Guideline-concordant prescribing remains low in older adults, especially among those with cardiorenal conditions. Future studies should examine barriers to prescribing guideline-concordant medications and interventions to improve guideline-concordant prescribing.

A Placebo-Controlled, Double-Blind Clinical Investigation to Evaluate the Efficacy of a Patented Trigonella foenum-graecum Seed Extract "Fenfuro®" in Type 2 Diabetics.

BACKGROUND: Trigonella foenum-graecum (Fenugreek) is an extensively researched phytotherapeutic for the management of Type 2 diabetes without any associated side effects. The major anti-diabetic bioactive constituents present in the plant are furostanolic saponins, which are more abundantly available in the seed of the plant. However, the bioavailability of these components depends on the method of extraction and hence formulation of the phytotherapeutic constitutes a critical step for its success. OBJECTIVE: The present study reports the efficacy of a novel, patented fenugreek seed extract, Fenfuro®, containing significant amount of furostanolic saponins, in an open-labelled, two-armed, single centric study on a group of 204 patients with Type 2 diabetes mellitus over a period of twelve consecutive weeks. RESULTS: Administration of Fenfuro® in the dosage of 500 mg twice daily along with metformin and/or sulfonylurea-based prescribed antidiabetic drug resulted in a reduction of post-prandial glucose by more than 33% along with significant reduction in fasting glucose, both of which were greater than what resulted for the patient group receiving only Metformin and/or Sulfonylurea therapy. Fenfuro® also resulted in reduction in mean baseline HOMA index from 4.27 to 3.765, indicating restoration of insulin sensitivity which was also supported by a significant decrease in serum insulin levels by >10% as well as slight reduction in the levels of C-peptide. However, in the case of the Metformin and/or Sulfonylurea group, insulin levels were found to increase by more than 14%, which clearly indicated that drug-induced suppression of glucose levels instead of restoration of glucose homeostasis. Administration of the formulation was also found to be free from any adverse side effects as there were no changes in hematological profile, liver function and renal function. CONCLUSION: The study demonstrated the promising potential of this novel phytotherapeutic, Fenfuro®, in long-term holistic management of type-2 diabetes.

The Current Place of DPP4 Inhibitors in the Evolving Landscape of Type 2 Diabetes Management: Is It Time to Bid Adieu?

During the last decade, the landscape of type 2 diabetes (T2D) management has been completely transformed, moving from a glucose-centric perspective to a holistic approach that also takes into account weight control and organ protection. Dipeptidyl peptidase-4 inhibitors (DPP4i) are oral agents that have been used for the treatment of T2D for almost 20 years. Although they present an excellent safety profile, including the risk of hypoglycemia, they lack the spectacular cardiorenal benefits and weight-loss effects of the newer antidiabetic agents. This poses the question of whether they still deserve a place in the arsenal of drugs against T2D. In this article, we use a hypothetical case scenario to illustrate possible patient profiles where DPP4i could prove useful in the clinical setting. We discuss the advantages and disadvantages of the category, focusing on glycemic control, weight management, and cardiorenal protection, which are the pillars of modern T2D management, also considering its safety profile and cost-effectiveness. We conclude that in most cases, DPP4i present a more favorable risk-benefit ratio compared to sulfonylureas, which are still widely prescribed throughout the world. We also suggest that future research should clarify the reasons behind the contradictory findings between human and animal studies on cardiorenal effects of the class and identify subgroups of patients who would derive most benefit with DPP4i treatment.

Glycemic control and diabetes complications across health status categories in older adults treated with insulin or insulin secretagogues: The Diabetes & Aging Study.

BACKGROUND: For older adults with type 2 diabetes (T2D) treated with insulin or sulfonylureas, Endocrine Society guideline recommends HbA1c between 7% to <7.5% for those in good health, 7.5% to <8% for those in intermediate health, and 8% to <8.5% for those in poor health. Our aim was to examine associations between attained HbA1c below, within (reference), or above recommended target range and risk of complication or mortality. METHODS: Retrospective cohort study of adults ≥65 years old with T2D treated with insulin or sulfonylureas from an integrated healthcare delivery system. Cox proportional hazards models of complications during 2019 were adjusted for sociodemographic and clinical variables. Primary outcome was a combined outcome of any microvascular or macrovascular event, severe hypoglycemia, or mortality during 12-month follow-up. RESULTS: Among 63,429 patients (mean age: 74.2 years, 46.8% women), 8773 (13.8%) experienced a complication. Complication risk was significantly elevated for patients in good health (n = 16,895) whose HbA1c was above (HR 1.97, 95% CI 1.62-2.41) or below (HR 1.29, 95% CI 1.02-1.63) compared to within recommended range. Among those in intermediate health (n = 30,129), complication risk was increased for those whose HbA1c was above (HR 1.45, 95% CI 1.30-1.60) but not those below the recommended range (HR 0.99, 95% CI 0.89-1.09). Among those in poor health (n = 16,405), complication risk was not significantly different for those whose HbA1c was below (HR 0.98, 95% CI 0.89-1.09) or above (HR 0.96, 95% CI 0.88-1.06) recommended range. CONCLUSIONS: For older adults with T2D in good health, HbA1c below or above the recommended range was associated with significantly elevated complication risk. However, for those in poor health, achieving specific HbA1c levels may not be helpful in reducing the risk of complications.

The Effect of Dual Bioactive Compounds Artemisinin and Metformin Co-loaded in PLGA-PEG Nano-particles on Breast Cancer Cell lines: Potential Apoptotic and Anti-proliferative Action.

The most prevalent malignancy among women is breast cancer. Phytochemicals and their derivatives are rapidly being recognized as possible cancer complementary therapies because they can modify signaling pathways that lead to cell cycle control or directly alter cell cycle regulatory molecules. The phytochemicals' poor bioavailability and short half-life make them unsuitable as anticancer drugs. Applying PLGA-PEG NPs improves their solubility and tolerance while also reducing drug adverse effects. According to the findings, combining anti-tumor phytochemicals can be more effective in regulating several signaling pathways linked to tumor cell development. The point of the study was to compare the anti-proliferative impacts of combined artemisinin and metformin on cell cycle arrest and expression of cyclin D1 and apoptotic genes (bcl-2, Bax, survivin, caspase-7, and caspase-3), and also hTERT genes in breast cancer cells. T-47D breast cancer cells were treated with different concentrations of metformin (MET) and artemisinin (ART) co-loaded in PLGA-PEG NPs and free form. The MTT test was applied to assess drug cytotoxicity in T47D cells. The cell cycle distribution was investigated using flow cytometry and the expression levels of cyclin D1, hTERT, Bax, bcl-2, caspase-3, and caspase-7, and survivin genes were then determined using real-time PCR. The findings of the MTT test and flow cytometry revealed that each state was cytotoxic to T47D cells in a time and dose-dependent pattern. Compared to various state of drugs (free and nano state, pure and combination state) Met-Art-PLGA/PEG NPs demonstrated the strongest anti-proliferative impact and considerably inhibited the development of T-47D cells; also, treatment with nano-formulated forms of Met-Art combination resulted in substantial downregulation of hTERT, Bcl-2, cyclin D1, survivin, and upregulation of caspase-3, caspase-7, and Bax, in the cells, as compared to the free forms, as indicated by real-time PCR findings. The findings suggested that combining an ART/MET-loaded PLGA-PEG NP-based therapy for breast cancer could significantly improve treatment effectiveness.

Comparison of Metformin-sulfonylurea and Metformin-acarbose Combination Therapies on Glycemic Outcomes: A Retrospective Cohort Study.

OBJECTIVE: Pharmacological therapy for type 2 diabetes mellitus features various combinations of treatments, with different therapies providing different levels of effectiveness. In clinical settings, choices are driven by cost, effectiveness, and safety considerations, and these choices are still under question in Indonesia. This study aimed to compare the effectiveness of metformin-sulfonylurea and metformin-acarbose combination therapies on glycemic parameters in patients with type 2 diabetes mellitus. METHODS: This study was carried out at Gatot Soebroto Army Hospital in Jakarta and utilized a retrospective cohort study design. Participants had consumed the same drug without switching for six months and were divided into a metformin-sulfonylurea group (n = 100) and a metformin-acarbose group (n = 100). The effectiveness of treatment was evaluated by considering hemoglobin A1c (HbA1c), two hours postprandial glucose, and fasting blood glucose. RESULTS: After six months' consumption, there were no statistical differences between results for the metformin-sulfonylurea and metformin-acarbose groups in terms of change of HbA1c (p = 0.062), controlled two hours postprandial blood glucose (p = 0.649), and controlled fasting blood glucose (p = 0.282). Regular exercise was the most significant factor for constant/decreased HbA1c, whereas being male and following a diet were the most significant factors for controlled two hours postprandial blood glucose and fasting blood glucose, respectively. CONCLUSION: Based on the analysis performed, there was no significant difference in the effectiveness of six months' consumption of metformin-sulfonylurea and metformin-acarbose on HbA1c, two hours postprandial blood glucose, and fasting blood glucose.

Novel perspectives of super-high dose sulfonylurea and high-dose oral prednisolone in an infant with DEND syndrome due to V64M heterozygote KCNJ11 mutation.

AIMS: To report a novel mutation associated with developmental delay, epilepsy, and neonatal diabetes-DEND Syndrome, responsive to a novel management combination. METHODS: We describe the investigation, treatment, and genetic diagnosis of a newborn diagnosed with DEND syndrome. RESULTS: The patient was found to be de-novo heterozygous for pathogenic KCNJ11 missense variant: c.190G > A, p. (Val64Met), associated with DEND syndrome, responsive to a combination of super high doses of sulfonylurea (SU) and oral high-dose steroids. A single case was reported so far due to this mutation, presenting with severe DEND syndrome, treated by insulin only. His phenotypic description and management during 18 months, demonstrates this mutation is responsive to super-high doses of SU combined with high dose 6 weeks steroids protocol. CONCLUSIONS: We have identified a heterozygous missense mutation as the etiology for severe DEND syndrome in a one-day old neonate, presenting with asymptomatic hyperglycemia, responsive to a novel management combination.

Successful transition from insulin to sulfonylurea, on second attempt, in a 24-year-old female with neonatal diabetes secondary to KCNJ11 gene mutation.

Neonatal diabetes (NDM) is defined as diabetes that occurs in the first 6 months of life, the majority of cases are due to sporadic mutations. ATP-sensitive potassium channels located in the beta cells of the pancreas play a major role in insulin secretion and blood glucose homeostasis. Mutations that alter the function of these channels may lead to NDM. We report a case of a 26-year-old Irish woman who was diagnosed with NDM at the age of 4 weeks and treated as type 1 diabetes mellitus, with multiple daily injections of insulin with suboptimal glycaemic control and frequent episodes of hypoglycaemic. She underwent genetic testing for NDM and was diagnosed with a KCNJ11 gene mutation. She was transitioned to high dose glibenclamide at the age of 16 years, but the trial failed due to poor glycaemic control and patient preference, and she was restarted on insulin. At 24 years of age, she was successfully transitioned from insulin (total daily dose 50 units) to high dose sulfonylurea (SU) (glibenclamide 15 mg twice daily). This resulted in optimal control of blood glucose (HbA1C fell from 63 to 44 mmol/mol), lower rates of hypoglycaemic and better quality of life. This case demonstrates that a second trial of SU in later life may be successful.

A High-Throughput Assay for the Pancreatic Islet Beta-Cell Potassium Channel: Use in the Pharmacological Characterization of Insulin Secretagogues Identified from Phenotypic Screening.

Phenotypic screening is a neoclassical approach for drug discovery. We conducted phenotypic screening for insulin secretion enhancing agents using INS-1E insulinoma cells as a model system for pancreatic beta-cells. A principal regulator of insulin secretion in beta-cells is the metabolically regulated potassium channel Kir6.2/SUR1 complex. To characterize hit compounds, we developed an assay to quantify endogenous potassium channel activity in INS-1E cells. We quantified ligand-regulated potassium channel activity in INS-1E cells using fluorescence imaging and thallium flux. Potassium channel activity was metabolically regulated and coupled to insulin secretion. The pharmacology of channel opening agents (diazoxide) and closing agents (sulfonylureas) was used to validate the applicability of the assay. A precise high-throughput assay was enabled, and phenotypic screening hits were triaged to enable a higher likelihood of discovering chemical matter with novel and useful mechanisms of action.

Metformin use and long-term risk of benign prostatic hyperplasia: a population-based cohort study.

OBJECTIVE: To assess whether metformin use affects risk of benign prostatic hyperplasia (BPH) by comparing the risk of BPH in men with type 2 diabetes who initiated first-line treatment with either metformin or sulfonylurea monotherapy between 2000 or 2006 in Northern Denmark. In this period, sulfonylurea and metformin were both frequently used as first-line glucose-lowering drug (GLD) treatment. DESIGN: A population-based cohort study. SETTING: Northern Denmark. PARTICIPANTS: All men who filled at least two prescriptions for metformin or for sulfonylurea, respectively, during their first 6 months of GLD treatment. Follow-up started 6 months after treatment start. PRIMARY OUTCOME MEASURES: Rates of subsequent BPH, identified based on community prescriptions for BPH-related treatment or hospital BPH diagnoses, and rates of transurethral resection of the prostate (TURP). Rates in metformin and sulfonylurea users were compared overall and stratified by 6-month haemoglobin A1c (HbA1c) using Cox regression and an intention-to-treat (ITT) approach and an as-treated analysis. RESULTS: During follow-up, less than five persons were lost to follow-up due to emigration. In 3953 metformin initiators with a median follow-up of 10 years, the 10-year cumulative BPH incidence was 25.7% (95% CI 24.2 to 27.1). Compared with 5958 sulfonylurea users (median follow-up 8 years, 10-year cumulative incidence 27.4% (95% CI 26.2 to 28.6)), the crude HR for BPH was 0.83 (95% CI 0.77 to 0.89) and adjusted HR in the ITT analyses was 0.97 (95% CI 0.88 to 1.06). For TURP, the adjusted HR was 0.96 (95% CI 0.63 to 1.46). In the as-treated analysis, adjusted HR for BPH was 0.91 (95% CI 0.81 to 1.02). CONCLUSIONS: Compared with sulfonylurea, metformin did not substantially reduce the incidence of BPH in men with diabetes.

Sulphonylureas monotherapy and risk of hospitalization for heart failure in patients with type 2 diabetes mellitus: A population-based cohort study in China.

PURPOSE: The risk of heart failure associated with sulphonylureas is unclear. We evaluated the association between sulphonylureas and hospitalization of heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM) in China. METHODS: A retrospective cohort study was implemented using the Yinzhou Regional Health Care Database (YRHCD). We identified 15 752 adult patients with T2DM who were newly exposed to sulphonylurea monotherapy (N = 12 487) or acarbose monotherapy (N = 3265) from January 2010 to September 2016. Cox proportional hazards models weighted by inverse probability of treatment weights were used to compare the risk of HHF between initiators of sulphonylurea and acarbose. RESULTS: During a median follow-up of 0.55 (0.49, 1.11) and 0.49 (0.35, 0.70) years for sulphonylureas and acarbose initiators separately, 320 patients developed HHF, with 279 events in sulphonylureas group, and 41 events in acarbose group. The incidence rates of HHF among sulphonylureas initiators and acarbose initiators were 22.2 (95% CI 19.6-24.9) and 18.3 (95% CI 13.2-24.9) per 1000 person-years, respectively. The adjusted hazard ratio (aHR) of HHF for sulphonylureas vs acarbose was 1.61 (95% CI 1.14-2.27). When stratified by history of heart failure, aHR was 1.55 (95% CI 0.79-3.06) in patients with a history of heart failure, and 1.64 (95% CI 1.10-2.45) in patients with no history of heart failure. CONCLUSIONS: Our study suggested that use of sulphonylureas monotherapy compared with acarbose monotherapy for initial treatment of T2DM for approximately 0.5 years are significantly associated with a higher risk of HHF.

Rhodopseudomonas sphaeroides treating mesosulfuron-methyl waste-water.

The soybean processing wastewater (SPW) supplementation to facilitate the simultaneously treatment (SPW and mesosulfuron-methyl) of wastewater and production of biological substances by Rhodopseudomonas sphaeroides (R. sphaeroides) was discussed. Compared with the control group, with the addition of SPW, mesosulfuron-methyl was removed, and the yields of single-cell proteins, carotenoids, and bacteriochlorophyll were increased. In the 3 mg/L dose group, the mesosulfuron-methyl removal rate reached 97% after 5 days. Molecular analysis revealed that mesosulfuron-methyl exhibited induction effects on expression of the cpm gene and regulation effects on the synthesis of cytochrome P450 monooxygenases (P450) by activating HKs gene in TCS signal transduction pathway. For R. sphaeroides, this induction process required 1 day. The synthesis of P450 occurred 1 day after inoculation. Prior to expressing cpm gene and synthesizing P450, R. sphaeroides need a period of time to adapt to external mesosulfuron-methyl stimulation. However, the R. sphaeroides growth could not be maintained for more than 1 day due to the lack of organic matter in the raw wastewater. The SPW supplementation provided a sufficient carbon source in four groups with added SPW. After 5 days, R. sphaeroides became the dominant microflora in the wastewater. This new method could complete the treatment of mixed wastewater, the increased of biological substances output and the reuse of wastewater and R. sphaeroides cells as resources at the same time.

Use of Antihyperglycemic Medications in U.S. Adults: An Analysis of the National Health and Nutrition Examination Survey.

OBJECTIVE: 1) To examine trends in the use of diabetes medications and 2) to determine whether physicians individualize diabetes treatment as recommended by the American Diabetes Association (ADA). RESEARCH DESIGN AND METHODS: We conducted a retrospective, cross-sectional analysis of 2003-2016 National Health and Nutrition Examination Survey (NHANES) data. We included people ≥18 years who had ever been told they had diabetes, had an HbA1c >6.4%, or had a fasting plasma glucose >125 mg/dL. Pregnant women and patients aged <20 years receiving only insulin were excluded. We assessed trends in use of ADA's seven preferred classes from 2003-2004 to 2015-2016. We also examined use by hypoglycemia risk (sulfonylureas, insulin, and meglitinides), weight effect (sulfonylureas, thiazolidinediones [TZDs], insulin, and meglitinides), cardiovascular benefit (canagliflozin, empagliflozin, and liraglutide), and cost (brand-name medications and insulin analogs). RESULTS: The final sample included 6,323 patients. The proportion taking any medication increased from 58% in 2003-2004 to 67% in 2015-2016 (P < 0.001). Use of metformin and insulin analogs increased, while use of sulfonylureas, TZDs, and human insulin decreased. Following the 2012 ADA recommendation, the choice of drug did not vary significantly by older age, weight, or presence of cardiovascular disease. Patients with low HbA1c, or HbA1c <6%, and age ≥65 years were less likely to receive hypoglycemia-inducing medications, while older patients with comorbidities were more likely. Insurance, but not income, was associated with the use of higher-cost medications. CONCLUSIONS: Following ADA recommendations, the use of metformin increased, but physicians generally did not individualize treatment according to patients' characteristics. Substantial opportunities exist to improve pharmacologic management of diabetes.

A possible alternative therapy for type 2 diabetes using Myristica fragrans Houtt in combination with glimepiride: in vivo evaluation and in silico support.

The current study aimed to evaluate the in vivo hypoglycemic potential of Myristica fragrans seed extract co-administered with glimepiride in Swiss albino mice. Computational tools were used to further verify the in vivo findings and to help compare this combination to the glimepiride-pioglitazone combination in terms of the binding affinity of the ligands to their respective target protein receptors and the relative stability of the drug-protein complexes. The effect of the combined therapy was observed both in alloxan- and glucose-induced hyperglycemic Swiss albino mice. The mean fasting blood glucose level of the test groups was measured and statistically evaluated using Student's t test. The combined therapy significantly reduced the blood glucose level in a time-dependent manner compared to glimepiride alone. The binding affinity of glimepiride was found to be -7.6 kcal/mol with sulfonylurea receptor 1 in molecular docking. Conversely, macelignan-peroxisome proliferator-activated receptor (PPAR) α and macelignan-PPAR γ complexes were stabilized with -9.2 and -8.3 kcal/mol, respectively. Molecular dynamic simulation revealed that macelignan-PPAR α and γ complexes were more stable than pioglitazone complexes. The combination shows promise in animal and computer models and requires further trials to provide evidence of its activity in humans.

Application of Methylopila sp. DKT for Bensulfuron-methyl Degradation and Peanut Growth Promotion.

Bensulfuron-methyl is an herbicide widely used for weed control although its residues cause damage to other crops during crop rotations. In this study, the biodegrading activity of bensulfuron-methyl by a plant growth-promoting bacterial strain was carried out. Methylopila sp. DKT isolated from soil was determined for bensulfuron-methyl degradation and phosphate solubilization in the liquid media and soil. Moreover, the effects of the herbicide on peanut development and the role of Methylopila sp. DKT on the growth promotion of peanut were investigated. The results showed that the isolate effectively utilized the compound as a sole carbon source and solubilized low soluble inorganic phosphates. Methylopila sp. DKT also utilized 2-amino-4,6-dimethoxypyrimidine, a metabolite of bensulfuron-methyl degradation, as a sole carbon and energy source, and released ammonium and nitrate. The supplementation with Methylopila sp. DKT in soil increased the peanut biomass and the phosphorus content in the plant. In addition, the inoculation with Methylopila sp. DKT in soil and peanut cultivation increased the bensulfuron-methyl degradation by 57.7% for 1 month, which suggests that both plants and the bacterial isolate play a key role in herbicide degradation. These results indicate that the studied strain has a high potential for soil remediation and peanut growth promotion.

Rosmarinic acid, the active component of Salvia miltiorrhizae, improves gliquidone transport by regulating the expression and function of P-gp and BCRP in Caco-2 cells.

Salvia miltiorrhiza (Danshen) is typically used in the treatment of diabetic complications and is often co-prescribed with gliquidone in China. However, whether danshen affects the absorption of gliquidone has not been elucidated. In this study, the effects of an aqueous extract of danshen (danshen injection, DSI) and its primary compounds (danshensu, protocatechuic aldehyde, rosmarinic acid and salvianolic acid B) on gliquidone transport across Caco-2 monolayer cells was investigated. DSI enhanced the transport of gliquidone in Caco-2 cell monolayers from the apical (AP) to basolateral (BL) sides and from the BL to AP sides. Rosmarinic acid (RA) also significantly increased the Papp (AP-BL) value for gliquidone transport. Verapamil (a P-gp inhibitor) and Ko143 (a BCRP inhibitor) inhibited the BL-AP transport of gliquidone and promoted the AP-BL transport of gliquidone, whereas MK571 (an MRP1 inhibitor), probenecid (an MRP2 inhibitor), and benzbromarone (an MRP3 inhibitor) had no effect on gliquidone transport. RA also enhanced the intracellular accumulation of Rho123 and Hoechst 33342. The expression of P-gp and BCRP was significantly downregulated, and P-gp ATPase activity was promoted by RA in a dose-dependent manner. These results indicate that an aqueous extract of danshen can increase the transport of gliquidone in Caco-2 cell monolayers and that RA may be the primary compound associated with this activity, which is in agreement with RA simultaneously suppressing the function and expression of P-gp and BCRP.

Determination of sulfonylurea pesticide residues in edible seeds used as nutraceuticals by QuEChERS in combination with ultra-high-performance liquid chromatography-tandem mass spectrometry.

This work proposes a novel Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method in combination with ultra-high performance liquid chromatography-tandem mass spectrometry for the determination of sulfonylurea residues in edible seeds. The chromatographic separation of nine sulfonylureas was accomplished in less than 5.5 min, using a Luna Omega C18 column (50 × 2.1 mm, 1.6 µm). Mobile phase was supplied at 0.55 mL min-1 and consisted of 0.01% (v/v) aqueous acetic acid as eluent A and a mixture methanol/acetonitrile (80/20, v/v) as eluent B. Column temperature was established at 25 °C. A QuEChERS procedure was investigated as sample treatment for sulfonylureas extraction and sample clean-up. Different clean-up agents (i.e. PSA, Z-Sep+, EMR-Lipid and C18) were evaluated, selecting Z-Sep+ (25 mg) as the best option. The proposed method provided an extraction efficiency greater than 86.2%, while absolute matrix effect was lower than 50.1%. Matrix-matched calibration curves were required for analyte quantification. The analytical method was characterized according to SANTE/11813/2017 guideline, and including limits of detection and quantification, precision, and trueness. Linear dynamic ranges were established from 5 to 150 µg kg-1 for all analytes. Linearity (R2 ≥ 0.9974) and precision in terms of repeatability and intermediate precision (relative standard deviation ≤ 14.7%) are reported. The reporting limit was established at 5 µg kg-1, which is above the limits of quantification of the proposed method (≤ 1.64 µg kg-1) and below the maximum residue levels currently established by European legislation. In general, trueness is within the range of 70-120%. Despite greater recoveries were obtained at the reporting limit (i.e. 120-138%), relative standard deviations lower than 20% were obtained at this concentration level, so fulfilling the requirements of SANTE/11813/2017 guideline. This work represents the first analytical method intended for the analysis of sulfonylureas in sunflower, pumpkin and chia seeds, which are complex matrices due to their high content of fat as well as of growing interest due to their current commercialization as nutraceuticals.

Effect of berberine on in vitro metabolism of sulfonylureas: A herb-drug interactions study.

Patients with type 2 diabetes may co-ingest herbal and prescription medicines to control their blood sugar levels. Competitive binding of drug and herb may mutually affect their metabolism. This can alter the level of drug and its kinetics in the body, potentially causing toxicities or loss of efficacy. Understanding how the metabolism of sulfonylureas like glyburide and gliclazide can be affected by the presence of berberine and vice versa can provide valuable information on the possible risk of toxicities caused by co-ingestion of drugs. METHODS: Berberine and sulfonylureas (glyburide and gliclazide) were co-incubated with rat liver microsomes in the presence of a NADPH-regenerating system. The metabolites of berberine and sulfonylureas were analysed using liquid chromatography with high-resolution mass spectrometry in the positive ion mode. The role of individual isozymes in the metabolism of berberine, glyburide and gliclazide was investigated by using specific inhibitors. RESULTS: In vitro metabolism of berberine led to the formation of demethyleneberberine (B1a) and its isomer B1b through demethylenation. Berberrubine (B2a) and its isomer B2b were formed through demethylation. The isozymes CYP3A and CYP2D were found to be involved in the metabolism of berberine. In vitro metabolism of glyburide and gliclazide led to the formation of hydroxylated metabolites. The isozymes CYP3A and CYP2C were found to be involved in the metabolism of glyburide. Gliclazide was metabolised by CYP2C. In vitro co-incubation of glyburide or gliclazide with berberine showed that each drug's metabolism was compromised as they share a common isozyme. A strong negative linear correlation of glyburide or gliclazide metabolite levels and the concentration of berberine confirmed the effect of berberine on the metabolism of sulfonylureas. CONCLUSIONS: The metabolism of sulfonylureas and berberine was affected when these compounds were co-incubated with each other. This may be attributable to competitive binding of the herb and drug to the catalytic sites of the same isozymes.