Effects of metformin, saxagliptin and repaglinide on gut microbiota in high-fat diet/streptozocin-induced type 2 diabetic mice.

INTRODUCTION: There has been increasing evidence that the gut microbiota is closely related to type 2 diabetes (T2D). Metformin (Met) is often used in combination with saxagliptin (Sax) and repaglinide (Rep) for the treatment of T2D. However, little is known about the effects of these combination agents on gut microbiota in T2D. RESEARCH DESIGN AND METHODS: A T2D mouse model induced by a high-fat diet (HFD) and streptozotocin (STZ) was employed. The T2D mice were randomly divided into six groups, including sham, Met, Sax, Rep, Met+Sax and Met+Rep, for 4 weeks. Fasting blood glucose level, serum biochemical index, H&E staining of liver, Oil red O staining of liver and microbiota analysis by 16s sequencing were used to access the microbiota in the fecal samples. RESULTS: These antidiabetics effectively prevented the development of HFD/STZ-induced high blood glucose, and the combination treatment had a better effect in inhibiting lipid accumulation. All these dosing regimens restored the decreasing ratio of the phylum Bacteroidetes: Firmicutes, and increasing abundance of phylum Desulfobacterota, expect for Met. At the genus level, the antidiabetics restored the decreasing abundance of Muribaculaceae in T2D mice, but when Met was combined with Rep or Sax, the abundance of Muribaculaceae was decreased. The combined treatment could restore the reduced abundance of Prevotellaceae_UCG-001, while Met monotherapy had no such effect. In addition, the reduced Lachnospiraceae_NK4A136_group was well restored in the combination treatment groups, and the effect was much greater than that in the corresponding monotherapy group. Therefore, these dosing regimens exerted different effects on the composition of gut microbiota, which might be associated with the effect on T2D. CONCLUSIONS: Supplementation with specific probiotics may further improve the hypoglycemic effects of antidiabetics and be helpful for the development of new therapeutic drugs for T2D.

Feasibility, safety, efficacy and potential scaling-up of sofosbuvir-based HCV treatment in Central and West Africa: (TAC ANRS 12311 trial).

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

Development of a simple polymer-based sensor for detection of the Pirimicarb pesticide.

In this study, a sensitive and selective fluorescent chemosensor was developed for the determination of pirimicarb pesticide by adopting the surface molecular imprinting approach. The magnetic molecularly imprinted polymer (MIP) nanocomposite was prepared using pirimicarb as the template molecule, CuFe2O4 nanoparticles, and graphene quantum dots as a fluorophore (MIP-CuFe2O4/GQDs). It was then characterized using X-ray diffraction (XRD) technique, Fourier transforms infrared (FT-IR) spectroscopy, scanning electron microscope (SEM), and transmission electron microscopy (TEM). The response surface methodology (RSM) was also employed to optimize and estimate the effective parameters of pirimicarb adsorption by this polymer. According to the experimental results, the average particle size and imprinting factor (IF) of this polymer are 53.61 nm and 2.48, respectively. Moreover, this polymer has an excellent ability to adsorb pirimicarb with a removal percentage of 99.92 at pH = 7.54, initial pirimicarb concentration = 10.17 mg/L, polymer dosage = 840 mg/L, and contact time = 6.15 min. The detection of pirimicarb was performed by fluorescence spectroscopy at a concentration range of 0-50 mg/L, and a sensitivity of 15.808 a.u/mg and a limit of detection of 1.79 mg/L were obtained. Real samples with RSD less than 2 were measured using this chemosensor. Besides, the proposed chemosensor demonstrated remarkable selectivity by checking some other insecticides with similar and different molecular structures to pirimicarb, such as diazinon, deltamethrin, and chlorpyrifos.

[Dramatic response to encorafenib plus binimetinib in a patient with leukemoid reaction from metastatic melanoma.] / Melanoma metastatico e reazione leucemoide: il ruolo della combo target.

Paraneoplastic leukemoid reaction (PLR) is an extremely rare condition in patients with melanoma and it is frequently associated with poor prognosis. BRAF gene mutational analysis represents the gold standard in patients with inoperable or metastatic melanoma as the possible presence of target mutations allows the use of the combination treatment with BRAF and MEK inhibitors. In this article, the case of a young woman with BRAF V600E mutated metastatic melanoma associated with PLR who received encorafenib and binimetinib is presented and discussed, with a focus on the relevant treatment response.

Effects of biochar and compost on microbial community assembly and metabolic processes in glyphosate, imidacloprid and pyraclostrobin polluted soil under freezethaw cycles.

Biochar and organic compost are widely used in agricultural soil remediation as soil immobilization agents. However, the effects of biochar and compost on microbial community assembly processes in polluted soil under freezingthawing need to be further clarified. Therefore, a freezethaw cycle experiment was conducted with glyphosate (herbicide), imidacloprid (insecticide) and pyraclostrobin (fungicide) polluted to understand the effect of biochar and compost on microbial community assembly and metabolic behavior. We found that biochar and compost could significantly promote the degradation of glyphosate, imidacloprid and pyraclostrobin in freezethaw soil decrease the half-life of the three pesticides. The addition of immobilization agents improved soil bacterial and fungal communities and promoted the transformation from homogeneous dispersal to homogeneous selection. For soil metabolism, the combined addition of biochar and compost alleviated the pollution of glyphosate, imidacloprid and imidacloprid to soil through up-regulation of metabolites (DEMs) in amino acid metabolism pathway and down-regulation of DEMs in fatty acid metabolism pathway. The structural equation modeling (SEM) results showed that soil pH and DOC were the main driving factors affecting microbial community assembly and metabolites. In summary, the combined addition of biochar and compost reduced the adverse effects of pesticides residues.

Swellable microneedle-coupled light-addressable photoelectrochemical sensor for in-situ tracking of multiple pesticides pollution in vivo.

In vivo monitoring of multiple pesticide contamination is of great significance for evaluating the health risks of different pesticides, agricultural production safety, and ecological and environmental assessment. Here, we report a hydrogel microneedle array coupled light-addressable photoelectrochemical sensor for tracking multiple pesticide uptake and elimination in living animals and plants, holding three prominent merits: i) enables in-situ detection of in vivo pesticides, avoiding cumbersome and complex sample transportation and handling processes; ii) allows repeated in vivo sampling of the same organism, improving tracking test controllability and accuracy; iii) avoids lethal sampling, providing a better understanding of the pesticides fate in living organisms. The coupled sensor is mechanically robust for withstanding more than 0.35 N per needle and highly swellable (800 %) for timely extraction of sufficient in vivo solution for analysis. For proof-of-concept, it achieves in-situ detection of atrazine, acetamiprid, and carbendazim efficiently and quantitatively in artificial agarose skin models, mouse skin interstitial fluids, and plant leaves with little inflammatory reaction. This simple, highly integrated, minimally invasive, and high-throughput in vivo monitoring method is ideal for future field environmental monitoring and plant and animal disease diagnosis.

Meta-analysis of the global distribution of clinically relevant CYP2C8 alleles and their inferred functional consequences.

BACKGROUND: CYP2C8 is responsible for the metabolism of 5% of clinically prescribed drugs, including antimalarials, anti-cancer and anti-inflammatory drugs. Genetic variability is an important factor that influences CYP2C8 activity and modulates the pharmacokinetics, efficacy and safety of its substrates. RESULTS: We profiled the genetic landscape of CYP2C8 variability using data from 96 original studies and data repositories that included a total of 33,185 unrelated participants across 44 countries and 43 ethnic groups. The reduced function allele CYP2C8*2 was most common in West and Central Africa with frequencies of 16-36.9%, whereas it was rare in Europe and Asia (< 2%). In contrast, CYP2C8*3 and CYP2C8*4 were common throughout Europe and the Americas (6.9-19.8% for *3 and 2.3-7.5% for *4), but rare in African and East Asian populations. Importantly, we observe pronounced differences (> 2.3-fold) between neighboring countries and even between geographically overlapping populations. Overall, we found that 20-60% of individuals in Africa and Europe carry at least one CYP2C8 allele associated with reduced metabolism and increased adverse event risk of the anti-malarial amodiaquine. Furthermore, up to 60% of individuals of West African ancestry harbored variants that reduced the clearance of pioglitazone, repaglinide, paclitaxel and ibuprofen. In contrast, reduced function alleles are only found in < 2% of East Asian and 8.3-12.8% of South and West Asian individuals. CONCLUSIONS: Combined, the presented analyses mapped the genetic and inferred functional variability of CYP2C8 with high ethnogeographic resolution. These results can serve as a valuable resource for CYP2C8 allele frequencies and distribution estimates of CYP2C8 phenotypes that could help identify populations at risk upon treatment with CYP2C8 substrates. The high variability between ethnic groups incentivizes high-resolution pharmacogenetic profiling to guide precision medicine and maximize its socioeconomic benefits, particularly for understudied populations with distinct genetic profiles.

Asymmetries among soil fungicide residues, nitrous oxide emissions and microbiomes regulated by nitrification inhibitor at different moistures.

Carbendazim residue has been widely concerned, and nitrous oxide (N2O) is one of the dominant greenhouse gases. Microbial metabolisms are fundamental processes of removing organic pollutant and producing N2O. Nitrification inhibitor 3,4-dimethylpyrazole phosphate (DMPP) can change soil abiotic properties and microbial communities and simultaneously affect carbendazim degradation and N2O emission. In this study, the comprehensive linkages among carbendazim residue, N2O emission and microbial community after the DMPP application were quantified under different soil moistures. Under 90% WHC, the DMPP application significantly reduced carbendazim residue by 54.82% and reduced soil N2O emission by 98.68%. The carbendazim residue was negatively related to soil ammonium nitrogen (NH4+-N), urease activity, and ratios of Bacteroidetes, Thaumarchaeota and Nitrospirae under 90% WHC, and the N2O emission was negatively related to NH4+-N content and relative abundance of Acidobacteria under the 60% WHC condition. In the whole (60% and 90% WHC together), the carbendazim residue was negatively related to the abundances of nrfA (correlation coefficient = -0.623) and nrfH (correlation coefficient = -0.468) genes. The hao gene was negatively related to the carbendazim residue but was positively related to the N2O emission rate. The DMPP application had the promising potential to simultaneously reduce ecological risks of fungicide residue and N2O emission via altering soil abiotic properties, microbial activities and communities and functional genes. ENVIRONMENTAL IMPLICATION: Carbendazim was a high-efficiency fungicide that was widely used in agricultural production. Nitrous oxide (N2O) is the third most important greenhouse gas responsible for global warming. The 3, 4-dimethylpyrazole phosphate (DMPP) is an effective nitrification inhibitor widely used in agricultural production. This study indicated that the DMPP application reduced soil carbendazim residues and N2O emission. The asymmetric linkages among the carbendazim residue, N2O emission, microbial community and functional gene abundance were regulated by the DMPP application and soil moisture. The results could broaden our horizons on the utilizations DMPP in decreasing fungicide risks and N2O emission.

Occurrence and risk assessment of pesticides and their transformation products related to olive groves in surface waters of the Guadalquivir river basin.

Pesticides are considered one of the main sources of contamination of surface waters, especially in rural areas highly influenced by traditional agricultural practices. The objective of this work was to evaluate the impact caused by pesticides and their transformation products (TPs) related to olive groves in surface waters with strong agricultural pressure. 11 streams were monitored during four sampling campaigns over 2 years. A solid-phase extraction, followed by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) analysis was used in the quantitative target approach, with more than 70 validated compounds. Target method was combined with a suspect screening strategy involving more than 500 pesticides and TPs, using ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) to identify additional pesticides and TPs out of the scope of analysis. A total of 43 different compounds were detected with the target method. The herbicide MCPA was present in all samples and at the highest concentration (1260 ng L-1), followed by the fungicide carbendazim (1110 ng L-1), and the herbicide chlorotoluron (706 ng L-1). The suspect screening strategy revealed the presence of 7 compounds out of the target analysis (1 pesticide and 6 TPs). 6 analytes were confirmed with the analytical standards. Semi-quantification results revealed that TPs exhibited higher concentrations than their corresponding parent compounds, indicating higher persistency. Some small streams showed a comparable number of pesticides and concentrations to the most polluted large river. The determined pesticide and TPs concentrations represented an estimated environmental hazard in almost all sampling sites under study. This work underscores the importance of including pesticide TPs and small streams impacted by extensive agricultural activities in water quality monitoring programs.

Synchronous spectrofluorimetry and chemometric modeling: A synergistic approach for analyzing simeprevir and daclatasvir, with application to pharmacokinetics evaluation.

Simeprevir and daclatasvir represent a cornerstone in the management of Hepatitis C Virus infection, a global health concern that affects millions of people worldwide. In this study, we propose a synergistic approach combining synchronous spectrofluorimetry and chemometric modeling i.e. Partial Least Squares (PLS-1) for the analysis of simeprevir and daclatasvir in different matrices. Moreover, the study employs firefly algorithms to further optimize the chemometric models via selecting the most informative features thus improving the accuracy and robustness of the calibration models. The firefly algorithm was able to reduce the number of selected wavelengths to 47-44% for simeprevir and daclatasvir, respectively offering a fast and sensitive technique for the determination of simeprevir and daclatasvir. Validation results underscore the models' effectiveness, as evidenced by recovery rates close to 100% with relative root mean square error of prediction (RRMSEP) of 2.253 and 2.1381 for simeprevir and daclatasvir, respectively. Moreover, the proposed models have been applied to determine the pharmacokinetics of simeprevir and daclatasvir, providing valuable insights into their distribution and elimination patterns. Overall, the study demonstrates the effectiveness of synchronous spectrofluorimetry coupled with multivariate calibration optimized by firefly algorithms in accurately determining and quantifying simeprevir and daclatasvir in HCV antiviral treatment, offering potential applications in pharmaceutical formulation analysis and pharmacokinetic studies for these drugs.

Treatment of patients with BRAFV600E-mutated metastatic colorectal cancer after progression to encorafenib and cetuximab: data from a real-world nationwide dataset.

BACKGROUND: Targeted therapy (TT) with encorafenib and cetuximab is the current standard for patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) who received one or more prior systemic treatments. However, the median progression-free survival (mPFS) is ∼4 months, and little is known about the possibility of administering subsequent therapies, their efficacy, and clinicopathological determinants of outcome. METHODS: A real-world dataset including patients with BRAFV600E-mutated mCRC treated with TT at 21 Italian centers was retrospectively interrogated. We assessed treatments after progression, attrition rates, and outcomes. RESULTS: Of the 179 patients included, 85 (47%), 32 (18%), and 7 (4%) received one, two, or three lines of treatment after TT, respectively. Those receiving TT in the second line were more likely to receive at least one subsequent therapy (53%), as compared with those treated with TT in the third line or beyond (30%; P < 0.0001), and achieved longer postprogression survival (PPS), also in a multivariate model (P = 0.0001). Among 62 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors receiving one or more lines of treatment after second-line TT, combinatory chemotherapy ± anti-vascular endothelial growth factor (anti-VEGF) was associated with longer PFS and PPS as compared with trifluridine-tipiracil or regorafenib (mPFS: 2.6 versus 2.0 months, P = 0.07; PPS: 6.5 versus 4.4 months, P = 0.04). CONCLUSIONS: Our real-world data suggest that TT should be initiated as soon as possible after the failure of first-line treatment in BRAFV600E-mutated mCRC. Among patients with pMMR/MSS tumors, combinatory chemotherapy ± anti-VEGF appears the preferred treatment choice after TT failure.

Natural Amino Acid-Bearing Carbamate Prodrugs of Daidzein Increase Water Solubility and Improve Phase II Metabolic Stability for Enhanced Oral Bioavailability.

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.

Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov, NCT02851797, and is complete. FINDINGS: Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1-11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17-1·37) for boys receiving givinostat and 1·48 (1·32-1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745-0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred. INTERPRETATION: Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy. FUNDING: Italfarmaco.

Response Rate and Molecular Correlates to Encorafenib and Binimetinib in BRAF-V600E Mutant High-Grade Glioma.

PURPOSE: Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600-mutated HGG. PATIENTS AND METHODS: In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy. RESULTS: Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. CONCLUSIONS: Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.

Dual-channel hypergraph convolutional network for predicting herb-disease associations.

Herbs applicability in disease treatment has been verified through experiences over thousands of years. The understanding of herb-disease associations (HDAs) is yet far from complete due to the complicated mechanism inherent in multi-target and multi-component (MTMC) botanical therapeutics. Most of the existing prediction models fail to incorporate the MTMC mechanism. To overcome this problem, we propose a novel dual-channel hypergraph convolutional network, namely HGHDA, for HDA prediction. Technically, HGHDA first adopts an autoencoder to project components and target protein onto a low-dimensional latent space so as to obtain their embeddings by preserving similarity characteristics in their original feature spaces. To model the high-order relations between herbs and their components, we design a channel in HGHDA to encode a hypergraph that describes the high-order patterns of herb-component relations via hypergraph convolution. The other channel in HGHDA is also established in the same way to model the high-order relations between diseases and target proteins. The embeddings of drugs and diseases are then aggregated through our dual-channel network to obtain the prediction results with a scoring function. To evaluate the performance of HGHDA, a series of extensive experiments have been conducted on two benchmark datasets, and the results demonstrate the superiority of HGHDA over the state-of-the-art algorithms proposed for HDA prediction. Besides, our case study on Chuan Xiong and Astragalus membranaceus is a strong indicator to verify the effectiveness of HGHDA, as seven and eight out of the top 10 diseases predicted by HGHDA for Chuan-Xiong and Astragalus-membranaceus, respectively, have been reported in literature.

Biocatalytic enantioselective synthesis of cenobamate, an antiepileptic drug.

A green and efficient process for the synthesis of cenobamate has been accomplished in 70% yield and >99% ee through the bio-reduction of ß-ketotetrazole using Daucus carota whole plant cells. The corresponding ß-hydroxytetrazole was isolated in 60% yield and >98% ee. This is the first report on the biocatalytic reduction of ß-ketotetrazole using plant enzymes derived from D. carota root cells with excellent enantioselectivity.

Dual effect of anandamide on spinal nociceptive transmission in control and inflammatory conditions.

Anandamide (AEA) is an important modulator of nociception in the spinal dorsal horn, acting presynaptically through Cannabinoid (CB1) and Transient receptor potential vanilloid (TRPV1) receptors. The role of AEA (1 µM, 10 µM, and 30 µM) application on the modulation of nociceptive synaptic transmission under control and inflammatory conditions was studied by recording miniature excitatory postsynaptic currents (mEPSCs) from neurons in spinal cord slices. Inhibition of the CB1 receptors by PF514273, TRPV1 by SB366791, and the fatty acid amide hydrolase (FAAH) by URB597 was used. Under naïve conditions, the AEA application did not affect the mEPSCs frequency (1.43±0.12 Hz) when all the recorded neurons were considered. The mEPSC frequency increased (180.0±39.2%) only when AEA (30 µM) was applied with PF514273 and URB597. Analysis showed that one sub-population of neurons had synaptic input inhibited (39.1% of neurons), the second excited (43.5%), whereas 8.7% showed a mixed effect and 8.7% did not respond to the AEA. With inflammation, the AEA effect was highly inhibitory (72.7%), while the excitation was negligible (9.1%), and 18.2% were not modulated. After inflammation, more neurons (45.0%) responded even to low AEA by mEPSC frequency increase with PF514273/URB597 present. AEA-induced dual (excitatory/inhibitory) effects at the 1st nociceptive synapse should be considered when developing analgesics targeting the endocannabinoid system. These findings contrast the clear inhibitory effects of the AEA precursor 20:4-NAPE application described previously and suggest that modulation of endogenous AEA production may be more favorable for analgesic treatments.

Bacteria-mediated green synthesis of silver nanoparticles and their antifungal potentials against Aspergillus flavus.

The best biocontroller Bacillus subtilis produced silver nanoparticles (AgNPs) with a spherical form and a 62 nm size through green synthesis. Using UV-vis spectroscopy, PSA, and zeta potential analysis, scanning electron microscopy, and Fourier transform infrared spectroscopy, the properties of synthesized silver nanoparticles were determined. Silver nanoparticles were tested for their antifungicidal efficacy against the most virulent isolate of the Aspergillus flavus fungus, JAM-JKB-BHA-GG20, and among the 10 different treatments, the treatment T6 [PDA + 1 ml of NP (19: 1)] + Pathogen was shown to be extremely significant (82.53%). TG-51 and GG-22 were found to be the most sensitive groundnut varieties after 5 and 10 days of LC-MS QTOF infection when 25 different groundnut varieties were screened using the most toxic Aspergillus flavus isolate JAM- JKB-BHA-GG20, respectively. In this research, the most susceptible groundnut cultivar, designated GG-22, was tested. Because less aflatoxin (1651.15 g.kg-1) was observed, treatment T8 (Seed + Pathogen + 2 ml silver nanoparticles) was determined to be much more effective. The treated samples were examined by Inductively Coupled Plasma Mass Spectrometry for the detection of metal ions and the fungicide carbendazim. Ag particles (0.8 g/g-1) and the fungicide carbendazim (0.025 g/g-1) were found during Inductively Coupled Plasma Mass Spectrometry analysis below detectable levels. To protect plants against the invasion of fungal pathogens, environmentally friendly green silver nanoparticle antagonists with antifungal properties were able to prevent the synthesis of mycotoxin by up to 82.53%.