Inhibition Of Enzyme Activity Research Articles

Myricetin inhibits CYP3A4, GST, and MRP1 in hepatic cancer cells

AbstractHerbal and nutritional supplements are widely used to prevent and treat many diseases, including cancer. Tumor cells modify metabolic enzyme systems like CYP3A4 and GST. They also overexpress MRP1, an ATP-binding cassette transporter subfamily G (ABCG2) member. Drug efflux may increase, reducing tumor cell drug accumulation and developing drug resistance that leads to significant obstacles in cancer care. Natural products' ability to overcome cancer's multidrug resistance is interesting. Their ability to affect several targets makes them valuable in addressing drug resistance from diverse approaches. The potential of natural flavonoid; Myricetin (MYR) to modulate CYP3A4, GST, and MRP1 activity and expression in hepatic cancer cells was evaluated to prove its targeting and preventing these pathways of multidrug resistance. The cell proliferation of MYR was determined using an MTT assay. Specific enzyme assays, efflux assay, and gene expression using RT-PCR were used to evaluate MYR effect in hepatic cell lines HepG-2 and Huh-7. MYR has a noteworthy cytotoxic effect compared to doxorubicin (DOX) with IC50 > 100 μM in HepG-2 and Huh-7 cells. MYR showed potent inhibition of CYP3A4 and GST enzyme activity and MRP1 efflux function and downregulated their gene expression in a dose-dependent manner in both cells. MYR100 dose was the most significant effective dose. MRY100 decreased CYP3A4 activity by 67.5% (P < 0.05) and 55% (P < 0.01) and downregulated the gene by 0.2-fold (P < 0.001) and 0.3-fold (P < 0.001) in HepG-2 and Hub-7 cells, respectively. After treatment with MRY100, GST activity decreased significantly in both cells, reaching 47.6% (P < 0.001) and 33.2% and GST gene downregulation was 0.12 and 0.21-fold (P < 0.001). MRY100 inhibited MRP1 efflux pump 2.3 times (P < 0.001) and 1.9 times (P < 0.001) more effectively than PC, resulting in a 0.23-fold and 0.12-fold downregulation of MRP1 genes in HepG-2 and Hub-7 cells. The result will validate the use of MYR to interact with the metabolism phases and could be used as adjuvant therapy in cancer prevention and treatment approaches.

Study on the extraction of Phycocyanin and the impact of in vitro simulated digestion on its anti-diabetic ability

Phycocyanin (PC) has significant anti-diabetic activity. However, research on the impact of digestion on the anti-diabetic properties of PC is still rare. In this study, we successfully extracted food-grade PC with a purity of 1.64 ± 0.06 from Ge Xian Mi. The results of antioxidant and enzyme activity inhibition experiments indicate that the biological activity of PC is positively correlated with its purity. Fluorescence and UV–Vis spectroscopy revealed the degradation of apolipoprotein and chromophore structures in PC during digestion. During digestion, the characteristic peaks of chromophores gradually disappeared, accompanied by a continuous decrease in antioxidant activity. The results of secondary structure determination indicate that after 0.5 h of digestion, the α-helix content decreased by approximately 50%, while the β-sheet content decreased by 6.87%. At the end of digestion, the α-helix structure was completely lost. The inhibitory effect of PC on the two enzymes decreased by approximately 20% after digestion started, followed by a rebound at 1.0 h, and then declined again at 3.0 h. At the end of digestion, the inhibition rates against α-amylase and α-glucosidase were only 22.09% and 25.76%, respectively. Digestion significantly decreased the antidiabetic ability of PC.

Antioxidant and anti-urease activities of Cardamine bulbifera: Insights from molecular docking and density functional theory studies

IntroductionCardamine bulbifera (L.) Crantz, commonly known as “Asian bittercress”, is a plant species widely distributed across Asia. It belongs to the Brassicaceae and has been traditionally used in medicinal applications. This study investigates the phytochemical composition, phenolic content, antioxidant properties, and anti-urease activity of C. bulbifera. MethodsIn this study, the aerial parts of the C. bulbifera were collected. The total polyphenol content of the extracts was determined using spectrophotometric methods, and its antioxidant and anti-urease activities were assessed. The chemical composition was characterised using gas chromatography-mass spectroscopic (GC-MS) analysis. Additionally, molecular docking studies explored potential interactions between the identified compounds and Helicobacter pylori CagA oncoprotein. Furthermore, Density Functional Theory (DFT) analysis provided valuable insights into the electronic properties of the main compounds. ResultThe total phenolic content of C. bulbifera extract was 225 ± 0.02 mg GAE/g extract DW, and the total flavonoid content was 62.64 ± 3.27 mg QE/g extract DW. The 2,2-Diphenyl-1-Picrylhydrazyl (DPPH) assay revealed an IC50 value of 1.01 ± 0.04 mg/mL, indicating significant antioxidant activity. The IC50 value for anti-urease activity was determined to be 2.74 ± 0.03 µg/mL, suggesting potent inhibition of urease enzyme activity. GC-MS analysis identified 15 bioactive compounds in the extract. Molecular docking studies highlighted Phenol, 3,5-bis(1,1-dimethylethyl) and 1-dodecanol as compounds with the highest binding affinity for the H. pylori CagA oncoprotein, suggesting potential therapeutic implications against H. pylori-related cancers. Additionally, DFT analysis emphasised these compounds' electronic properties and chemical reactivities, indicating their potential role in future pharmaceutical developments. ConclusionC. bulbifera exhibits rich phenolic and flavonoid content and significant antioxidant and intense urease inhibition activities. These findings suggest that C. bulbifera may offer potential therapeutic options for conditions related to H. pylori infections, including cancer. Further research is needed to explore its mechanisms of action and clinical applications in more detail.

Discovery and clinical translation of ceperognastat, an O‐GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer's disease

AbstractINTRODUCTIONThe aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O‐GlcNAcylation, an important post‐translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O‐GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O‐GlcNAcase (OGA) catalyzes the removal of O‐GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD.METHODSA multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure‐based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O‐GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy.RESULTSCeperognastat is a potent, central nervous system (CNS)‐penetrant, low‐dose inhibitor of OGA, which can achieve > 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat.DISCUSSIONCeperognastat is an orally available, highly potent, CNS‐penetrant OGA inhibitor that achieved high (> 80%) OGA enzyme occupancy and increased brain O‐GlcNAc‐tau preclinically. Ceperognastat demonstrated > 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program.Highlights Ceperognastat is a highly potent, CNS‐penetrant OGA inhibitor. Ceperognastat is both orally available and CNS‐penetrant even when given at low doses. Ceperognastat can achieve > 95% OGA enzyme occupancy in the animal and human brain. Ceperognastat had an acceptable safety profile in Phase 1 clinical studies.

Response of earthworm enzyme activity and gut microbial functional diversity to carbendazim in the manured soil.

The effect of pesticide pollution on environmental microorganisms in soil has become the focus of widespread concern in society today. The response of earthworm gut and surrounding soil microbial functional diversity and enzyme activity to carbendazim (CBD) was studied in a soil-earthworm ecosystem amended with manure. In the experiment, CBD was added to the manured soil (MS). Meanwhile, the pesticide treatment without manure and the control treatment without pesticides were also set up. The activities of catalase (CAT) and acetylcholinesterase (AChE) were measured to evaluate the toxicity of CBD. The Biolog method was used to assess the functional diversity of the microbial community. In the 2 mg/kg CBD treatment, earthworm AChE activity decreased significantly in the MS after 14 d, which occurred earlier than in the un-manured soil (NS). The changes of earthworm CAT activity in the pesticide treatments showed a trend of initially increasing and then maintaining at a high activity level. However, the CAT activities at 28 d in the manured soils were clearly lower than that at 7 d for both the CBD treatments, while they remained stable in the control treatments. The carbon source utilization, Simpson index, Shannon index, and McIntosh index of soil microorganisms in the MS treatments were significantly higher than those in the NS treatments. The overall activity of earthworm gut microorganisms in the MS treated with 2 mg/kg CBD was higher than that in the control. Also, CBD treatment (2 mg/kg) increased significantly the Simpson index and McIntosh index of earthworm gut microorganisms. The results indicated that the enzyme activities in the manured soils increased before 7 d for the pesticide treatments. Furthermore, exposure to CBD at a high concentration in the MS not only led to the earlier inhibition of earthworm enzyme activity but also significantly improved the overall activity of earthworm gut microorganisms and microbial functional diversity. This study revealed the ecotoxicological effects of earthworms in response to pesticide stress following the use of organic fertilizers under facility environmental conditions, which can provide a theoretical basis for the remediation of pesticide pollution in soil in the future.

Inhibitory effects of cuminaldehyde on human liver cytochrome P450 enzymes

This work explored the influence of cuminaldehyde on the metabolic activity of four primary human cytochrome P450 (CYP) enzymes. Human liver microsomes (HLM) with and without cuminaldehyde were incubated with specific substrates of different CYP enzymes. The influence of cuminaldehyde on “CYP1A2, CYP2C9, CYP2D6 and CYP3A4” activities was examined. The formation of specific metabolites was analyzed by HPLC analytical methods. It was observed that cuminaldehyde appears to have a negligible influence on CYP1A2 activity. However, CYP2C9 activity was significantly and potently inhibited by cuminaldehyde at all investigated concentrations. It was found that cuminaldehyde (1 µM) inhibited the most CYP2C9 enzyme activity with 64.87 % inhibition followed by CYP3A4 (38.90 %), CYP2D6 (25.76 %) and CYP1A2 (4.99 %). Inhibition of both CYP2D6 and CYP3A4 enzyme activity was observed in response to cuminaldehyde concentrations. Findings of the current investigation indicate that herb-drug interactions are very possible when cuminaldehyde is concurrently taken with medicines predominantly metabolized by CYP2C9 and CYP3A4. Cuminaldehyde should be tested further to examine how it affects CYP2C9 and CYP3A4-metabolized drugs.

The exploitation of local electric field generated by oxygen vacancies on BiOIO3 nano-antibacterial agents for enhanced photocatalytic sterilisation

Methicillin-resistant Staphylococcus aureus (MRSA) is a typical Gram-positive foodborne pathogen, and its infection has been reported since its discovery. Photocatalysis has emerged as a safe and efficient new sterilization method in clinical and food sectors. In this study, we developed an oxygen vacancy-rich BiOIO3 nano-antibacterial agent using a hydrothermal method, which was successfully synthesized and confirmed through various characterization techniques. Notably, the BiOIO3 nano-antibacterial agent exhibits almost complete inactivation of 107 CFU/mL MRSA within 2 h under visible light irradiation. Furthermore, with increasing exposure duration to irradiation, gradual shrinkage and disintegration of the MRSA cell membrane were observed along with inhibition of the intracellular enzyme activity. Haemolysis tests were performed to prove the biological safety of the agent. Mechanistic investigations revealed that surface oxygen vacancies of BiOIO3 facilitated adsorption binding of water and oxygen within a local electric field promoting reactive oxygen species (ROS) generation. This leads to the rapid accumulation of ROS, which attacks the cell membrane causing significant damage, disrupting normal physiological metabolism of the bacteria, and ultimately killing MRSA. The present study is expected to provide a favourable solution for developing novel efficient and green nano-antibacterial agents through surface modifications.

Bioactive Properties of Enzymatic Gelatin Hydrolysates Based on In Silico, In Vitro, and In Vivo Studies.

This current study aims to analyze the potential bioactivities possessed by the enzymatic hydrolysates of commercial bovine, porcine, and tilapia gelatins using bioinformatics in combination with in vitro and in vivo studies. The hydrolysate with superior inhibition of angiotensin converting enzyme (ACE) activity was used to treat the D-galactose (DG)-induced amnesic mice. In silico digestion of the gelatins led to the identification of peptide sequences with potential antioxidant, ACE-inhibitory, and anti-amnestic properties. The results of in vitro digestion revealed that the <1 kDa peptide fraction of porcine gelatin hydrolysate obtained after 1 h digestion with papain (PP) (PP1, <1 kDa) potently inhibited ACE, acetylcholinesterase, and prolyl endopeptidase activities at 87.42%, 21.24%, and 48.07%, respectively. Administering the PP1 to DG-induced amnesic mice ameliorated the spatial cognitive impairment and Morris water maze learning abilities. The dentate area morphology in the PP1-treated mice was relatively similar to the control group. In addition, PP1 enhanced the antioxidant capacity in the DG-induced amnesic mice. This study suggests that PP1 could serve as a potential treatment tool against oxidative stress, hypertension, and neurodegenerative diseases.

Alpha-1 antitrypsin inhibits Clostridium botulinum C2 toxin, Corynebacterium diphtheriae diphtheria toxin and B. anthracis fusion toxin

The bacterium Clostridium botulinum, well-known for producing botulinum neurotoxins, which cause the severe paralytic illness known as botulism, produces C2 toxin, a binary AB-toxin with ADP-ribosyltranferase activity. C2 toxin possesses two separate protein components, an enzymatically active A-component C2I and the binding and translocation B-component C2II. After proteolytic activation of C2II to C2IIa, the heptameric structure binds C2I and is taken up via receptor-mediated endocytosis into the target cells. Due to acidification of endosomes, the C2IIa/C2I complex undergoes conformational changes and consequently C2IIa forms a pore into the endosomal membrane and C2I can translocate into the cytoplasm, where it ADP-ribosylates G-actin, a key component of the cytoskeleton. This modification disrupts the actin cytoskeleton, resulting in the collapse of cytoskeleton and ultimately cell death. Here, we show that the serine-protease inhibitor α1-antitrypsin (α1AT) which we identified previously from a hemofiltrate library screen for PT from Bordetella pertussis is a multitoxin inhibitor. α1AT inhibits intoxication of cells with C2 toxin via inhibition of binding to cells and inhibition of enzyme activity of C2I. Moreover, diphtheria toxin and an anthrax fusion toxin are inhibited by α1AT. Since α1AT is commercially available as a drug for treatment of the α1AT deficiency, it could be repurposed for treatment of toxin-mediated diseases.

Green directional conversion of food waste into glycerol in a two-step differentiation enzymolysis and facultative fermentation using Saccharomyces cerevisiae: Performance assessment and mechanism

Valorization of food waste into high value-added glycerol was designed and prepared via directional green transformation using multi-enzymolysis saccharification coupled facultative fermentation by Saccharomyces cerevisiae. The optimal conditions for the first step of multienzyme hydrolysis and the second step of facultative fermentation were 55 °C and pH 5.0 for 6 h, 30 °C and pH 7.0 for 70 h, respectively. The glycerol yield efficiency and kinetic rate constant were 73.6 % (w/w) and 0.681 h−1 for dry component of food waste, while the other 27.4 % was utilized as the growth energy substrate. The key points of transformation were the synergistic directed enzymolysis to produce 3 % glycerol and 95 % reducing sugars. Furthermore, the reducing sugars were converted into glycerol by switch the metabolic pathway from ethanol into glycerol through the quantitative expression of functional gpd1 and gpp2 genes activated GPD and GPP enzymatic activity and synchronous inhibition of adh gene for glycerol production with Na2SO3 regulation. The economic income was 135.52 USD/ton for converting 80 % water content of kitchen waste into glycerol. This finding provided an economic value-added approach to produce high-value glycerol for cost-effective recycling of food waste using commercial yeast.

Algerian Prickly Pear Seed By-Products: Fatty Acids Composition, Antioxidant, Enzyme Inhibitory Activities towards Tyrosinase, Urease, α-Amylase, and Cholinesterase, along with the Ability to Protect from Thermal Protein Denaturation.

Prickly pear seed is a source of the most expensive oil in the world, which is rich in vitamins and polyunsaturated fatty acids. Its extraction generates a large quantity of press cake. These two by-products need to be valued. The current study aimed to assess the fatty acid composition of oil and the phytochemical composition of press cake. In addition, the antioxidant and the inhibition of thermal protein denaturation effects of both Algerian seed by-products were evaluated with their inhibitory action against the activities of urease, tyrosinase, α-amylase, and cholinesterase enzymes. The GC MS analysis result revealed the richness of our oil in linoleic (74%) and palmitic (13%) acids methyl esters, respectively. The chemical composition of press cake was characterized by a high value of dry matter (94.94 ± 0.05%), especially the carbohydrates (85.13 ± 0.94%). The results of antioxidant activity presented by IC50 and A0.5 ranged from 7.51 ± 0.03 to 88.10 ± 0.92 µg/mL. Furthermore, the IC50 values were 40.19 ± 1.21 and 61.18 ± 0.03 µg/mL in thermal protein denaturation assay, and ranging from 22.97 ± 0.72 to 385.99 ± 0.27 µg/mL for the inhibition of enzymatic activities. These results indicate that the studied oil can be one of the strongest oils for its impressive effects and also encourage us to reuse its press cake in feed livestock.

Skin Improvement Effects of Ultrasound-Enzyme-Treated Collagen Peptide Extracts from Flatfish (Paralichthys olivaceus) Skin in an In Vitro Model.

Collagen is considered to be an intercellular adhesive that prevents tissue stretching or damage. It is widely utilized in cosmetic skin solutions, drug delivery, vitreous substitutions, 3D cell cultures, and surgery. In this study, we report the development of a green technology for manufacturing collagen peptides from flatfish skin using ultrasound and enzymatic treatment and a subsequent assessment on skin functionality. First, flatfish skin was extracted using ultrasound in distilled water (DW) for 6 h at 80 °C. Molecular weight analysis via high-performance liquid chromatography (HPLC) after treatment with industrial enzymes (alcalase, papain, protamex, and flavourzyme) showed that the smallest molecular weight (3.56 kDa) was achieved by adding papain (0.5% for 2 h). To determine functionality based on peptide molecular weight, two fractions of 1100 Da and 468 Da were obtained through separation using Sephadex™ G-10. We evaluated the effects of these peptides on protection against oxidative stress in human keratinocytes (HaCaT) cells, inhibition of MMP-1 expression in human dermal fibroblast (HDF) cells, reduction in melanin content, and the inhibition of tyrosinase enzyme activity in murine melanoma (B16F10) cells. These results demonstrate that the isolated low-molecular-weight peptides exhibit superior skin anti-oxidant, anti-wrinkle, and whitening properties.

Development of Transdermal Formulation Integrating Polymer-Based Solid Microneedles and Thermoresponsive Gel Fucoidan for Antiaging: Proof of Concept Study.

Skin can be damaged by intense and prolonged exposure to ultraviolet (UV) radiation. Photoaging and acute damage from sun exposure result in collagen degradation and enzymatic activity decline in the skin. Fucoidan (FUC) exhibits potential antiaging properties, including collagen synthesis promotion and enzyme activity inhibition. However, FUC's limited ability to penetrate the skin layers due to its large molecular weight makes it a challenge for topical application. In this study, we successfully developed a new approach by integrating thermoresponsive gel (TRG) containing FUC with solid microneedles (SMNs) as a delivery system. TRG is formulated using a combination of Pluronic F127 (PF127) and Pluronic F68 (PF68) polymers, while SMNs are made from a mixture of poly(vinyl alcohol) (PVA) and poly(vinylpyrrolidone) (PVP) polymers with a variety of cross-linkers. Based on the results of ex vivo testing, it was shown that more than 80% of FUC can be delivered using the optimized formula. Furthermore, the results of the in vitro blood hemolytic test showed that TRG-FUC-SMNs were relatively biocompatible. In vivo antiaging activity tests using a rat model exposed to UV for 14 days showed that histological assessment, skin elasticity measurement, wrinkle evaluation, and skin moisture content had no significant differences (p < 0.05) compared to the positive control group. In contrast, a significant difference (p < 0.05) was observed when comparing the TRG-FUC-SMNs group with the group that received only TRG-FUC without pretreatment and negative controls. These findings suggest that FUC has potential to be delivered using the TRG system in combination with SMNs to harness its antiaging properties.

Phillyrin and its metabolites exert antipyretic effects by targeting the NAD+ binding domain of GAPDH, MDH2 and IDH2

BackgroundFever is one of the main pathophysiological reactions that occurs during the acute phase of various diseases. Excessive body temperature can lead to various adverse consequences such as brain tissue damage and abnormal immune responses. Phillyrin (Phr) is the main active ingredient in Forsythia suspensa (Thunb.) Vahl (Lian Qiao) and has antipyretic effects; however, its antipyretic mechanism of action remains unclear. PurposeThis study aimed to explore the antipyretic mechanisms of Phr and provide a new treatment plan for fever. MethodsThe antipyretic effects of Phr were evaluated using a mouse model of pneumonia fever. The main metabolites of Phr involved in its antipyretic function were identified using a mitochondrial temperature-sensitive probe. Further synthesis of the main metabolite, phillygenin (Phg), an alkynylated probe, was performed, and chemical proteomics was used to capture and analyze its direct target for antipyretic effects. The mechanism of action of Phg and its antipyretic targets was explored using metabolomics and various molecular biology methods. ResultsPhr showed significant antipyretic and anti-inflammatory effects in a mouse model of lipopolysaccharide-induced fever. Phg reversibly targeted the nicotinamide adenine dinucleotide (NAD+) binding domain of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), malate dehydrogenase 2 (MDH2), and isocitrate dehydrogenase 2 (IDH2) to inhibit their enzymatic activity. In-depth analysis of cellular metabolomics and mitochondrial stress testing indicated that inhibition of GAPDH, MDH2, and IDH2 enzyme activity by Phg led to a decrease in cellular energy supply and heat production regulated by glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation signaling pathways. Phg specifically targeted macrophages and inhibited LPS-induced macrophage activation by downregulating GAPDH enzyme activity, thereby exerting anti-inflammatory effects. In vivo experiments also confirmed that the antipyretic effect of Phr in LPS-induced fever model mice was related to its main metabolites, Phg and Phg-sulfonate (Phg-S), which directly targeted the NAD+ binding domain of GAPDH, IDH2, and MDH2, inhibiting the activity of these enzymes, thereby reducing energy supply and regulating febrile-related inflammatory factors. ConclusionThis study reported for the first time that the antipyretic effect of Phr is produced by targeting GAPDH, IDH2, and MDH2 to regulate energy supply and febrile-related inflammatory factors through its main metabolites Phg and Phg-S. This study not only provides potential drugs for fever treatment but also provides new ideas for improving clinical fever treatment plans.

Effects of Wildfire on Soil CO2 Emission and Bacterial Community in Plantations.

In order to study the effects of wildfires on soil carbon dioxide (CO2) emissions and microbial communities in planted forests, Pinus massoniana Lamb. and Cunninghamia lanceolata (Lamb.) Hook. forests were selected as the research subjects. Through a culture test with 60 days of indoor constant temperature, the soil physical and chemical properties, organic carbon mineralization, organic carbon components, enzyme activity, and microbial community structure changes of the two plantations after fire were analyzed. The results showed that wildfires significantly reduced soil CO2 emissions from the Pinus massoniana forests and Cunninghamia lanceolata forests by 270.67 mg·kg-1 and 470.40 mg·kg-1, respectively, with Cunninghamia lanceolata forests exhibiting the greatest reduction in soil CO2 emissions compared to unburned soils. Bioinformatics analysis revealed that the abundance of soil Proteobacteria in the Pinus massoniana and Cunninghamia lanceolata forests decreased by 6.00% and 4.55%, respectively, after wildfires. Additionally, redundancy analysis indicated a significant positive correlation between Proteobacteria and soil CO2 emissions, suggesting that the decrease in Proteobacteria may inhibit soil CO2 emissions. The Cunninghamia lanceolata forests exhibited a significant increase in soil available nutrients and inhibition of enzyme activities after the wildfire. Additionally, soil CO2 emissions decreased more, indicating a stronger adaptive capacity to environmental changes following the wildfire. In summary, wildfire in the Cunninghamia lanceolata forests led to the most pronounced reduction in soil CO2 emissions, thereby mitigating soil carbon emissions in the region.

Electrochemical Synthesis of Isoquinoline Sulfone Compounds and Study of their Inhibition of Acetolactate Synthase Enzyme Activity

AbstractBoth of sulfone compounds and isoqunoline derivatives are important compounds. In this paper, Isoquinoline C1 and C3 Sulfone compounds have been synthesized by electrochemical means using isoquinoline N‐Oxides and some sodium benzenesulfinate as reactants, inexpensive and easily available sodium iodide as electrolytes, and a mixture of acetonitrile, water and acetic acid as reaction solvents. By using the method, a series of isoquinoline sulfone compounds have been synthesized in high yields. The reaction does not need oxidants and catalysts, and the reaction conditions are mild, environmentally friendly, efficient and suitable. In addition, we also carried out ALS enzyme inhibition experiments on the synthesized isoquinoline sulfone compounds, six of the isoquinoline sulfone compounds synthesized herein were found to inhibit ALS enzyme at a high rate, four of them inhibited ALS enzyme at a rate comparable to that of the commercialized herbicides Halosulfuron and Broadstrike, and the other two compounds also inhibited ALS enzyme at a rate higher than that of Halosulfuron and Broadstrike. Therefore, it is possible to find lead compounds with good herbicidal activity potential from these 6 compounds.

Chemical characterization and angiotensin-I converting enzyme inhibitory activity of Indonesian stinky beans

The chemical composition of four Indonesian stinky beans has been explored. Those bean are Petai (Parkia speciosa), Lamtoro Gung (Leucaena leucochepala ssp. Glabrata (Rose) S. Zarate), Jengkol (Pithecellobium jiringa) and Kabau (Archidendron bubalinum). This exploration belongs to the local food utilization research theme of functional food sources. Those beans have a unique flavour and usually lead to foul stools, sweat, urine or mouth odour. Their intense flavour may be due to the content of amino acids. High hydrophobic and negative charge hydrophilic amino acids are crucial in preventing hypertension through inhibition of angiotensin I-converting enzyme (ACE) activity. This study evaluated the chemical properties of beans and its angiotensin I-converting enzyme inhibitory (ACE-I) peptides. The amino acid profile was determined as preliminary data to ensure the content of hydrophobic and negative charge hydrophilic amino acids. Their ability to inhibit ACE was studied to represent an antihypertensive effect. In vitro gastrointestinal digestion was applied to obtain more small molecular peptides and evaluate their ACE-I activity after digestion. Petai has the highest glutamic acid (20.90 g/100 g protein d.b.), lysine (13.31 g/100 g protein d.b.), arginine (11.76 g/100 g protein d.b.), leucine (10.98 g/100 g protein d.b.), and aspartic acid (10.72 g/100 g protein d.b.). Fresh Jengkol has the highest ACE-I activity (67.59%). Subsequential digestion by pepsin and pancreatin improves the ACE-I activity, and Kabau had the highest (79.87%). Based on the results, Indonesian stinky beans can prevent hypertension by inhibiting ACE activity and being used as a protein source alternative

Drug-induced enzyme activity inhibition and CYP3A4 genetic polymorphism significantly shape the metabolic characteristics of furmonertinib

This study aimed to elucidate the impact of variations in liver enzyme activity, particularly CYP3A4, on the metabolism of furmonertinib. An in vitro enzyme incubation system was established for furmonertinib using liver microsomes and recombinant CYP3A4 baculosomes, with analytes detected by LC-MS/MS. The pharmacokinetic characteristics of furmonertinib were studied in vivo using Sprague-Dawley rats. It was found that telmisartan significantly inhibited the metabolism of furmonertinib, as demonstrated by a significant increase in the AUC of furmonertinib when co-administered with telmisartan, compared to the furmonertinib-alone group. Mechanistically, it was noncompetitive in rat liver microsomes, while it was mixed competitive and noncompetitive in human liver microsomes and CYP3A4. Considering the genetic polymorphism of CYP3A4, the study further investigated its effect on the kinetics of furmonertinib. The results showed that compared to CYP3A4.1, CYP3A4.29 had significantly increased activity in catalyzing furmonertinib, whereas CYP3A4.7, 9, 10, 12, 13, 14, 18, 23, 33, and 34 showed markedly decreased activity. The inhibitory activity of telmisartan varied in CYP3A4.1 and CYP3A4.18, with IC50 values of 8.56 ± 0.90 μM and 27.48 ± 3.52 μM, respectively. The key loci affecting the inhibitory effect were identified as ARG105, ILE301, ALA370, and LEU373. Collectively, these data would provide a reference for the quantitative application of furmonertinib.

Arginyltransferase 1 (ATE1)-mediated proteasomal degradation of viral haemagglutinin protein: a unique host defence mechanism.

The extensive protein production in virus-infected cells can disrupt protein homeostasis and activate various proteolytic pathways. These pathways utilize post-translational modifications (PTMs) to drive the ubiquitin-mediated proteasomal degradation of surplus proteins. Protein arginylation is the least explored PTM facilitated by arginyltransferase 1 (ATE1) enzyme. Several studies have provided evidence supporting its importance in multiple physiological processes, including ageing, stress, nerve regeneration, actin formation and embryo development. However, its function in viral pathogenesis is still unexplored. The present work utilizes Newcastle disease virus (NDV) as a model to establish the role of the ATE1 enzyme and its activity in pathogenesis. Our data indicate a rise in levels of N-arginylated cellular proteins in the infected cells. Here, we also explore the haemagglutinin-neuraminidase (HN) protein of NDV as a presumable target for arginylation. The data indicate that the administration of Arg amplifies the arginylation process, resulting in reduced stability of the HN protein. ATE1 enzyme activity inhibition and gene expression knockdown studies were also conducted to analyse modulation in HN protein levels, which further substantiated the findings. Moreover, we also observed Arg addition and probable ubiquitin modification to the HN protein, indicating engagement of the proteasomal degradation machinery. Lastly, we concluded that the enhanced levels of the ATE1 enzyme could transfer the Arg residue to the N-terminus of the HN protein, ultimately driving its proteasomal degradation.

Star anise (Illicium verum Hook. F.) polysaccharides: Potential therapeutic management for obesity, hypertension, and diabetes

This study explores the extraction of polysaccharides from star anise (Illicium verum Hook. f.) with its anti-obesity, antihypertensive, antidiabetic, and antioxidant properties. The aim is to optimize the extraction conditions of star anise polysaccharides (SAP) utilizing propane alcohols-based deep eutectic solvents and microwave-assisted methods. The optimized conditions resulted in an extraction yield of 5.14%. The characteristics of acidic pectin-like SAP, including high viscosity (44.86 mPa s), high oil-holding capacity (14.39%), a high degree of esterification (72.53%), gel-like properties, highly amorphous, a high galacturonic acid concentration, and a highly branching size polysaccharide structure, significantly contribute to their potent inhibition of pancreatic lipase (86.67%), angiotensin-converting enzyme (73.47%), and α-glucosidase (82.33%) activities as well as to their antioxidant properties of azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS, 34.94%) and ferric ion reducing antioxidant power (FRAP, 0.56 mM FeSO4). Therefore, SAP could be used as a potential therapeutic agent for obesity, hypertension, and diabetes mellitus management.