The Impact of Baohuoside I on the Metabolism of Tofacitinib in Rats.

Purpose: To study the potential drug-drug interactions between tofacitinib and baohuoside I and to provide the scientific basis for rational use of them in clinical practice. Methods: A total of eighteen Sprague-Dawley rats were randomly divided into three groups: control group, single-dose group (receiving a single dose of 20 mg/kg of baohuoside I), and multi-dose group (receiving multiple doses of baohuoside I for 7 days). On the seventh day, each rat was orally administered with 10 mg/kg of tofacitinib 30 minutes after giving baohuoside I or vehicle. Blood samples were collected and determined using UPLC-MS/MS. In vitro effects of baohuoside I on tofacitinib was investigated in rat liver microsomes (RLMs), as well as the underlying mechanism of inhibition. The semi-inhibitory concentration value (IC50) of baohuoside I was subsequently determined and its inhibitory mechanism against tofacitinib was analyzed. Furthermore, the interactions between baohuoside I, tofacitinib and CYP3A4 were explored using Pymol molecular docking simulation. Results: The administration of baohuoside I orally has been observed to enhance the area under the concentration-time curve (AUC) of tofacitinib and decrease the clearance (CL). The observed disparity between the single-dose and multi-dose groups was statistically significant. Furthermore, our findings suggest that the impact of baohuoside I on tofacitinib metabolism may be a mixture of non-competitive and competitive inhibition. Baohuoside I exhibit an interaction with arginine (ARG) at position 106 of the CYP3A4 enzyme through hydrogen bonding, positioning itself closer to the site of action compared to tofacitinib. Conclusion: Our study has demonstrated the presence of drug-drug interactions between baohuoside I and tofacitinib, which may arise upon pre-administration of tofacitinib. Altogether, our data indicated that an interaction existed between tofacitinib and baohuoside I and additional cares might be taken when they were co-administrated in clinic.

Chemico-pharmacological evaluation of the methanolic leaf extract of Catharanthus ovalis: GC-MS/MS, in vivo, in vitro, and in silico approaches.

Introduction: Natural plant-based medicines have gained popularity recently as a major source of inventive, risk-free, and more potent secondary bioactive compounds with medicinal potential. Catharanthus ovalis is a perennial shrub containing various indole alkaloids cultivated extensively for local medical purposes. Methods: This research is conducted to identify the phytocompounds present in the leaves of C. ovalis and its central and peripheral analgesic, thrombolytic, and membrane-stabilizing activities through tail immersion, acetic acid-induced writhing, human blood clot lysis, and erythrocyte lysis by heat and hypotonic solution methods, respectively. Results and discussion: A total of 39 compounds were identified using GC-MS/MS techniques, including hexadecanoic acid, methyl ester (56.749%), methyl stearate (29.782%), carvacrol and its TBDMS derivative (12.586%), and 9-octadecenoic acid, methyl ester, (E)-] (9.297%) presented in high quantity. The highest tail immersion latency was observed for the 600 mg/kg extract of C. ovalis crude extract. Both 400 and 600 mg/kg doses of C. ovalis crude extract exhibited prominent peripheral analgesic activity. The maximum thrombolytic effect was observed by DCM soluble fraction extract by inhibiting 54.87% of the clot. However, the aqueous-soluble fraction of this extract manifested an excellent membrane-stabilizing effect by showing 73.98% and 87.51% hemolysis against heat- and hypotonic-induced hemolysis, respectively. Some of the compounds were identified as active agents against different receptors related to these diseases, which supported the findings of in vitro and in vivo tests. Conclusion: Further investigation needs to be conducted to specify and identify the exact mechanism of action of these compounds.

A comprehensive evaluation of the therapeutic potential of silibinin: a ray of hope in cancer treatment.

Natural compounds hold promise in the search for cancer therapies due to their unique chemical structures and combinations that may effectively combat cancer while minimizing toxicity and side effects compared to conventional treatments. Silibinin, a natural lignan, has been found to possess strong anti-cancer activity against several types of human cancers based on emerging research. This study aims to provide an overview of the therapeutic potential of silibinin in the treatment and prevention of cancers. A comprehensive search was conducted using various internet databases such as PubMed, Google Scholar, and ScienceDirect to identify relevant research papers. Silibinin has been shown to exhibit anticancer activity against several types of cancers, including liver, lungs, breast, prostate, colorectal, skin, and bladder cancers. Its multifaceted mechanisms of action contribute to its therapeutic effects. Silibinin exerts antioxidant, anti-inflammatory, anti-proliferative, pro-apoptotic, anti-metastatic, and anti-angiogenic activities, making it a promising candidate for cancer therapy. One of the key mechanisms underlying the anticancer effects of silibinin is its ability to modulate multiple signaling pathways involved in cancer development and progression. It can inhibit the activation of various oncogenic pathways, including PI3K/Akt, NF-κB, Wnt/ß-catenin, and MAPK pathways, thereby suppressing cancer cell proliferation, inducing cell cycle arrest, and promoting apoptosis. Silibinin possesses great potential as an effective treatment agent for cancer. The multifaceted mechanisms of action, favorable safety profile, and potential synergistic effects of silibinin with conventional therapies make it an attractive candidate for further investigation and development as a cancer treatment. However, more extensive clinical studies are necessary to fully establish the efficacy, optimal dosage, and long-term effects of silibinin in cancer treatment.

Anti-oxidant and neuro-modulatory effects of bioactive Byttneria pilosa leaf extract in swiss albino mice using behavioral models.

Byttneria pilosa, a flowering plant from the Malvaceae family traditionally used to treat ailments such as boils and scabies, is here investigated for its potential health benefits. The study focused on evaluating its antioxidant and antidiabetic properties in vitro, as well as the in vivo anxiolytic and antidepressant activities of the methanol extract of B. pilosa leaf (MEBP). The study employed various assays to evaluate antioxidant activity, including 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, reducing power capacity, and quantification of the total phenolic and flavonoid contents of MEBP. Additionally, anxiolytic and antidepressant activities were evaluated through four tests: elevated plus-maze test (EPMT), light-dark box test (LDBT), forced swimming test (FST), and tail suspension test (TST). Antidiabetic effect was determined using α-amylase inhibition assay. Docking analysis was performed using BIOVIA and Schrödinger Maestro (v11.1), and the absorption, distribution, metabolism, and excretion/toxicity (ADME/T) properties of bioactive substances were investigated using a web-based technique. MEBP exhibited moderate antioxidant activity in DPPH radical scavenging and reducing power capacity assays, with a dose-dependent response. The total phenolic and flavonoid contents measured were 70 ± 1.53 mg and 22.33 ± 1.20 mg, respectively. MEBP demonstrated significant effects in α-amylase inhibition comparable to acarbose. In behavioral tests, MEBP dose-dependently altered time spent in open arms/light box and closed arms/dark box, indicating anxiolytic effects. Moreover, MEBP significantly reduced immobility duration in FST and TST, suggesting antidepressant properties. Molecular docking analysis revealed favorable interactions between beta-sitosterol and specific targets, suggesting the potential mediation of anxiolytic and antidiabetic effects. Overall, MEBP exhibits notable anxiolytic and antidepressant properties, along with moderate antioxidant and antidiabetic activities.

Polyphenols and extracts from Zingiber roseum (Roxb.) Roscoe leaf mitigate pain, inflammation and pyrexia by inhibiting cyclooxygenase-2: an in vivo and in silico studies.

Zingiber roseum (Roxb.) Roscoe, a perennial herb from the Zingiberaceae family, has a long history of traditional use in the treatment of several ailments including pain, inflammation, fever, cough, arthritis, skin diseases, and liver infections. This study sought to confirm the efficacy of Zingiber roseum (Roxb.) Roscoe leaves methanol extract (ZrlME) as reported in traditional usage by evaluating its analgesic, anti-inflammatory, and antipyretic capabilities. In addition, in silico molecular docking of the metabolites identified in ZrlME was studied to verify the experimental outcomes. ZrlME demonstrated strong dose-dependent analgesic efficacy against all analgesic tests. ZrlME (400 mg/kg) showed higher anti-inflammatory activity than the standard in the carrageenan-induced paw edema test model. A significant reduction of rectal temperature (3.97°F↓) was also recorded at the same dose of ZrLME after 24 h of treatment. Seven polyphenolic metabolites were identified and quantified by HPLC-DAD analysis, including 3, 4- dihydroxy benzoic acid, (-) epicatechin, rutin hydrate, p-coumaric acid, trans-ferulic acid, rosmarinic acid, and myricetin. Strong binding affinities (ranges from -5.8 to -8.5 Kcal/mol) between the aforesaid polyphenols and cyclooxygenase-2 were discovered. Moreover, molecular dynamics simulations (MDS) demonstrated that these polyphenols exhibit significant COX-2 inhibitory activity due to their high stability in the COX-2 active site. In computational prediction, the polyphenols were also found to be nontoxic, and a variety of biological activities, such as antioxidant, analgesic, anti-inflammatory, antipyretic, and hepatoprotective, were observed. The results of this study revealed that ZrlME possesses notable analgesic, anti-inflammatory, and antipyretic properties.

Evaluation of the inhibitory effect of azoles on pharmacokinetics of lenvatinib in rats both in vivo and in vitro by UPLC-MS/MS.

BACKGROUND: Lenvatinib is a multitargeted tyrosine kinase inhibitor used in the treatment of a variety of solid tumors. This study aims to investigate the potential pharmacokinetic interactions between lenvatinib and various azoles (ketoconazole, voriconazole, isavuconazole and posaconazole) when orally administered to rats. METHODS: A total of 30 Sprague-Dawley rats were randomly allocated into five groups and administered 20 mg/kg of ketoconazole, voriconazole, isavuconazole and 30 mg/kg of posaconazole and 0.5% CMC-Na, through gavage for a duration of 7 days prior to the commencement of the experiment. On the final day, the rats were given 10 mg/kg of lenvatinib. The blood concentration of lenvatinib was determined using UPLC-MS-MS. In vitro lenvatinib were incubated with azoles and rat liver microsomes (RLMs) or human liver microsomes (HLMs). Molecular docking was lastly used to examine the binding strength of the enzymes and ligands with Autodock Vina. RESULTS: AUC and Cmax of lenvatinib significantly increased with each of the azoles (p < 0.05), whereas CLz/F decreased 0.83-flod, 0.41-fold (p < 0.05) and 0.72-fold (p < 0.01) in voriconazole, isavuconazole and ketoconazole in rats. The IC50 of lenvatinib with the azoles were 0.237, 1.300, 0.355 and 2.403 µM in RLMs and 0.160, 1.933, 3.622 and 1.831 µM in HLMs. Molecular docking analysis suggested that azoles exhibited a strong binding ability towards the target enzymes. CONCLUSION: It is imperative to acknowledge the potential drug-drug interactions mediated by CYP3A4 between azoles and lenvatinib, as these interactions hold significant implications for their clinical utilization.

Amorphous CoP nanoparticle composites with nitrogen-doped hollow carbon nanospheres for synergetic anchoring and catalytic conversion of polysulfides in Li-S batteries.

The commercial viability of Li-S batteries was obstructed by short cycle life and poor capability owing to slow redox kinetics and polysulfide shuttle effect. To tackle these challenges, the amorphous CoP anchored on N-doped carbon nanospheres with hollow porous structures (CoP/HCS) has been synthesized as a superior sulfur host via a facial pyrolysis approach. The debilitating effect would be hampered during the cycling processing resulting from two reasons:(1) the powerful chemical anchoring between unsaturated Co and Li-polysulfides, (2) the remarkable adaption of volume variation originating from the hollow porous architectures. The amorphous CoP nanoparticles not only catalyze the transformation of lithium polysulfides as electrocatalyst, but also acquired a high sulfur loading as sulfur host materials. More importantly, the synergistic incorporation of CoP and HCS improved the inherit low conductivity by anchoring on the N-doped carbon hollow, thus leading to excellent performance for Li-S batteries. Benefiting from these advantages, the amorphous CoP/HCS-based sulfur electrodes exhibited outstanding rate performance (685.6 mAh g-1 at 3C), excellent long-cycling stability with a low capacity decay of only 0.03% per cycle over 1000 cycles at 2C, and a high areal capacity of 5.16 mAh cm-2 under high sulfur loading.

Evaluation of acacetin inhibition potential against cytochrome P450 in vitro and in vivo.

Acacetin is a natural flavonoid that is widely distributed in plants and possesses numerous pharmacological activities. The aim of the present study was to investigate the effects of acacetin on the activities of the cytochrome P450 family members CYP1A2, CYP2B1, CYP2C11, CYP2D1, CYP2E1, and CYP3A2 in rat liver microsomes in vitro and rats in vivo to evaluate potential herb-drug interactions by using a cocktail approach. Phenacetin, bupropion, tolbutamide, dextromethorphan, chlorzoxazone, and midazolam were chosen as the probe substrates. An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous detection of the probe substrates and their metabolites. In vitro, the mode of acacetin inhibition of CYP2B1, CYP2C11, and CYP2E1 was competitive, while mixed inhibition was observed for CYP1A2 and CYP3A2. The Ki values in this study were less than 8.32 µM. In vivo, the mixed probe substrates were administered by gavage after daily intraperitoneal injection with 50 mg/kg acacetin or saline for 2 weeks. The main pharmacokinetic parameters, area under the plasma concentration-time curve (AUC), plasma clearance (CL), and maximum plasma concentration (Cmax) of the probe substrates were significantly different in the experimental group than in the control group. Overall, the in vitro and in vivo results indicated that acacetin would be at high risk to cause toxicity and drug interactions via cytochrome P450 inhibition.

Green Hydrothermal Synthesis of N-doped Carbon Dots from Biomass Highland Barley for the Detection of Hg2.

Totally water-soluble N-doped Carbon dots (N-CDs) were synthesized by a green hydrothermal method from biomass using Highland barley as a carbon source and ethanediamine as nitrogen source. TEM and XRD showed the graphitic amorphous structure and narrow diameter distribution of these N-CDs. N-doping to the crystal lattice and carrying many hydrophilic groups on the surface of N-CDs were verified by XPS and FT-IR. The as-synthesized N-CDs emitted strong blue fluorescence at 480 nm and owned a relatively high quantum yield of 14.4%. The product also could sensitively and selectively detect Hg2+ ions in the range of 10-160 µM and the limit of detection was equal to 0.48 µM.

An aqueous fluorescent sensor for Pb2+ based on phenothiazine-polyamide.

A sensitive and selective fluorescent sensor for Pb2+ ion based on phenothiazine-polyamide was built (named sensor PP). Due to introducing of four diethanolamine groups to polyamide, this sensor was totally water soluble. PP could detect Pb2+ ion within 1 min in the presence of other metal ions in aqueous solution, the detect limit was 9.11 × 10-8 M.

In situ green oxidation synthesis of Ti3+ and N self-doped SrTiO x N y nanoparticles with enhanced photocatalytic activity under visible light.

A simple in situ green oxidation synthesis route was developed to prepare Ti3+ and N self-doped SrTiO x N y nanoparticles using TiN and H2O2 as precursors. X-ray diffraction (XRD), scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (HRTEM) were used to characterize the crystallinity, structure and morphology. X-ray photoelectron spectroscopy (XPS) tests confirmed the presence of Ti3+ and N in the prepared SrTiO x N y nanoparticles. The resultant nanoparticles were shown to have strong absorption from 400 to 800 nm using UV-vis diffuse reflectance spectroscopy (UV-vis DRS). The formation mechanism of the Ti3+ and N self-doped SrTiO x N y nanoparticles was also discussed. Under visible light irradiation, the obtained Ti3+ and N self-doped samples showed higher photocatalytic activity for the degradation of the model wastewater, methylene blue (MB) solution. The most active sample T-130-Vac, obtained at 130 °C under vacuum, showed a 9.5-fold enhancement in the visible light decomposition of MB in comparison to the commercial catalyst nano-SrTiO3. The sample also showed a relatively high cycling stability for photocatalytic activity.

A Ratiometric Fluorescent Sensor for Cd2+ Based on Internal Charge Transfer.

This work reports on a novel fluorescent sensor 1 for Cd2+ ion based on the fluorophore of tetramethyl substituted bis(difluoroboron)-1,2-bis[(1H-pyrrol-2-yl)methylene]hydrazine (Me4BOPHY), which is modified with an electron donor moiety of N,N-bis(pyridin-2-ylmethyl)benzenamine. Sensor 1 has absorption and emission in visible region, at 550 nm and 675 nm, respectively. The long wavelength spectral response makes it easier to fabricate the fluorescence detector. The sensor mechanism is based on the tunable internal charge transfer (ICT) transition of molecule 1. Binding of Cd2+ ion quenches the ICT transition, but turns on the π - π transition of the fluorophore, thus enabling ratiometric fluorescence sensing. The limit of detection (LOD) was projected down to 0.77 ppb, which is far below the safety value (3 ppb) set for drinking water by World Health Organization. The sensor also demonstrates a high selectivity towards Cd2+ in comparison to other interferent metal ions.

Effects of CYP2C19 Variants on Fluoxetine Metabolism in vitro.

AIMS: CYP2C19 is an important member of the cytochrome P450 enzyme superfamily. We recently identified 31 CYP2C19 alleles in the Han Chinese population. The aim of this study was to assess the catalytic activities of these allelic isoforms and their effects on the metabolism of fluoxetine in vitro. METHODS: The wild-type and 30 CYP2C19 variants were expressed in insect cells and each variant was characterized using fluoxetine as the substrate. Reactions were performed at 37°C with 20-1,000 µmol/L substrate for 30 min. By using ultra-high performance liquid chromatography-mass spectrometry to detect the products, the kinetic parameters Km, Vmax, and intrinsic clearance (Vmax/Km) of norfluoxetine were determined. RESULTS: Among the CYP2C19 variants tested, T130M showed similar intrinsic clearance (Vmax/Km) values with CYP2C19*1, while the intrinsic clearance values of other variants were significantly decreased (from 9.56 to 77.77%). In addition, CYP2C19*3 and *35FS could not be detected because they have no detectable enzyme activity. CONCLUSION: In China, the assessment of CYP2C19 variants in vitro offers valuable information relevant to the personalized medicine for CYP2C19-metabolized drug.

A Cu2+-Selective Probe Based on Phenanthro-Imidazole Derivative.

A novel fluorescent Probe 1, based on phenanthro-imidazole has been developed as an efficient chemosensor for the trace detection of copper ions (Cu2+). Probe 1 demonstrated sensitive fluorescence quenching upon binding with Cu2+ through 1:1 stoichiometric chelation. The detection limit for Cu2+ ions was projected through linear quenching fitting to be as low as 2.77 × 10-8 M (or 1.77 ppb). The sensing response was highly selective towards Cu2+ with minimal influence from other common metal ions, facilitating the practical application of Probe 1 in trace detection.

ß-Furan-Fused bis(Difluoroboron)-1,2-bis((1H-pyrrol-2-yl)methylene)hydrazine Fluorescent Dyes in the Visible Deep-Red Region.

Novel ß-furan-fused bis(difluoroboron)-1,2-bis((1H-pyrrol-2-yl)methylene)hydrazine (BOPHY) fluorescent dyes (F-BOPHY1-3) were prepared through an efficient process, and their structures were confirmed by (1)H NMR spectroscopy, (13)C NMR spectroscopy, MALDI-TOF HRMS, and element analysis. Their optical properties were then characterized by UV-vis absorption and photoluminescence (PL) spectroscopy. The UV-vis absorption and PL spectra of the dyes shifted to longer wavelengths relative to those of BOPHY because of the fusion of their furan rings, which extended π-conjugation of the molecules. All of the dyes exhibited large extinction coefficients (109700-12300 M(-1) cm(-1)), deep-red fluorescence emission (646-667 nm), moderate fluorescence quantum yields (0.30-0.45), as well as high chemical stability and photostability in solution. These advantageous properties show that these compounds are important to the design of efficient long-wavelength fluorescent dyes and are suitable for various applications in biotechnology and materials science.

A Fluorescent Sensor Synthesized Using Silica Nanoparticles for Detecting Hg²âº in Aqueous Solution.

With the aim of detecting Hg²âº in aqueous solution, a new fluorescent nanosensor (RhB-APTES-SiNPs) for the determination of Hg²âº has been successfully developed. This senor was synthesized by immobilizing RhB-APTES on the surface of silica nanoparticles (SiNPs), which were prepared using the reverse microemulsion method. RhB-APTES-SiNPs can detect Hg²âº on-line, in real time and with the naked eye, thus providing "turn-on" fluorescence enhancement. The developed nanosensor exhibits highly sensitivity and selectivity over several cations in aqueous solution. Additionally, RhB-APTES-SiNPs exhibits an excellent ability to detect Hg²âº within a linear range from 1 to 6 µM, and its detection limit was calculated to be 0.5 ppb.

4,4'-Bipyridine-dimethyl-glyoxime (1/1).

In the title compound, C(10)H(8)N(2)·C(4)H(8)N(2)O(2), both the dimethyl-glyoxime and the 4,4'-bipyridine mol-ecules have crystallographic C(i) symmetry. The mol-ecules stack along the a-axis direction with a dihedral angle of 20.4 (8)° between their planes. In the crystal, the components are linked by O-H⋯N hydrogen bonds into alternating chains along [120] and [1[Formula: see text]0].