Myricetin mitigates motor disturbance and decreases neuronal ferroptosis in a rat model of Parkinson's disease.

Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson's disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+), respectively. Ferroptosis was identified by assessing the levels of Fe2+, ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe2+, ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP+-induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP+-treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.

Icariside II in NSCLC and COVID-19: Network pharmacology and molecular docking study.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) are susceptible to coronavirus disease-2019 (COVID-19), but current treatments are limited. Icariside II (IS), a flavonoid compound derived from the plant epimedin, showed anti-cancer,anti-inflammation and immunoregulation effects. The present study aimed to evaluate the possible effect and underlying mechanisms of IS on NSCLC patients with COVID-19 (NSCLC/COVID-19). METHODS: NSCLC/COVID-19 targets were defined as the common targets of NSCLC (collected from The Cancer Genome Atlas database) and COVID-19 targets (collected from disease database of Genecards, OMIM, and NCBI). The correlations of NSCLC/COVID-19 targets and survival rates in patients with NSCLC were analyzed using the survival R package. Prognostic analyses were performed using univariate and multivariate Cox proportional hazards regression models. Furthermore, the targets in IS treatment of NSCLC/COVID-19 were defined as the overlapping targets of IS (predicted from drug database of TMSCP, HERBs, SwissTarget Prediction) and NSCLC/COVID-19 targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of these treatment targets were performed aiming to understand the biological process, cellular component, molecular function and signaling pathway. The hub targets were analyzed by a protein-protein interaction network and the binding capacity with IS was characterized by molecular docking. RESULTS: The hub targets for IS in the treatment of NSCLC/COVID-19 includes F2, SELE, MMP1, MMP2, AGTR1 and AGTR2, and the molecular docking results showed that the above target proteins had a good binding degree to IS. Network pharmacology showed that IS might affect the leucocytes migration, inflammation response and active oxygen species metabolic process, as well as regulate the interleukin-17, tumor necrosus factor and hypoxia-inducible factor-1 signaling pathway in NSCLC/COVID-19. CONCLUSIONS: IS may enhance the therapeutic efficacy of current clinical anti-inflammatory and anti-cancer therapy to benefit patients with NSCLC combined with COVID-19.

Phytochemical profiling, antiviral activities, molecular docking, and dynamic simulations of selected Ruellia species extracts.

The antiviral properties of the flowering aerial extracts of Ruellia tuberosa and Ruellia patula were investigated through phytochemical profiling via LC-MS/MS and HPLC techniques. Qualitative LC-MS/MS analyses identified seventy-seven metabolites from both Ruellia species. R. tuberosa had the highest phenolic content (49.3%), whereas R. patula had the highest flavonoid content (57.8%). Additionally, quantitative HPLC investigations of the compounds identified by LC-MS/MS were performed using the available standard compounds. The main constituents in the R. tuberosa extract was found to be catechin (5321.63 µg/g), gallic acid (2878.71 µg/g), and ellagic acid (2530.79 µg/g), whereas the major compounds in the R. patula extract was found to be rutin (11,074.19 µg/g) and chlorogenic acid (3157.35 µg/g). Furthermore, the antiviral activities of both Ruellia species against HAdV-40, herpes simplex type 2 and H1N1 were evaluated. These findings demonstrated that R. tuberosa was more active than R. patula against all tested viruses, except for the HSV-2 virus, against which R. patula showed greater activity than R. tuberosa, with IC50 values of 20, 65, 22.59, and 13.13 µg/ml for R. tuberosa flowering aerial parts and 32.26, 11.66, and 23.03 µg/ml for R. patula flowering aerial parts, respectively for HAdV-40, herpes simplex type 2, and H1N1. Additionally, computational docking and molecular dynamics simulations were used to assess the molecular interactions between the bioactive compounds and specific viral targets. The combined findings from the in-vitro and in-silico experiments comprehensively evaluated the antiviral activities of both Ruellia species extracts.

Synergistic Effects of Icariin and Extracellular Vesicles Derived from Rabbit Synovial Membrane-Derived Mesenchymal Stem Cells on Osteochondral Repair via the Wnt/ß-Catenin Pathway.

Objectives: Osteochondral defects (OCDs) are localized areas of damaged cartilage and underlying subchondral bone that can produce pain and seriously impair joint function. Literature reports indicated that icariin (ICA) has the effect of promoting cartilage repair. However, its mechanism remains unclear. Here, we explored the effects of icariin and extracellular vesicles (EVs) from rabbit synovial-derived mesenchymal stem cells (rSMSCs) on repairing of OCDs. Materials and Methods: Rabbit primary genicular chondrocytes (rPGCs), knee skeletal muscle cells (rSMCKs), and rSMSCs, and extracellular vesicles derived from the latter two cells (rSMCK-EVs and rSMSC-EVs) were isolated and identified. The rPGCs were stimulated with ICA, rSMSC-EVs either separately or in combination. The rSMCK-EVs were used as a control. After stimulation, chondrogenic-related markers were analyzed by quantitative RT-PCR and western blotting. Cell proliferation was determined by the CCK-8 assay. The preventative effects of ICA and SMSC-EVs in vivo were determined by H&E and toluidine blue staining. Immunohistochemical analyses were performed to evaluate the levels of COL2A1 and ß-catenin in vivo. Results. In vitro, the proliferation of rPGCs was markedly increased by ICA treatment in a dose-dependent manner. When compared with ICA or rSMSC-EVs treatment alone, combined treatment with ICA and SMSC-EVs produced stronger stimulative effects on cell proliferation. Moreover, combined treatment with ICA and rSMSC-EVs promoted the expression of chondrogenic-related gene, including COL2A1, SOX-9, and RUNX2, which may be via the activation of the Wnt/ß-catenin pathway. In vivo, combined treatment with rSMSC-EVs and ICA promoted cartilage repair in joint bone defects. Results also showed that ICA or rSMSC-EVs both promoted the COL2A1 and ß-catenin protein accumulation in articular cartilage, and that was further enhanced by combined treatment with rSMSC-EVs and ICA. Conclusion: Our findings highlight the promising potential of using combined treatment with ICA and rSMSC-EVs for promoting osteochondral repair.

Activity and safety evaluation of natural preservatives.

Synthetic preservatives are widely used in the food industry to control spoilage and growth of pathogenic microorganisms, inhibit lipid oxidation processes and extend the shelf life of food. However, synthetic preservatives have some side effects that can lead to poisoning, cancer and other degenerative diseases. With the improvement of living standards, people are developing safer natural preservatives to replace synthetic preservatives, including plant derived preservatives (polyphenols, essential oils, flavonoids), animal derived preservatives (lysozyme, antimicrobial peptide, chitosan) and microorganism derived preservatives (nisin, natamycin, ε-polylysine, phage). These natural preservatives exert antibacterial effects by disrupting microbial cell wall/membrane structures, interfering with DNA/RNA replication and transcription, and affecting protein synthesis and metabolism. This review summarizes the natural bioactive compounds (polyphenols, flavonoids and terpenoids, etc.) in these preservatives, their antioxidant and antibacterial activities, and safety evaluation in various products.

Bioisosteric heterocyclic analogues of natural bioactive flavonoids by scaffold-hopping approaches: State-of-the-art and perspectives in medicinal chemistry.

The flavonoid family is a set of well-known bioactive natural molecules, with a wide range of potential therapeutic applications. Despite the promising results obtained in preliminary in vitro/vivo studies, their pharmacokinetic and pharmacodynamic profiles are severely compromised by chemical instability. To address this issue, the scaffold-hopping approach is a promising strategy for the structural optimization of natural leads to discover more potent analogues. In this scenario, this Perspective provides a critical analysis on how the replacement of the chromon-4-one flavonoid core with other bioisosteric nitrogen/sulphur heterocycles might affect the chemical, pharmaceutical and biological properties of the resulting new chemical entities. The investigated derivatives were classified on the basis of their biological activity and potential therapeutic indications. For each session, the target(s), the specific mechanism of action, if available, and the key pharmacophoric moieties were highlighted, as revealed by X-ray crystal structures and in silico structure-based studies. Biological activity data, in vitro/vivo studies, were examined: a particular focus was given on the improvements observed with the new heterocyclic analogues compared to the natural flavonoids. This overview of the scaffold-hopping advantages in flavonoid compounds is of great interest to the medicinal chemistry community to better exploit the vast potential of these natural molecules and to identify new bioactive molecules.

Comprehensive Bio-Screening of Phytochemistry and Biological Capacity of Oregano (Origanum vulgare) and Salvia triloba Extracts against Oral Cariogenic and Food-Origin Pathogenic Bacteria.

This study utilized phytochemical screening to conduct the qualitative analysis of plant extracts, aiming to identify various classes of secondary metabolites. Moreover, the antibacterial activity of different types of Oregano vulgare and Salvia triloba extracts was determined. To achieve the aim of this study, aqueous, ethanolic, and enzymatic extracts were prepared and screened for phytochemical capacity and antioxidant activities. The determination of the antibacterial activity included phenotypic screening of antibiotic susceptibility pattern of oral and food pathogenic bacterial strains, determination of the minimum inhibitory concentration and minimum bactericidal concentration-via microdilution broth test and in vitro valuation of antibacterial efficacies-of the anti-biofilm properties of the studied herbal extractions. Results: Our study evaluated the phytochemical composition and the antioxidant, antibacterial, and anti-biofilm properties of O. vulgare and S. triloba extracts. The analyzed samples contained bioactive compounds, such as phenolics and flavonoids, contributing to the observed strong antioxidant effect. Furthermore, they exhibited notable activity against oral biofilm formation and demonstrated significant antibacterial efficacy against dental caries' microorganisms as well as food pathogens. Despite methodological variations, all extracts showed significant antioxidant capacity and promising antibacterial activity against various pathogens, including resistant strains, while also inhibiting biofilm formation. Although limited to two plant species and facing methodological constraints, this study lays the groundwork for future research, indicating the therapeutic potential of O. vulgare and S. triloba extracts. Further exploration is needed to report on underlying mechanisms and validate efficacy through clinical trials.

Myricetin ameliorates the severity of pancreatitis in mice by regulating cathepsin B activity and inflammatory cytokine production.

Cathepsin B (CTSB) and inflammatory cytokines are critical in initiating and developing pancreatitis. Calcineurin, a central calcium (Ca2+)-responsive signaling molecule, mediates acinar cell death and inflammatory responses leading to pancreatitis. However, the detailed mechanisms for regulating CTSB activity and inflammatory cytokine production are unknown. Myricetin (MC) exhibits various biological activities, including anti-inflammatory effects. Here, we aimed to investigate MC effects on pancreatitis and the underlying mechanisms. Prophylactic and therapeutic MC treatment ameliorated the severity of cerulein-, L-arginine-, and PDL-induced acute pancreatitis (AP). The inhibition of CTSB activity by MC was mediated via decreased calcineurin activity and macrophage infiltration, not neutrophils infiltration, into the pancreas. Additionally, calcineurin activity inhibition by MC prevented the phosphorylation of Ca2+/CaM-dependent protein kinase kinase 2 (CaMKK2) during AP, resulting in the inhibition of CaMKIV phosphorylation and adenosine monophosphate-activated protein kinase (AMPK) dephosphorylation. Furthermore, MC reduced nuclear factor-κB activation by modulating the calcineurin-CaMKIV-IKKα/ß-Iκ-Bα and calcineurin-AMPK-sirtuin1 axes, resulting in reduced production of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6. Our results showed that MC alleviated AP severity by inhibiting acinar cell death and inflammatory responses, suggesting that MC as a calcineurin and CaMKK2 signaling modulator may be a potential treatment for AP.

Myricetin inhibits 4 T1 breast tumor growth in mice via induction of Nrf-2/GPX4 pathway-mediated Ferroptosis.

Ferroptosis is a recently identified form of programmed cell death that is iron-dependent and closely involved in the pathogenesis of breast cancer. Past studies have identified myricetin as being able to inhibit breast cancer growth through its targeting of apoptotic mechanisms, but the precise mechanisms whereby it exerts its antitumoral effects in breast cancer remain to be characterized in detail. Here, the effects of myricetin on the induction of ferroptosis in breast cancer cells were investigated. It was found that myricetin was able to significantly inhibit 4 T1 tumor cell viability and colony forming activity, increasing the level of MDA, Fe2+, and ROS within these cells. From a mechanistic perspective, myricetin was found to induce ferroptotic 4 T1 cell death via downregulating Nrf-2 and GPX4. In vivo experimentation demonstrated that myricetin treatment was sufficient to reduce the growth of subcutaneous breast tumors in female mice as evidenced by decreases in tumor weight and volume, while significantly inhibiting Nrf-2 and GPX4 expression within the tumors of treated mice. Myricetin is capable of readily suppressing breast tumor growth in mice via the induction of ferroptotic activity through the Nrf-2/GPX4 pathway. Myricetin may thus offer utility as a therapeutic agent for the management of breast cancer in clinical settings.

Investigation into the Phytochemical Composition, Antioxidant Properties, and In-Vitro Anti-Diabetic Efficacy of Ulva lactuca Extracts.

In this research, the chemical compositions of various extracts obtained from Ulva lactuca, a type of green seaweed collected from the Nador lagoon in the northern region of Morocco, were compared. Their antioxidant and anti-diabetic properties were also studied. Using GC-MS technology, the fatty acid content of the samples was analyzed, revealing that palmitic acid, eicosenoic acid, and linoleic acid were the most abundant unsaturated fatty acids present in all samples. The HPLC analysis indicated that sinapic acid, naringin, rutin, quercetin, cinnamic acid, salicylic acid, apigenin, flavone, and flavanone were the most prevalent phenolic compounds. The aqueous extract obtained by maceration showed high levels of polyphenols and flavonoids, with values of 379.67 ± 0.09 mg GAE/g and 212.11 ± 0.11 mg QE/g, respectively. This extract also exhibited an impressive ability to scavenge DPPH radicals, as indicated by its IC50 value of 0.095 ± 0.12 mg/mL. Additionally, the methanolic extract obtained using the Soxhlet method demonstrated antioxidant properties by preventing ß-carotene discoloration, with an IC50 of 0.087 ± 0.14 mg/mL. Results from in-vitro studies showed that extracts from U. lactuca were able to significantly inhibit the enzymatic activity of α-amylase and α-glucosidase. Among the various extracts, methanolic extract (S) has been identified as the most potent inhibitor, exhibiting a statistically similar effect to that of acarbose. Furthermore, molecular docking models were used to evaluate the interaction between the primary phytochemicals found in these extracts and the human pancreatic α-amylase and α-glucosidase enzymes. These findings suggest that U. lactuca extracts contain bioactive substances that are capable of reducing enzyme activity more effectively than the commercially available drug, acarbose.

Icaritin exhibits potential drug-drug interactions through the inhibition of human UDP-glucuronosyltransferase in vitro.

Icaritin is a prenylflavonoid derivative of the genus Epimedium (Berberidaceae) and has a variety of pharmacological actions. Icaritin is approved by the National Medical Products Administration as an anticancer drug that exhibits efficacy and safety advantages in patients with hepatocellular carcinoma cells. This study aimed to evaluate the inhibitory effects of icaritin on UDP-glucuronosyltransferase (UGT) isoforms. 4-Methylumbelliferone (4-MU) was employed as a probe drug for all the tested UGT isoforms using in vitro human liver microsomes (HLM). The inhibition potentials of UGT1A1 and 1A9 in HLM were further tested by employing 17ß-estradiol (E2) and propofol (PRO) as probe substrates, respectively. The results showed that icaritin inhibits UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A10, 2B7, and 2B15. Furthermore, icaritin exhibited a mixed inhibition of UGT1A1, 1A3, and 1A9, and the inhibition kinetic parameters (Ki) were calculated to be 3.538, 2.117, and 0.306 (µM), respectively. The inhibition of human liver microsomal UGT1A1 and 1A9 both followed mixed mechanism, with Ki values of 2.694 and 1.431 (µM). This study provides supporting information for understanding the drug-drug interaction (DDI) potential of the flavonoid icaritin and other UGT-metabolized drugs in clinical settings. In addition, the findings provide safety evidence for DDI when liver cancer patients receive a combination therapy including icaritin.

Unveiling the Antioxidative Potential of Galangin: Complete and Detailed Mechanistic Insights through Density Functional Theory Studies.

A comprehensive quantum mechanical investigation delved into the antioxidative activity of galangin (Glg). Thermochemical and kinetic data were used to assess antiradical, chelating, and renewal potential under physiological conditions. A brief comparison with reference antioxidants and other flavonoids characterized Glg as a moderate antioxidative agent. The substance showed significantly lower performance in lipid compared to aqueous solvent─the reaction rates for scavenging •OOH in both media were established at 3.77 × 103 M-1 s-1 and 6.21 × 104 M-1 s-1, respectively, accounting for the molar fraction of both interacting molecules at the given pH. The impact of pH value on the kinetics was assessed. Although efficient at chelating Cu(II) ions, the formed complexes can still undergo the Fenton reaction. On the other hand, they persistently scavenge •OH in statu nascendi. The flavonoid effectively repairs oxidatively damaged biomolecules except model lipid acids. All Glg radicals are readily restored by physiologically prevailing O2•-. Given this, the polyphenol is expected to participate in antiradical and regenerating activities multiple times, amplifying its antioxidative potential.

Myeloid Targeted Human MLL-ENL and MLL-AF9 Induces cdk9 and bcl2 Expression in Zebrafish Embryos.

Acute myeloid leukemia (AML) accounts for greater than twenty thousand new cases of leukemia annually in the United States. The average five-year survival rate is approximately 30%, pointing to the need for developing novel model systems for drug discovery. In particular, patients with chromosomal rearrangements in the mixed lineage leukemia (MLL) gene have higher relapse rates with poor outcomes. In this study we investigated the expression of human MLL-ENL and MLL-AF9 in the myeloid lineage of zebrafish embryos. We observed an expansion of MLL positive cells and determined these cells colocalized with the myeloid markers spi1b, mpx, and mpeg. In addition, expression of MLL-ENL and MLL-AF9 induced the expression of endogenous bcl2 and cdk9, genes that are often dysregulated in MLL-r-AML. Co-treatment of lyz: MLL-ENL or lyz:MLL-AF9 expressing embryos with the BCL2 inhibitor, Venetoclax, and the CDK9 inhibitor, Flavopiridol, significantly reduced the number of MLL positive cells compared to embryos treated with vehicle or either drug alone. In addition, cotreatment with Venetoclax and Flavopiridol significantly reduced the expression of endogenous mcl1a compared to vehicle, consistent with AML. This new model of MLL-r-AML provides a novel tool to understand the molecular mechanisms underlying disease progression and a platform for drug discovery.

Comparative study of antioxidant activities of Allium sativum (a novel variety, HG17) and Allium ampeloprasum (SMG): Revealing the higher potential of HG17 and analyzing its phytochemicals.

Garlic, belonging to the genus Allium, is renowned for its rich antioxidant potential. Snow Mountain garlic (SMG) (Allium ampeloprasum) has been traditionally used for medicinal purposes because of its higher antioxidant potential. Considering its potential in medical therapies, we compared the antioxidant activity of SMG with a novel variety of Allium sativum, Hisar garlic 17 (HG17). Comparative antioxidant activity data (2,2-diphenyl-1-picrylhydrazyl and 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) revealed the higher antioxidant activity of HG17 than SMG, which prompted us to conduct a comprehensive phytochemical investigation to elucidate the factors contributing to antioxidant potential of HG17. To get a detailed antioxidant and phytoconstituents profiling, we differentially extracted HG17 by processing it in different forms (fresh, dry, heated, and aged) with two solvents (50% methanol and n-butanol). Our data (antioxidant activities, total phenolics, and flavonoids) showed that dry garlic methanolic extract (DgM) had maximum potential than other HG17 forms/solvents, which concludes that different extraction techniques had direct impact on the phenolics/flavonoids and antioxidant potential of the extracts. Further, phytochemical analysis of HG17 extracts by high resolution liquid chromatograph mass spectrometer quadrupole time of flight validated the maximum potential of DgM. LCMS revealed the presence of garcimangosone C, osmanthuside A, and protoaphin aglucone polyphenols exclusively in DgM compared to other HG17 extracts, which possibly contributing in its high antioxidant potential. The overall differential extraction and LCMS data of HG17 strongly depict that it may be used as an alternative of SMG under diverse medical applications. HG17 higher antioxidant potential and rich array of unique phytochemicals make it valuable for food and pharmaceutical industries to integrate into functional foods/therapeutics. PRACTICAL APPLICATION: Garlic unique phytochemical composition and its remarkable ability to scavenge different radicals make it valuable therapeutic asset to mitigate diseases associated with oxidative stress. SMG is well known for its anti-arthritic and anti-inflammatory properties. HG17 showed higher antioxidant potential than SMG and can be used as an alternative of SMG for anti-arthritic properties.

Nutraceutical activities of Trigonella foenum-graecum and Nigella sativa seeds in the management of diabetes-induced in albino rats.

Diabetes causes elevated blood sugar levels, and it has been categorized as one of the most frequent causes of death worldwide. This work aimed to analyze and compare the nutraceutical and therapeutic efficacy of fenugreek seeds (FSs) (Trigonella foenum-graecum) and black cumin seeds (BCSs) (Nigella sativa) against streptozotocin-induced diabetes mellitus in albino rats. FS and BCSs were evaluated for proximate analysis, phytochemicals, and antioxidant activities. Male albino rats were used to evaluate the in vivo antidiabetic activities of these medicinal plants for 42 days. Blood samples were drawn at regular intervals of 1 week to analyze blood glucose, plasma insulin, and cholesterol levels and to determine the homeostatic model assessment of insulin resistance (HOMA IR) index. At the end of the trial, pancreas tissue was also collected for histological examination. Results of the proximate analysis showed the significant presence of moisture, ash, fat, protein, and fiber. Antioxidant parameters like 2,2-diphenyl-1-picrylhydrazyl, total phenolic content, and total flavonoid content were found to be significant. There was a significant (p < 0.05) decrease in blood glucose level, serum cholesterol level, and insulin resistance in treatment groups T3-T5. Insulin and body weight results of treatment groups were significant (p < 0.05) compared to streptozotocin-intoxicated animals. Histological examination revealed the nutraceutical impact of selected herbal plants due to enhancing impact on the size and the number of ß-cells in the pancreas. Findings of current research work explore the antidiabetic capacity of selected nutraceutical and medicinal plants.

Natural Prenylflavonoids from Sophora flavescens Root Bark against Multidrug-Resistant Methicillin-Sensitive Staphylococcus aureus Targeting the Membrane Permeability.

The overuse of antibiotics in animal farming and aquaculture has led to multidrug-resistant methicillin-sensitive Staphylococcus aureus (MR-MSSA) becoming a common pathogen in foodborne diseases. Sophora flavescens Ait. serves as a traditional plant antibacterial agent and functional food ingredient. A total of 30 compounds (1-30) were isolated from the root bark of S. flavescens, consisting of 20 new compounds (1-20). In the biological activity assay, compound 1 demonstrated a remarkable inhibitory effect on MR-MSSA, with an MIC of 2 µg/mL. Furthermore, 1 was found to rapidly eliminate bacteria, inhibit biofilm growth, and exhibit exceptionally low cytotoxicity. Mechanistic studies have revealed that 1 possesses an enhanced membrane-targeting ability, binding to the bacterial cell membrane components phosphatidylglycerol (PG), phosphatidylethanolamine (PE), and cardiolipin (CL). This disruption of bacterial cell membrane integrity increases intracellular reactive oxygen species, protein and DNA leakage, reduced bacterial metabolism, and ultimately bacterial death. In summary, these findings suggest that compound 1 holds promise as a lead compound against MR-MSSA.

Total flavonoids of Chrysanthemum indicum L inhibit colonic barrier injury induced by acute pancreatitis by affecting gut microorganisms.

BACKGROUND: Acute pancreatitis (AP) is a prevalent acute abdominal condition, and AP induced colonic barrier dysfunction is commonly observed. Total flavonoids of Chrysanthemum indicum L (TFC) have exhibited noteworthy anti-inflammatory and anti-apoptotic properties. METHODS: We established AP models, both in animals and cell cultures, employing Cerulein. 16S rRNA gene sequencing was performed to investigate the gut microorganisms changes. RESULTS: In vivo, TFC demonstrated a remarkable capacity to ameliorate AP, as indicated by the inhibition of serum amylase, myeloperoxidase (MPO) levels, and the reduction in pancreatic tissue water content. Furthermore, TFC effectively curtailed the heightened inflammatory response. The dysfunction of colonic barrier induced by AP was suppressed by TFC. At the in vitro level, TFC treatment resulted in attenuation of increased cell apoptosis, and regulation of apoptosis related proteins expression in AR42J cells. The increase of Bacteroides sartorial, Lactobacillus reuteri, Muribaculum intestinale, and Parabacteroides merdae by AP, and decrease of of Helicobacter rodentium, Pasteurellaceae bacterium, Streptococcus hyointestinalis by AP were both reversed by TFC treatment. CONCLUSIONS: TFC can effectively suppress AP progression and AP induced colonic barrier dysfunction by mitigating elevated serum amylase, MPO levels, water content in pancreatic tissue, as well as curtailing inflammation, apoptosis. The findings presented herein shed light on the potential mechanisms by which TFC inhibit the development of AP progression and AP induced colonic barrier dysfunction.

Kuwanon C inhibits proliferation and induction of apoptosis via the intrinsic pathway in MDA-MB231 and T47D breast cancer cells.

Breast cancer ranks as the most prevalent malignancy, presenting persistent therapeutic challenges encompassing issues such as drug resistance, recurrent occurrences, and metastatic progression. Therefore, there is a need for targeted drugs that are less toxic and more effective against breast cancer. Kuwanon C, an isoamylated flavonoid derived from mulberry resources, has shown promise as a potential candidate due to its strong cytotoxicity against cancer cells. The present study focused on investigating the anticancer activity of kuwanon C in two human breast cancer cell lines, MDA-MB231 and T47D cells. MTS assay results indicated a decrease in cell proliferation with increasing concentrations of kuwanon C. Furthermore, kuwanon C upregulated the expression levels of the cyclin-dependent kinase inhibitor p21 and effectively inhibited cell DNA replication and induced DNA damage. Flow cytometry confirmed that kuwanon C induced cell apoptosis and upregulated the expression levels of pro-apoptotic proteins (Bax and c-caspase3). Additionally, it stimulated the production of reactive oxygen species (ROS) in the cells. Transmission electron microscopy and Fluo-4 AM-calcium ion staining experiments provided insights into the endoplasmic reticulum (ER), revealing that kuwanon C induced ER stress. Kuwanon C upregulated the expression levels of unfolded protein response-related proteins (ATF4, GADD34, HSPA5, and DDIT3). Overall, the present findings suggested that kuwanon C exerts a potent inhibitory effect on breast cancer cell proliferation through modulating of the p21, induction of mitochondrial-mediated apoptosis, activation of ER stress and induction of DNA damage. These results position kuwanon C as a potential targeted therapeutic agent for breast cancer.

Prenylated Flavonoids in Sophora flavescens: A Systematic Review of Their Phytochemistry and Pharmacology.

Sophora flavescens has been widely used in traditional Chinese medicine for over 1700 years. This plant is known for its heat-clearing, damp-drying, insecticidal, and diuretic properties. Phytochemical research has identified prenylated flavonoids as a unique class of bioactive compounds in S. flavescens. Recent pharmacological studies reveal that the prenylated flavonoids from S. flavescens (PFS) exhibit potent antitumor, anti-inflammatory, and glycolipid metabolism-regulating activities, offering significant therapeutic benefits for various diseases. However, the pharmacokinetics and toxicological profiles of PFS have not been systematically studied. Despite the diverse biological effects of prenylated flavonoid compounds against similar diseases, their structure-activity relationship is not yet fully understood. This review aims to summarize the latest findings regarding the chemical composition, drug metabolism, pharmacological properties, toxicity, and structure-activity relationship of prenylated flavonoids from S. flavescens. It seeks to highlight their potential for clinical use and suggest directions for future related studies.

Preparation, Optimization, and Anti-Pulmonary Infection Activity of Casein-Based Chrysin Nanoparticles.

Introduction: Chrysin has a wide range of biological activities, but its poor bioavailability greatly limits its use. Here, we attempted to prepare casein (cas)-based nanoparticles to promote the biotransfer of chrysin, which demonstrated better bioavailability and anti-infection activity compared to free chrysin. Methods: Cas-based chrysin nanoparticles were prepared and characterized, and most of the preparation process was optimized. Then, the in vitro and in vivo release characteristics were studied, and anti-pulmonary infection activity was evaluated. Results: The constructed chrysin-cas nanoparticles exhibited nearly spherical morphology with particle size and ζ potential of 225.3 nm and -33 mV, respectively. These nanoparticles showed high encapsulation efficiency and drug-loading capacity of 79.84% ± 1.81% and 11.56% ± 0.28%, respectively. In vitro release studies highlighted a significant improvement in the release profile of the chrysin-cas nanoparticles (CCPs). In vivo experiments revealed that the relative oral bioavailability of CCPs was approximately 2.01 times higher than that of the free chrysin suspension. Further investigations indicated that CCPs effectively attenuated pulmonary infections caused by Acinetobacter baumannii by mitigating oxidative stress and reducing pro-inflammatory cytokines levels, and the efficacy was better than that of the free chrysin suspension. Conclusion: The findings underscore the advantageous bioavailability of CCPs and their protective effects against pulmonary infections. Such advancements position CCPs as a promising pharmaceutical agent and candidate for future therapeutic drug innovations.