Citrus supplementation in subjective cognitive decline: results of a 36-week, randomized, placebo-controlled trial.

BACKGROUND: Developing interventions for older adults with subjective cognitive decline (SCD) has the potential to prevent dementia in this at-risk group. Preclinical models indicate that Citrus-derived phytochemicals could benefit cognition and inflammatory processes, but results from clinical trials are still preliminary. The aim of this study is to determine the effects of long-term supplementation with Citrus peel extract on cognitive performance and inflammation in individuals with SCD. METHODS: Eighty participants were randomly assigned to active treatment (400 mg of Citrus peel extract containing 3.0 mg of naringenin and 0.1 mg of auraptene) or placebo at 1:1 ratio for 36 weeks. The primary endpoint was the change in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score across the 36-week trial period. Other cognitive outcomes included tests and scales evaluating verbal memory, attention, executive and visuospatial functions, and memory concerns. The secondary endpoint was the change of interleukin-8 (IL-8) levels over the 36-week trial period in a subsample of 60 consecutive participants. An Intention-to-treat approach with generalized linear mixed models was used for data analysis. RESULTS: The RBANS total score showed significant improvement in both Citrus peel extract and placebo groups at 36 weeks (p for time < .001, d = 0.36, p time x treatment = .910). Significant time effects were also found in cognitive domains of short- and long-term verbal memory (p < .001) and scales of subjective memory (p < .01), with no significant time x treatment interaction. The largest effect sizes were observed in verbal memory in the placebo group (d = 0.69 in short-term, and d = 0.78 in long-term verbal memory). Increased IL-8 levels were found at 36-week follow-up in both Citrus peel extract and placebo groups (p for time = .010, d = 0.21, p time x treatment = .772). Adverse events were balanced between groups. CONCLUSIONS: In this randomized clinical trial, long-term Citrus peel extract supplementation did not show cognitive benefits over placebo in participants with SCD, possibly due to high placebo response. These findings might have specific implications for designing future nutraceutical trials in individuals experiencing SCD. TRIAL REGISTRATION: The trial has been registered at the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 ( https://www. CLINICALTRIALS: gov/ct2/show/NCT04744922 ).

Three bioactive compounds from Huangqin decoction ameliorate Irinotecan-induced diarrhea via dual-targeting of Escherichia coli and bacterial ß-glucuronidase.

Irinotecan (CPT-11) is a commonly prescribed chemotherapeutic for the treatment of colon cancer. Unfortunately, acute and delayed diarrhea are prominent side effects of CPT-11 use, and this limits its therapeutic potential. The curative effect of Huangqin decoction (HQD) on chemotherapy-induced diarrhea has been proven. This study investigated the efficacy of the components of HQD (baicalein, baicalin, and paeoniflorin) on CPT-11-induced diarrhea and their underlying mechanisms. Baicalein was found to be the most effective component in improving CPT-11-induced enterotoxicity by intestinal permeability test, ELISA, fluorescence co-localization, and IHC. The combination of baicalin, baicalin and paeoniflorin can obtain similar therapeutic effect to that of HQD. Mendelian randomization analysis, 16 s rRNA sequencing, and fluorescence imaging revealed that baicalein and baicalin significantly inhibited ß-glucuronidase (ß-GUS) activity. Bacterial abundance analysis and scanning electron microscopy showed that baicalein inhibited the proliferation of Escherichia coli by destroying its cell wall. The molecular dynamics and site-directed mutagenesis results revealed the structural basis for the inhibition of ß-GUS by baicalein and baicalin. The results above provide a new idea for the development of drug therapy for adjuvant chemotherapy and theoretical guidance for the optimization of molecular structure targeting ß-GUS.

Cytotoxic Impact of Naringenin-Loaded Solid Lipid Nanoparticles on RIN5F Pancreatic ß Cells via Autophagy Blockage.

BACKGROUND: Autophagy plays a crucial role in modulating the proliferation of cancer diseases. However, the application of Naringenin (Nar), a compound with potential benefits against these diseases, has been limited due to its poor solubility and bioavailability. OBJECTIVE: This study aimed to develop solid lipid nanoparticles (Nar-SLNs) loaded with Nar to enhance their therapeutic impact. METHODS: In vitro experiments using Rin-5F cells exposed to Nar and Nar-SLNs were carried out to investigate the protective effects of Nar and its nanoformulation against the pancreatic cancer cell line of Rin-5F. RESULTS: Treatment with Nar and Nar-SLN led to an increase in autophagic markers (Akt, LC3, Beclin1, and ATG genes) and a decrease in the level of miR-21. Both Nar and Nar-SLN treatments inhibited cell proliferation and reduced the expression of autophagic markers. Notably, Nar-SLNs exhibited greater efficacy compared to free Nar. CONCLUSION: These findings suggest that SLNs effectively enhance the cytotoxic impact of Nar, making Nar-SLNs a promising candidate for suppressing or preventing Rin-5F cell growth.

Oral colon-targeted pH-responsive polymeric nanoparticles loading naringin for enhanced ulcerative colitis therapy.

An oral colon-targeted drug delivery system holds great potential in preventing systemic toxicity and preserving the therapeutic benefits of ulcerative colitis (UC) treatment. In this study, we developed a negatively charged PLGA-PEG nanoparticle system for encapsulating naringin (Nar). Additionally, chitosan and mannose were coated on the surface of these nanoparticles to enhance their mucosal adsorption and macrophage targeting abilities. The resulting nanoparticles, termed MC@Nar-NPs, exhibited excellent resistance against decomposition in the strong acidic gastrointestinal environment and specifically accumulated at inflammatory sites. Upon payload release, MC@Nar-NPs demonstrated remarkable efficacy in alleviating colon inflammation as evidenced by reduced levels of pro-inflammatory cytokines in both blood and colon tissues, as well as the scavenging of reactive oxygen species (ROS) in the colon. This oral nanoparticle delivery system represents a novel approach to treating UC by utilizing Chinese herbal ingredient-based oral delivery and provides a theoretical foundation for local and precise intervention in specific UC treatment.

Impact of polyethylene microplastics exposure on kallikrein-3 levels, steroidal-thyroidal hormones, and antioxidant status in murine model: protective potentials of naringin.

The widespread presence of microplastics in the environment has raised significant concerns regarding their potential impact on human and animal health. Among various microplastic types, polyethylene microplastics (PE-MPs) are particularly prevalent due to the extensive use in packaging and consumer products. Exploring the uncharted therapeutic potentials of naringin, this study delves into its mitigating effects on disruptions in kallikrein-3 levels, steroidal-thyroidal hormone balance, and antioxidant defense triggered by PE-MPs exposure, paving the way for novel interventions in environmental toxin-induced endocrine and oxidative stress disorders. Male Wistar rats (n = 24) were randomly grouped into four: Control, PE-MPs (1.5 mg/kg), PE-MPs + NAR (1.5 mg/kg PE-MPs + 100 mg/kg NAR), and NAR (100 mg/kg). Hormonal and antioxidant parameters were assessed after 28 days of exposure. PE-MPs exposure caused a significant increase(p < 0.005) in the level of kallikrein-3 (KLK-3) while it significantly reduces the levels of testosterone (TST), luteinizing hormone, thyroid stimulating hormone (TSH) and Free-triiodothyronine (fT3) and Total cholesterol (TChol) concentration. PE-MPs exposure also disrupted significantly (p < 0.005) antioxidant profile by down-regulating the activities of glutathione-S-transferase, catalase (CAT), superoxide dismutase (SOD) and reducing levels of glutathione (GSH) and ascorbic acid (AA) while concentration of malondialdehyde (MDA) levels were increased relative to control. However, the mitigating potentials of naringin on disruptions in hormonal and antioxidant profiles caused by PE-MPs exposure were demonstrated, as NAR normalized KLK-3, steroid, and thyroid hormone levels, cholesterol concentration, and enhanced antioxidant defense. This suggests that NAR is a promising protective agent against endocrine and oxidative damage induced by environmental contaminants such as microplastics.

Protective Effects of Baicalein on Lipopolysaccharide-Induced AR42J PACs through Attenuation of Both Inflammation and Pyroptosis via Downregulation of miR-224-5p/PARP1.

Background: Baicalein has been used to treat inflammation-related diseases; nevertheless, its specific mechanism of action is unclear. Therefore, we examined the protective effects of baicalein on lipopolysaccharide-induced damage to AR42J pancreatic acinar cells (PACs) and determined its mechanism of action for protection. Methods: An in vitro cell model of acute pancreatitis (AP) was established using lipopolysaccharide (LPS) (1 mg/L)-induced PACs (AR42J), and the relative survival rate was determined using the 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) technique. Flow cytometry was applied to evaluate the apoptotic rates of AR42J PACs. The RNA and protein expression of miR-224-5p, poly ADP-ribose polymerase-1 (PARP1), nuclear transcription factor-κB65 (NF-κB65), phospho-kappa B alpha(p-IκB-α), interleukin(IL)-18R, NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), gasdermin D (GSDMD), apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1 was detected based on the WB and RT-PCR assays. IL-1ß, IL-6, IL-18, and TNF-α expression levels in AR42J cells were measured via ELISA method. The cell morphology was examined using the AO/EB method. Results: The experiment confirmed a significant increase in the activity of AR42J cells treated with various doses of baicalein. Moreover, IL-1ß, IL-6, TNF-α, and IL-18 expression levels in AR42J cells were dramatically reduced (P < 0.05), while miR-224-5p level was obviously enhanced. The protein and gene expression of PARP1, NF-κB65, p-IκB-α, IL-18R, GSDMD, ASC, NLRP3, and caspase-1 was obviously decreased (P < 0.05). Apoptosis in AR42J cells was significantly reduced with significant improvement in cell morphology. Conclusion: Baicalein may significantly alleviate LPS-induced AR42J PAC damage by inhibiting the inflammatory response and pyroptosis. Its mode of action might be linked to higher miR-224-5p expression, which inhibits the PARP1/NF-κB and NLPR3/ASC/caspase-1/GSDMD pathways.

A novel (-)-(2S)-7,4'-dihydroxyflavanone compound for treating age-related diabetes mellitus through immunoinformatics-guided activation of CISD3.

The iron-sulfur domain (CISD) proteins of CDGSH are classified into three classes: CISD1, CISD2, and CISD3. During premature ageing, mutations that affect these proteins, namely their binding sites, could result in reduced protein production and an inability to preserve cellular integrity. Consequently, this leads to the development of conditions such as diabetes. Notably, CISD3 plays a crucial role in the management of age-related disorders such as Wolfram syndrome, which is often referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Computational analyses have predicted that CISD3 regulates the redox state, safeguards the endoplasmic reticulum and mitochondria, and maintains intracellular calcium levels. CISD3, a member of a recently discovered gene family associated with the CDGSH iron protein apoptotic compensatory response, fulfils a crucial function in mitigating the effects of accelerated ageing. The compound "(-)-(2S)-7,4'-Dihydroxyflavanone" has been discovered by computational drug design as a possible activator of CISD3. It shows potential therapeutic benefits in ameliorating metabolic dysfunction and enhancing glucose regulation. The ligand binds to the binding pocket of the CISD3 protein, increasing the stability of the protein and enhancing its functionality. The current research investigates the binding processes of the molecule in various structures and its anticipated effects on these tissues, therefore providing valuable insights into the mitigation of age-related diabetes and metabolic dysfunction. The projected tripling of the worldwide population of individuals aged 50 and above by 2050 necessitates the urgent development of immunoinformatics-based approaches, including pharmaceutical therapies that target CISD3, to prevent age-related pathologies. The stimulation of CISD3, namely by compounds such as "(-)-(2S)-7,4'-Dihydroxyflavanone", has the potential to counteract telomere shortening and improve metabolic pathways.

Efficacy and Potential Mechanisms of Naringin in Atopic Dermatitis.

Atopic dermatitis (AD) is one of the most prevalent chronic inflammatory skin diseases. Topical treatments are recommended for all patients regardless of severity, making it essential to develop an effective topical AD treatment with minimal side effects; We investigated the efficacy of topical application of naringin in AD and explored the possible mechanisms using an AD mouse model induced by 1-chloro-2,4-dinitrobenzene (DNCB). Clinical, histological, and immunological changes related to AD and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling proteins in the skin tissues were measured as outcomes; Naringin treatment resulted in a significant improvement in dermatitis severity score and reduced epidermal thickness and mast cell count in the skin (p < 0.05). Naringin also demonstrated the ability to inhibit DNCB-induced changes in interleukin (IL) 4, chemokine (C-C motif) ligand (CCL) 17, CCL22, IL1ß, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) levels by quantitative real-time polymerase chain reaction (qRT-PCR) and IL13 by enzyme-linked immunosorbent assay (ELISA) (p < 0.05). Western blot results exhibited the decreased JAK1, JAK2, STAT1, STAT3, phospho-STAT3, and STAT6 expression in the naringin-treated groups (p < 0.05); The findings of this study suggest that topical naringin may effectively improve the symptoms of AD and could be used as a therapeutic agent for AD.

Combining network pharmacology, machine learning, molecular docking and molecular dynamic to explore the mechanism of Chufeng Qingpi decoction in treating schistosomiasis.

Background: Although the Chufeng Qingpi Decoction (CQD) has demonstrated clinical effectiveness in the treatment of schistosomiasis, the precise active components and the underlying mechanisms of its therapeutic action remain elusive. To achieve a profound comprehension, we incorporate network pharmacology, bioinformatics analysis, molecular docking, and molecular dynamics simulations as investigative methodologies within our research framework. Method: Utilizing TCMSP and UniProt, we identified formula components and targets. Cytoscape 3.10.0 was used to construct an herb-target interaction network. Genecards, DisGeNET, and OMIM databases were examined for disease-related objectives. A Venn diagram identified the intersection of compound and disease targets. Using Draw Venn, overlapping targets populated STRING for PPI network. CytoNCA identified schistosomiasis treatment targets. GO & KEGG enrichment analysis followed High-scoring genes in PPI were analyzed by LASSO, RF, SVM-RFE. Molecular docking & simulations investigated target-compound interactions. Result: The component's target network encompassed 379 nodes, 1629 edges, highlighting compounds such as wogonin, kaempferol, luteolin, and quercetin. Amongst the proteins within the PPI network, PTGS2, TNF, TGFB1, BCL2, TP53, IL10, JUN, MMP2, IL1B, and MYC stood out as the most prevalent entities. GO and KEGG revealed that mainly involved the responses to UV, positive regulation of cell migration and motility. The signal pathways encompassed Pathways in cancer, Lipid and atherosclerosis, Fluid shear stress and atherosclerosis, as well as the AGE-RAGE. Bioinformatics analysis indicated TP53 was the core gene. Ultimately, the molecular docking revealed that wogonin, kaempferol, luteolin, and quercetin each exhibited significant affinity in their respective interactions with TP53. Notably, kaempferol exhibited the lowest binding energy, indicating a highly stable interaction with TP53. Lastly, we validated the stability of the binding interaction between the four small molecules and the TP53 through molecular dynamics simulations. The molecular dynamics simulation further validated the strongest binding between TP53 and kaempferol. In essence, our research groundbreaking in its nature elucidates for the first time the underlying molecular mechanism of CQD in the therapeutic management of schistosomiasis, thereby providing valuable insights and guidance for the treatment of this disease. Conclusion: This study uncovered the efficacious components and underlying molecular mechanisms of the Chufeng Qingpi Decoction in the management of schistosomiasis, thereby offering valuable insights for future fundamental research endeavors.

Forward-reverse mutation cycles in cancer cell lines under chemical treatments.

Spontaneous forward-reverse mutations were reported by us earlier in clinical samples from various types of cancers and in HeLa cells under normal culture conditions. To investigate the effects of chemical stimulations on such mutation cycles, the present study examined single nucleotide variations (SNVs) and copy number variations (CNVs) in HeLa and A549 cells exposed to wogonin-containing or acidic medium. In wogonin, both cell lines showed a mutation cycle during days 16-18. In acidic medium, both cell lines displayed multiple mutation cycles of different magnitudes. Genomic feature colocalization analysis suggests that CNVs tend to occur in expanded and unstable regions, and near promoters, histones, and non-coding transcription sites. Moreover, phenotypic variations in cell morphology occurred during the forward-reverse mutation cycles under both types of chemical treatments. In conclusion, chemical stresses imposed by wogonin or acidity promoted cyclic forward-reverse mutations in both HeLa and A549 cells to different extents.

Naringenin Nanocrystals Mitigate Rotenone Neurotoxicity in SH-SY5Y Cell Line by Modulating Mitophagy and Oxidative Stress.

Naringenin, a potent antioxidant with anti-apoptotic effects, holds potential in counteracting rotenone-induced neurotoxicity, a model for Parkinson's disease, by reducing oxidative stress and supporting mitochondrial function. Rotenone disrupts ATP production in SH-SY5Y cells through mitochondrial complex-I inhibition, leading to increased reactive oxygen species (ROS) and cellular damage. However, the therapeutic use of naringenin is limited by its poor solubility, low bioavailability, and stability concerns. Nano crystallization of naringenin (NCs), significantly improved its solubility, dissolution rates, and stability for targeted drug delivery. The developed NAR-NC and HSA-NAR-NC formulations exhibit particle sizes of 95.23 nm and 147.89 nm, with zeta potentials of -20.6 mV and -28.5 mV, respectively. These nanocrystals also maintain high drug content and show stability over time, confirming their pharmaceutical viability. In studies using the SH-SY5Y cell line, these modified nanocrystals effectively preserved mitochondrial membrane potential, sustained ATP production, and regulated ROS levels, counteracting the neurotoxic effects of rotenone. Naringenin nanocrystals offer a promising solution for improving the stability and bioavailability of naringenin, with potential therapeutic applications in neurodegenerative diseases.

Baicalein Inhibits Cerebral Ischemia-Reperfusion Injury through SIRT6-Mediated FOXA2 Deacetylation to Promote SLC7A11 Expression.

Ischemic stroke (IS) poses a serious threat to patient survival. The inhibition of ferroptosis can effectively alleviate ischemia-reperfusion (I/R) injury, suggesting potential targets in the ferroptosis pathway for the treatment of IS. In this study, MCAO/R mice and OGD/R-induced HT22 cell were constructed. It was found that baicalein decreased ROS, MDA, and Fe2+ levels, upregulated GSH levels, and enhanced the expression of ferroptosis-related proteins (GPX4 and SLC7A11), downregulated the expression of proapoptotic proteins (Bax, cytochrome c, and cleaved caspase-3), and upregulated the expression of an antiapoptotic protein (Bcl-2), ameliorating cerebral I/R injury. In animal and cell models, Sirtuin6 (SIRT6) is downregulated, and Forkhead boxA2 (FOXA2) expression and acetylation levels are abnormally upregulated. SIRT6 inhibited FOXA2 expression and acetylation. Baicalein promoted FOXA2 deacetylation by upregulating SIRT6 expression. FOXA2 transcriptionally inhibits SLC7A11 expression. In conclusion, baicalein inhibited apoptosis and partially suppressed the role of ferroptosis to alleviate cerebral I/R injury via SIRT6-mediated FOXA2 deacetylation to promote SLC7A11 expression.

Naringin and Naringenin: Potential Multi-Target Agents for Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common forms of neurodegenerative dementia. The etiology of AD is multifactorial, and its complex pathophysiology involves tau and amyloid-ß deposition, increased oxidative stress, neuroinflammation, metabolic disorders, and massive neuronal loss. Due to its complex pathology, no effective cure for AD has been found to date. Therefore, there is an unmet clinical need for the development of new drugs against AD. Natural products are known to be good sources of compounds with pharmacological activity and have potential for the development of new therapeutic agents. Naringin, a naturally occurring flavanone glycoside, is predominantly found in citrus fruits and Chinese medicinal herbs. Mounting evidence shows that naringin and its aglycone, naringenin, have direct neuroprotective effects on AD, such as anti-amyloidogenic, antioxidant, anti-acetylcholinesterase, and anti-neuroinflammatory effects, as well as metal chelation. Furthermore, they are known to improve disordered glucose/lipid metabolism, which is a high risk factor for AD. In this review, we summarize the latest data on the impact of naringin and naringenin on the molecular mechanisms involved in AD pathophysiology. Additionally, we provide an overview of the current clinical applications of naringin and naringenin. The novel delivery systems for naringin and naringenin, which can address their widespread pharmacokinetic limitations, are also discussed. The literature indicates that naringin and naringenin could be multilevel, multitargeted, and multifaceted for preventing and treating AD.

Antimicrobial efficiency and cytocompatibility of resveratrol and naringin as chemical decontaminants on SLA surface.

Bacterial biofilms are the major etiology agent of peri-implant disease. Chemical decontamination is a promising treatment strategy against bacterial biofilms; however, its applications are limited by its low efficiency and poor biocompatibility. In contrast to three conventional cleaners (sterile saline, hydrogen peroxide, and chlorhexidine), this study used resveratrol and naringin solutions to remove mature Staphylococcus aureus and Porphyromonas gingivalis biofilm on sandblasted (with large grit and acid-etched (SLA) titanium surface. To determine changes in surface characteristics, the surface wettability and roughness were measured, and micromorphology was observed by scanning electron microscopy. With crystal violet (CV) and live/dead bacterial staining, residual plaque quantity and composition were measured. The biocompatibility was tested using pH and cytotoxicity, as well as by osteoblasts (MC3T3-E1) adhesion, proliferation, and differentiation, and fibroblasts (L-929) proliferation were also analyzed. It was found that resveratrol and naringin solutions were more effective in restoring surface characteristics and also showed that less plaque and viable bacteria were left. Naringin removed S. aureus biofilms better than chlorhexidine. Alkaline resveratrol and naringin solutions increased cell adhesion, proliferation, and osteogenic differentiation without any cytotoxicity. Resveratrol increased the expression of mRNA and protein associated with osteogenesis. In conclusion, resveratrol and naringin effectively restored SLA titanium surface characteristics and decontaminated the biofilm with good biocompatibility, suggesting their therapeutic potential as chemical decontaminants. IMPORTANCE: Bacterial biofilms are considered the primary etiology of peri-implant disease. Physical cleaning is the most common way to remove bacterial biofilm, but it can cause grooving, melting, and deposition of chemicals that alter the surface of implants, which may hamper biocompatibility and re-osseointegration. Chemical decontamination is one of the most promising treatments but is limited by low efficiency and poor biocompatibility. Our study aims to develop safer, more effective chemical decontaminants for peri-implant disease prevention and treatment. We focus on resveratrol and naringin, two natural compounds, which have shown to be more effective in decontaminating biofilms on dental implant surfaces and exerting better biocompatibility. This research is groundbreaking as it is the first exploration of natural plant extracts' impact on mature bacterial biofilms on rough titanium surfaces. By advancing this knowledge, we seek to contribute to more effective and biocompatible strategies for combating peri-implant diseases, enhancing oral health, and prolonging implant lifespan.

The natural flavonoid pinocembrin shows antithrombotic activity and suppresses septic thrombosis.

Sepsis, an extreme host response to systemic infection, remains one of the leading causes of mortality worldwide. Platelets, which are integral to both thrombosis and inflammation, play a crucial role in the pathophysiology of sepsis. Excessive platelet activation and aggregation significantly increase the risk of thrombosis, thereby elevating mortality in septic patients. However, the etiology and treatment of this condition have not been comprehensively studied. This study identifies pinocembrin, a natural flavonoid compound derived from propolis, as a potential therapeutic agent for mitigating platelet activation and treating sepsis. In vivo, pinocembrin effectively inhibited FeCl3-induced carotid arterial occlusive thrombus formation and collagen/epinephrine-induced pulmonary thromboembolism in mouse models. In vitro, pinocembrin treatment suppressed multiple facets of platelet activation, including aggregation, secretion, and αIIbß3-mediated signaling events. Mechanistically, pinocembrin repressed platelet functions by inhibiting Src/Syk/PLCγ2/MAPK signaling pathway. Using cecal ligation and puncture (CLP) mouse model to simulate human sepsis, pinocembrin reduced inflammatory cytokine release and septic thrombosis, thereby improving the survival rate of septic mice. Lipopolysaccharide (LPS)-induced model further substantiated these results. Overall, the inhibition of platelet activity by pinocembrin demonstrates significant therapeutic potential for managing life-threatening septic thrombosis.

Baicalein induces apoptosis by targeting ribosomes in Candida auris.

The emergence of the "super fungus" Candida auris poses a significant threat to human health, given its multidrug resistance and high mortality rates. Therefore, developing a new antifungal strategy is necessary. Our previous research showed that Baicalein (BE), a key bioactive compound from the dried root of the perennial herb Scutellaria baicalensis Georgi, has strong fungistatic properties against C. auris. Nevertheless, the antifungal activity of BE against C. auris and its mechanism of action requires further investigation. In this study, we explored how BE affects this fungus using various techniques, including scanning electron microscopy (SEM), Annexin V-FITC apoptosis detection, CaspACE FITC-VAD-FMK In Situ Marker, reactive oxygen species (ROS) assay, singlet oxygen sensor green (SOSG) fluorescent probe, enhanced mitochondrial membrane potential (MMP) assay with JC-1, DAPI staining, TUNEL assay and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Our findings revealed that BE induced several apoptotic features, including phosphatidylserine (PS) externalization, metacaspase activation, nuclear condensation and DNA fragmentation. BE also increased intracellular ROS levels and altered mitochondrial functions. Additionally, transcriptomic analysis and RT-qPCR validation indicated that BE may induce apoptosis in C. auris by affecting ribosome-related pathways, suggesting that ribosomes could be new targets for antifungal agents, in addition to cell walls, membranes, and DNA. This study emphasizes the antifungal activity and mechanism of BE against C. auris, offering a promising treatment strategy for C. auris infection.

Enantiomeric separation of flavanone on Chiralpak® IA column and determination of the chiral mechanism.

Thirteen flavanone racemates were successfully separated using a Chiralpak® IA column and isopropanol-hexane (50:50, v/v). The mobile phase flow rate and detection wavelength were 0.5 mL/min and 254 nm. The retention times values ranged from 5.50 and 56.45 min. The values of the retention, separation, and resolution factors ranged from 0.63 to 21.67, 1.12 to 2.45, and 0.13 to 11.94. The docking binding energies ranged from -6.2 to -8.2 kcal/mol, showing enthalpy-determined host-guest complex formation. The molecular docking results and the experimental data were agreed well. The results showed that S-enantiomers had stronger bindings with chiral selectors compared to R-enantiomers. Consequently, the R-enantiomers eluted first followed by S-enantiomers. The reported method is highly useful to determine the enantiomeric composition of the reported flavanone in any sample.

The Effect of the Extraction Conditions on the Antioxidant Activity and Bioactive Compounds Content in Ethanolic Extracts of Scutellaria baicalensis Root.

Ethanolic extracts of Baikal skullcap (Scutellaria baicalensis) root were obtained using various techniques, such as maceration, maceration with shaking, ultrasound-assisted extraction, reflux extraction, and Soxhlet extraction. The influence of the type and time of isolation technique on the extraction process was studied, and the quality of the obtained extracts was determined by spectrophotometric and chromatographic methods to find the optimal extraction conditions. Radical scavenging activity of the extracts was analyzed using DPPH assay, while total phenolic content (TPC) was analyzed by the method with the Folin-Ciocalteu reagent. Application of gas chromatography with mass selective detector (GC-MS) enabled the identification of some bioactive substances and a comparison of the composition of the particular extracts. The Baikal skullcap root extracts characterized by both the highest antioxidant activity and content of phenolic compounds were obtained in 2 h of reflux and Soxhlet extraction. The main biologically active compounds identified in extracts by the GC-MS method were wogonin and oroxylin A, known for their broad spectrum of biological effects, including antioxidant, anti-inflammatory, antiviral, anticancer, and others.

Uncovering naringin's anticancer mechanisms in glioblastoma via molecular docking and network pharmacology approaches.

Naringin, a flavonoid, exhibits diverse therapeutic properties and has been proven to exert cytotoxic effects on cancer cells. Nevertheless, the precise mechanism of naringin maintaining its cytotoxic effect on glioblastoma (GBM) remains unknown. Thus, the current study aimed to establish a plausible cellular mechanism for Naringin's inhibition of GBM. We employed various system biology techniques to forecast the primary targets, including gene ontology and cluster analysis, KEGG enrichment pathway estimation, molecular docking, MD (molecular dynamic) simulation and MMPBSA analysis. Glioblastoma target sequences were obtained via DisGeNet and Therapeutic Target Prediction, aligned with naringin targets, and analyzed for gene enrichment and ontology. Gene enrichment analysis identified the top ten hub genes. Further, molecular docking was conducted on all identified targets. For molecular dynamics modelling, we selected the two complexes that exhibited the most docking affinity and the two most prominent genes of the hub identified through analysis of the enrichment of genes. The PARP1 and ALB1 signalling pathways were found to be the main regulated routes. Naringin exhibited the highest binding potential of - 12.90 kcal/mol with PARP1 (4ZZZ), followed by ABL1 (2ABL), with naringin showing a - 8.4 kcal/mol binding score, as determined by molecular docking. The molecular dynamic approach and MM-PBSA investigation along with PCA study revealed that the complex of Naringin, with 4ZZZ (PARP1) and, 2ABL (ABL1), are highly stable compared to that of imatinib and talazoparib. Analyses of the signalling pathway suggested that naringin may have anticancer effects against GBM by influencing the protein PARP and ALB1 levels. Cytotoxicity assay was performed on two different glioblastoma cell lines C6 and U87MG cells. Naringin demonstrates a higher cytotoxic potency against U87MG human glioblastoma cells compared to C6 rat glioma cells.

LW-213, a derivative of wogonin, triggers reticulophagy-mediated cell death in NSCLC via lysosomal damage combined with NPC1 inhibition.

BACKGROUND: Maintaining intracellular equilibrium is essential for the viability of tumor cells, which tend to be particularly vulnerable to environmental stressors. Consequently, targeting the disruption of this homeostasis offers a promising approach for oncological treatments. LW-213, a novel derivative of wogonin, effectively induces apoptosis in cancer cells by initiating endoplasmic reticulum (ER) stress, although the precise molecular pathways involved remain intricate and multifaceted. PURPOSE: This research aimed to explore how LW-213 prompts apoptosis in non-small cell lung cancer (NSCLC) cells and to clarify the detailed mechanisms that govern this process. METHODS: Various NSCLC cell lines were utilized to delineate the apoptotic effects induced by LW-213. Advanced methodologies, including RNA sequencing (RNA-seq), Western blotting (WB), immunofluorescence (IF), immunoprecipitation (IP), flow cytometry (Fc), real-time quantitative polymerase chain reaction (RT-qPCR), and electron microscopy, were employed to investigate the underlying molecular interactions. The efficacy and mechanistic action of LW-213 were also assessed in a xenograft model using nude mice. RESULTS: We demonstrated that LW-213, a small molecule cationic amphiphilic drug (CAD), inhibited Niemann-Pick C1 (NPC1) function and induced lysosomal membrane damage, thereby activating the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway. This activation promoted cholesterol transport from the ER to the lysosome, perpetuating a cholesterol-deficient state in the ER, including massive exocytosis of Ca2+ and activation of FAM134B-mediated reticulophagy. Ultimately, excessive reticulophagy induced lethal ER stress. CONCLUSIONS: In summary, our study elucidates an organelle domino reaction initiated by lysosome damage and a series of self-rescue mechanisms that eventually lead to irreversible lethal effects, revealing a potential drug intervention strategy.