Licochalcone A: A Potential Multitarget Drug for Alzheimer's Disease Treatment.

Licochalcone A (Lico-A) is a flavonoid compound derived from the root of the Glycyrrhiza species, a plant commonly used in traditional Chinese medicine. While the Glycyrrhiza species has shown promise in treating various diseases such as cancer, obesity, and skin diseases due to its active compounds, the investigation of Licochalcone A's effects on the central nervous system and its potential application in Alzheimer's disease (AD) treatment have garnered significant interest. Studies have reported the neuroprotective effects of Lico-A, suggesting its potential as a multitarget compound. Lico-A acts as a PTP1B inhibitor, enhancing cognitive activity through the BDNF-TrkB pathway and exhibiting inhibitory effects on microglia activation, which enables mitigation of neuroinflammation. Moreover, Lico-A inhibits c-Jun N-terminal kinase 1, a key enzyme involved in tau phosphorylation, and modulates the brain insulin receptor, which plays a role in cognitive processes. Lico-A also acts as an acetylcholinesterase inhibitor, leading to increased levels of the neurotransmitter acetylcholine (Ach) in the brain. This mechanism enhances cognitive capacity in individuals with AD. Finally, Lico-A has shown the ability to reduce amyloid plaques, a hallmark of AD, and exhibits antioxidant properties by activating the nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant defense mechanisms. In the present review, we discuss the available findings analyzing the potential of Lico-A as a neuroprotective agent. Continued research on Lico-A holds promise for the development of novel treatments for cognitive disorders and neurodegenerative diseases, including AD. Further investigations into its multitarget action and elucidation of underlying mechanisms will contribute to our understanding of its therapeutic potential.

Effect of geranylated dihydrochalcone from Artocarpus altilis leaves extract on Plasmodium falciparum ultrastructural changes and mitochondrial malate: Quinone oxidoreductase.

Nearly half of the world's population is at risk of being infected by Plasmodium falciparum, the pathogen of malaria. Increasing resistance to common antimalarial drugs has encouraged investigations to find compounds with different scaffolds. Extracts of Artocarpus altilis leaves have previously been reported to exhibit in vitro antimalarial activity against P. falciparum and in vivo activity against P. berghei. Despite these initial promising results, the active compound from A. altilis is yet to be identified. Here, we have identified 2-geranyl-2', 4', 3, 4-tetrahydroxy-dihydrochalcone (1) from A. altilis leaves as the active constituent of its antimalarial activity. Since natural chalcones have been reported to inhibit food vacuole and mitochondrial electron transport chain (ETC), the morphological changes in food vacuole and biochemical inhibition of ETC enzymes of (1) were investigated. In the presence of (1), intraerythrocytic asexual development was impaired, and according to the TEM analysis, this clearly affected the ultrastructure of food vacuoles. Amongst the ETC enzymes, (1) inhibited the mitochondrial malate: quinone oxidoreductase (PfMQO), and no inhibition could be observed on dihydroorotate dehydrogenase (DHODH) as well as bc1 complex activities. Our study suggests that (1) has a dual mechanism of action affecting the food vacuole and inhibition of PfMQO-related pathways in mitochondria.

Oncopreventive and Oncotherapeutic Potential of Licorice Chalcone Compounds: Molecular Insights.

BACKGROUND: Licorice is an important traditional Chinese medicine commonly used in clinical practice and contains more than 300 flavonoids. Chalcone is one of the main types of flavonoids with a wide range of biological functions and pharmacological activities. In the anticancer research, chalcone compounds have shown excellent performance. OBJECTIVE: This review aims to summarize the biosynthetic pathway and pharmacokinetics of chalcone from licorice and provide evidence for the anticancer effects of chalcone and the underlying mechanisms involved. METHODS: For this review, the following databases were consulted: the PubMed Database (https://pubmed.ncbi.nlm.nih.gov), Chinese National Knowledge Infrastructure (http:// www.cnki.net), National Science and Technology Library (http://www.nstl.gov.cn/), Wanfang Data (http://www.wanfangdata.com.cn/), and the Web of Science Database (http:// apps.webofknowledge.com/). RESULTS: To date, about 56 chalcones have been isolated and identified from licorice, 14 of which have antitumor effects. These chalcones have a wide range of biological activities and can inhibit the viability, proliferation, and migration of cancer cells by blocking the cancer cell cycle, thus inducing apoptosis and autophagy. However, the molecular mechanism of the anticancer effects of chalcone is not fully understood. CONCLUSION: In this paper, the molecular mechanism of chalcone regulating different types of cancer is reviewed in detail from the biosynthetic pathway. This comprehensive review article summarizes the biosynthetic pathway and pharmacokinetics of chalcone from the traditional Chinese medicine licorice and provides evidence for the potential anticancer effects of chalcone and the respective mechanisms of action. This paper also provides a basis for structural modification, biosynthesis, and new drug development of chalcone compounds in Glycyrrhiza uralensis.

[Preventive and therapeutic effect of bioactive component of licorice on antidepressant-induced liver injury].

Since exploding rates of modern mental diseases, application of antidepressants has increased. Worryingly, the antidepressant-induced liver injury has gradually become a serious health burden. Furthermore, since most of the knowledge about antidepressant hepatotoxicity are from pharmacovigilance and clinical case reports and lack of observational studies, the underlying mechanisms are poorly understood and there is a lack of efficient treatment strategies. In this study, antidepressant paroxetine directly triggered inflammasome activation evidenced by caspase-1 activation and downstream effector cytokines interleukin(IL)-1ß secretion. The pretreatment of echinatin, a bioactive component of licorice, completely blocked the activation. This study also found that echinatin effectively inhibited the production of inflammasome-independent tumor necrosis factor α(TNF)-α induced by paroxetine. Mechanistically, the accumulation of mitochondrial reactive oxygen species(mtROS) was a key upstream event of paroxetine-induced inflammasome activation, which was dramatically inhibited by echinatin. In the lipopolysaccharide(LPS)-mediated idiosyncratic drug-induced liver injury(IDILI) model, the combination of LPS and paroxetine triggered aberrant activation of the inflammasome to induce idiosyncratic hepatotoxicity, which was reversed by echinatin pretreatment. Notably, this study also found that various bioactive components of licorice had an inhibitory effect on paroxetine-triggered inflammasome activation. Meanwhile, multiple antidepressant-induced aberrant activation of the inflammasome could be completely blocked by echinatin pretreatment. In conclusion, this study provides a novel insight for mechanism of antidepressant-induced liver injury and a new strategy for the treatment of antidepressant-induced hepatotoxicity.

Dimethyl Cardamonin from Fruits of Campomanesia reitziana D. Legrand Promotes Gastroprotection and Gastric Healing Effects in Rodents.

Campomanesia reitziana D. Legrand (Myrtaceae) displays antiulcer properties when given to rodents. The major active chemical components of C. reitziana are chalcones, including 4',6'-dihydroxy-2'-methoxy-3',5'-dimethylchalcone or dimethyl cardamonin (DMC); therefore, we hypothesized that this compound could have antiulcer effects and the present study aimed to evaluate its gastroprotective and gastric healing properties. DMC was isolated from the fruits of C. reitziana, and its gastroprotective effect was evaluated by ethanol and indomethacin-induced gastric ulcer models in mice (0.1 mg/kg, i.p. and 1 and 3 mg/kg, p.o.). Oxidative stress and inflammatory parameters were analyzed in the gastric tissue. Moreover, its gastric healing effect was evaluated in rats. In addition, the compound's mode of action was evaluated in vivo and in vitro by measuring H+ -K+ -ATPase activity. Finally, the cytotoxic potential of DMC was tested in fibroblasts and human gastric adenocarcinoma cells. The DMC reduced the ethanol-induced gastric ulcer in mice by 77 %, increased the adhered mucus, and reduced lipoperoxides levels. The block of nonprotein sulfhydryls (NP-SH) compounds by pretreatment with N-ethylmaleimide (NEM), the inhibition of nitric oxide synthase with Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), or the antagonism of α2 receptor using yohimbine reversed the gastroprotective effects of DMC. Furthermore, DMC reduced the acidity of gastric content in pylorus-ligated rats but did not change H+ , K+ -ATPase (isolated from rabbit) activity in vitro. DMC reduced the lesion area in acetic acid-induced ulcers and decreased myeloperoxidase activity. DMC did not change the viability of fibroblast cells (L929) but reduced the viability of human gastric adenocarcinoma cells (AGS). The results confirmed that DMC could significantly enhance the gastric healing process and prevent ulcers due to improving protective factors on the gastric mucosa and reducing gastric acid secretion.

Investigation of the mechanism of Isobavachalcone in treating rheumatoid arthritis through a combination strategy of network pharmacology and experimental verification.

ETHNOPHARMACOLOGY RELEVANCE: Isobavachalcone (IBC) is a natural chalcone compound widely distributed in traditional Chinese medicine Psoralea corylifolia L., and Tibetan medicine Abelmoschus manihot (L.) Medik. Etc.. Among them, Psoralea corylifolia has the effect of tonifying the kidney and strengthening Yang, and it is recorded in the Medicinal theory that it can be used in managing rheumatism and arthralgia. In addition, It has been included in many prescriptions in traditional Chinese medicine as the main herb for managing rheumatoid arthritis (RA). Similarly, Abelmoschus manihot is a common Tibetan medicinal herb and is a common medicinal material in Tibetan medicine and reported in ancient medicinal books such as Jing Zhu Ben Cao and Si Bu Yi Dian to possess the effect of Ganhuangshui and thus can be used in treating Huangshui diseases (such as RA). Previous research has demonstrated IBC to possess numerous biological activities, including anti-cancer, anti-inflammatory, antibacterial and immunomodulatory. Nevertheless, its efficacy and potential mechanism in treating rheumatoid arthritis are yet to be investigated. AIM OF THE STUDY: This study aimed at investigating the therapeutic efficacy and mechanism of IBC in treating RA through a combined strategy of network pharmacology, in vitro, and in vivo evaluation. MATERIALS AND METHODS: The Swiss Target Prediction and GeneCards databases were consulted to predict the potential targets of IBC and RA. Additionally, the potential targets for IBC in treating RA were predicted by consulting databases such as String, Cytoscape, MCODE, and Cytohubba. R software was utilized for enrichment analysis of GO and KEGG pathways, followed by in vitro experimentation using cell lines and in vivo experimentation using animals to explore the potential mechanism of IBC in RA treatment. RESULTS: By integrating the results of network pharmacological analysis, 17 genes were found to be strongly associated with RA, such as TNF, MAPK13, EGFR, PTGS2, MMP3, etc. The enrichment analysis indicated that IBC possessed tremendous therapeutic efficacy in managing RA through PI3K-AKT, rheumatoid arthritis, and TNF signaling pathways. The in vitro experimentation indicated that IBC inhibited the proliferation, migration, and invasion, and promoted apoptosis and inhibition of inflammation of MH7A cell lines stimulated with TNF-α. The IBC might also have an increasing effect on the intracellular ROS and reducing effect on the mitochondrial membrane potential. The western blotting results indicated that IBC markedly inhibited the expression of p-PI3K, p-AKT, p-JAK1, p-STAT3 and SOCS3 proteins in TNF-α stimulated MH7A cells. Furthermore, we found that IBC also significantly reduced paw swelling and arthritis severity in CIA model rats through in vivo animal studies. CONCLUSIONS: In short, this study explored the effect of IBC by combining network pharmacology prediction with in vitro and in vivo experimentation. The results indicated that IBC exerts its anti-rheumatoid arthritis effect by regulating cell proliferation and survival via PI3K/AKT and JAK/STAT signaling pathways. This may open a new horizon and provide a theoretical foundation for further development and utilization of IBC in RA management.

A chalcone-syringaldehyde hybrid inhibits triple-negative breast cancer cell proliferation and migration by inhibiting CKAP2-mediated FAK and STAT3 phosphorylation.

BACKGROUND: Although triple-negative breast cancer (TNBC) accounts for only 15% of breast cancer cases, it is associated with a high relapse rate and poor outcome after standard treatment. Currently, the effective drugs and treatment strategies for TNBC remain limited, and thus, developing effective treatments for TNBC is pressing. Several studies have demonstrated that both chalcone and syringaldehyde have anticancer effect, but their potential anti-TNBC bioactivity are still unknown. PURPOSE: The present study aimed to synthesize a chalcone-syringaldehyde hybrid (CSH1) and explore its potential anti-TNBC effects and the underlying molecular mechanism. METHODS: Cell cytotoxicity was determined by 3-(4,5-dimethythiazol)-2,5-diphenyltetrazolium bromide (MTT). The activity of cell proliferation was measured by colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) staining assay. Cell cycle distribution and cell apoptosis were determined by fluorescence-activated cell sorter (FACS). The situation of DNA damage was observed using fluorescence microscopy. The ability of cell-matrix adhesion, migration and invasion was detected using cell adhesion assay and transwell assay. Transcriptome sequencing was performed to find out the changed genes. Levels of various signaling proteins were assessed by western blotting. RESULTS: CSH1 treatment triggered DNA damage and inhibited DNA replication, cell cycle arrest, and cell apoptosis via suppressing signal transducer and activator of transcription 3 (STAT3) phosphorylation. Whole genome RNA-seq analysis suggested that 4% of changed genes were correlated to DNA damage and repair, and nearly 18% of changed genes were functionally related to cell adhesion and migration. Experimental evidence indicated that CSH1 treatment significantly affected the distribution of focal adhesion kinase (FAK) and its phosphorylation, resulting in cell-matrix-adhesion reduction and migration inhibition of TNBC cells. Further mechanistic studies indicated that CSH1 inhibited TNBC cell proliferation, adhesion, and migration by inhibiting cytoskeleton-associated protein 2 (CKAP2)-mediated FAK and STAT3 phosphorylation signaling. CONCLUSION: These results suggest that CKAP2-mediated FAK and STAT3 phosphorylation signaling is a valuable target for TNBC treatment, and these findings also reveal the potential of CSH1 as a prospective TNBC drug.

Anxiolytic effect of the heartwood of Haematoxylum campechianum L. and sappanchalcone in an in vivo model in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Haematoxylum campechianum L., is a well-known plant in the southeast region of Mexico, where it is named as "palo tinto" or "palo de Campeche", in English there are vernacular names such as "redwood", "bloodwood tree" or "campeachy wood". Traditional medicine refers its use for the treatment of different disorders including depression. AIM OF THE STUDY: Considering the traditional use of this plant for the alleviation of depression, the aim of this study was the evaluation of the anxiolytic effect of the methanolic and hydroalcoholic extracts from the heartwood of Haematoxylum campechianum L., and the sappanchalchone (Sapp). Additionally, it is presented the characterization of the new compound 4-hydroxyhematoxylol (2) isolated from the hydroalcoholic extract. MATERIAL AND METHODS: The anxiolytic effect of the extracts and Sapp was evaluated by using the Elevated Plus Maze (EPM) additionally the sedative effect was assessed with the Open Field Test (OFT). The chemical characterization of Sapp and 2 was performing by 1D and 2D NMR experiments. RESULTS: The EPM test showed that the administration of the plant extracts increased the percentage of time spent in open arms (76.32 ± 6.35 and 66.68 ± 20.64%, respectively for the methanolic and hydroalcoholic extracts), whereas the administration of Sapp increased the percentage of time spent in open arms by 60.07 ± 14.28%, these results are similar to Diazepam (DZP, positive control) which caused an increment of 74.06 ± 23.42%. For the OFT, all of the doses evaluated for both extracts and Sapp diminished the number of rearing (R) and total corssing (TC) behavior in a similar way to the positive control (DZO) and statistically different with respect to the vehicle. CONCLUSION: The results obtained showed that the polar extracts from the heartwood of Haematoxylum campechianum L. possess both anxiolytic and sedative effect and that the chalcone-type compound Sapp, isolated from the methanolic extract, is partially responsible of these activities.

Renoprotective effect of isoliquiritigenin on cisplatin-induced acute kidney injury through inhibition of FPR2 in macrophage.

Acute kidney injury (AKI) is a serious complication in critically ill patients. Accumulating evidences indicated that macrophages play an important pro-inflammatory role in AKI and isoliquiritigenin (ISL) can inhibit macrophagic inflammation, but its role in AKI and the underlying mechanism are unknown. The present study aims to investigate the renoprotective effect of ISL on AKI and the role of Formyl peptide receptors 2 (FPR2) in this process. In this study, cisplatin-induced AKI model and lipopolysaccharide-induced macrophage inflammatory model were employed to perform the in vivo and in vitro experiments. The results showed that ISL strongly relieved kidney injury and inhibited renal inflammation in vivo and suppress macrophagic inflammatory response in vitro. Importantly, it was found that FPR2 was significantly upregulated compared to the control group in AKI and LPS-induced macrophage, whereas it was strongly suppressed by ISL. Interestingly, overexpression of FPR2 with transfection of pcDNA3.1-FPR2 effectively reversed the anti-inflammatory effect of ISL in macrophage, suggesting that FPR2 may be the potential target for ISL to prevent inflammation and improve kidney injury of AKI. Take together, these findings indicated that ISL improved cisplantin-induced kidney injury by inhibiting FPR2 involved macrophagic inflammation, which may provide a potential therapeutic option for AKI.

Flavokawain C exhibits anti-tumor effects on in vivo HCT 116 xenograft and identification of its apoptosis-linked serum biomarkers via proteomic analysis.

Chalcones and their derivatives belong to the flavonoid family. They have been extensively studied for their anticancer properties and some have been approved for clinical use. In this study, the in vivo anti-tumor activity of flavokawain C (FKC), a naturally occurring chalcone found in Kava (Piper methysticum Forst) was evaluated in HCT 116 cells (colon carcinoma). We also attempted to identify potential biomarkers and/or molecular targets in serum with applicability in predicting treatment outcome. The anti-tumor effects and toxicity of FKC were assessed using the xenograft nude mice model. Cisplatin was used as positive control. The anti-proliferative and apoptotic activities were then evaluated in tumor tissues treated with FKC. Furthermore, two-dimensional electrophoresis (2-DE) followed by protein identification using MALDI-TOF/TOF-MS/MS was performed to compare the serum proteome profiles between healthy nude mice and nude mice bearing HCT 116 tumor treated with vehicle solution and FKC, respectively. Our results showed that FKC treatment significantly inhibited HCT 116 tumor growth. In vivo toxicity studies showed that administration of FKC did not cause damage to major organs and had no significant effect on body weight. FKC was found to induce apoptosis in tumor, and this was associated with increased expression of cleaved caspase-3 and decreased expression of Ki67 in tumor tissues. Our proteomic analysis identified five proteins that changed in abundance - Ig mu chain C region (secreted form), GRP78, hemopexin, kininogen-1 and apolipoprotein E. Overall, our findings demonstrated the potential of FKC as an anti-cancer agent for the treatment of colon carcinoma.

The efficacy of novel metabolic targeted agents and natural plant drugs for nonalcoholic fatty liver disease treatment: A PRISMA-compliant network meta-analysis of randomized controlled trials.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease characterized by excess accumulation of fat in hepatocytes. Because no drug has been approved for NAFLD treatment, this work analyzed the effects of agents resulting from 2 research hotspots, metabolic target agents, and natural plant drugs, on NAFLD with network meta-analysis. METHODS: Public databases were searched through August 14, 2020. Randomized controlled trials that compared obeticholic acid, elafibranor, cenicriviroc, selonsertib, curcumin, silymarin, and resveratrol to placebo were included. Liver pathology improvement, hepatic biochemical indicators, and lipid metabolism indicators were analyzed. RESULTS: Thirty-five studies were included in the meta-analysis. Obeticholic acid was found to significantly increase the frequency of liver biopsy improvement compared to placebo (OR: 2.10; 95% CI: 1.60, 2.77). The ranking results among the hepatic biochemical indicators showed that obeticholic acid (94.9%) and elafibranor (86.3%) have a relative advantage in reducing alanine aminotransferase (ALT) levels, and obeticholic acid also had an advantage (95.4%) in reducing aspartate aminotransferase (AST) levels. Considering lipid metabolic indicators, elafibranor (expSMD: 0.01; 95% CI: 0.00, 0.05; SUCRA: 100%), and obeticholic acid (expSMD: 0.48; 95% CI: 0.28,0.84; SUCRA: 75.6%) significantly reduced triglyceride (TG) levels compared with placebo; moreover, obeticholic acid, but not elafibranor, caused a serious increase in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels and a decrease in high-density lipoprotein cholesterol (HDL-C) levels. CONCLUSIONS: Novel metabolic targeted agents generally have better effects than natural plant drugs, especially obeticholic acid, and elafibranor. However, obeticholic acid showed serious adverse effects such as increasing LDL-C levels and decreasing HDL-C levels. Curcumin showed potential advantages for NAFLD but lacked statistical significance.

Pharmacological review of isobavachalcone, a naturally occurring chalcone.

Isobavachalcone (IBC), a naturally occurring chalcone, is mainly isolated from the seeds of Psoralea corylifolia Linn. IBC demonstrates multiple pharmacological activities, including anti-cancer, anti-microbial, anti-inflammatory, antioxidative, neuroprotective, and among others. Several potential targets of IBC, such as AKT, dihydroorotate dehydrogenase (DHODH), have been identified. The pharmacokinetic profiles of IBC have been reported as well. In this review, the pharmacological activities, the underlying mechanisms, the potential targets, and the pharmacokinetic profiles of IBC were summarized. IBC might be a promising lead compound for drug discovery.

Isolation and Characterization of Compounds from Glycyrrhiza uralensis as Therapeutic Agents for the Muscle Disorders.

Skeletal muscle is the most abundant tissue and constitutes about 40% of total body mass. Herein, we report that crude water extract (CWE) of G. uralensis enhanced myoblast proliferation and differentiation. Pretreatment of mice with the CWE of G. uralensis prior to cardiotoxin-induced muscle injury was found to enhance muscle regeneration by inducing myogenic gene expression and downregulating myostatin expression. Furthermore, this extract reduced nitrotyrosine protein levels and atrophy-related gene expression. Of the five different fractions of the CWE of G. uralensis obtained, the ethyl acetate (EtOAc) fraction more significantly enhanced myoblast proliferation and differentiation than the other fractions. Ten bioactive compounds were isolated from the EtOAc fraction and characterized by GC-MS and NMR. Of these compounds (4-hydroxybenzoic acid, liquiritigenin, (R)-(-)-vestitol, isoliquiritigenin, medicarpin, tetrahydroxymethoxychalcone, licochalcone B, liquiritin, liquiritinapioside, and ononin), liquiritigenin, tetrahydroxymethoxychalcone, and licochalcone B were found to enhance myoblast proliferation and differentiation, and myofiber diameters in injured muscles were wider with the liquiritigenin than the non-treated one. Computational analysis showed these compounds are non-toxic and possess good drug-likeness properties. These findings suggest that G. uralensis-extracted components might be useful therapeutic agents for the management of muscle-associated diseases.

The Bioavailability, Extraction, Biosynthesis and Distribution of Natural Dihydrochalcone: Phloridzin.

Phloridzin is an important phytochemical which was first isolated from the bark of apple trees. It is a member of the dihydrochalcones and mainly distributed in the plants of the Malus genus, therefore, the extraction method of phloridzin was similar to those of other phenolic substances. High-speed countercurrent chromatography (HSCCC), resin adsorption technology and preparative high-performance liquid chromatography (HPLC) were used to separate and purify phloridzin. Many studies showed that phloridzin had multiple pharmacological effects, such as antidiabetic, anti-inflammatory, antihyperglycaemic, anticancer and antibacterial activities. Besides, the physiological activities of phloridzin are cardioprotective, neuroprotective, hepatoprotective, immunomodulatory, antiobesity, antioxidant and so on. The present review summarizes the biosynthesis, distribution, extraction and bioavailability of the natural compound phloridzin and discusses its applications in food and medicine.

Design, synthesis and drug resistance reversal potential of novel curcumin mimics Van D: Synergy potential of curcumin mimics.

Being crucial part of plant-based novel discovery of drug from natural resources, a study was done to explore the antibacterial potential of curcumin mimics in combination with antibiotics against multidrug resistant isolates of Pseudomonas aeruginosa. The best candidate Van D, a curcumin mimics reduced the MIC of tetracycline (TET) up to 16 folds against multidrug resistant clinical isolates. VanD further inhibited the efflux pumps as evident by ethidium bromide efflux and by in-silico docking studies. In another experiment, it was also found that Van D inhibits biofilm synthesis. This derivative kills the KG-P2, an isolate of P. aeruginosa in a time dependent manner, the post-antibiotic effect (PAE) of tetracycline was extended as well as mutant prevention concentration (MPC) of TET was also decreased. In Swiss albino mice, Van D reduced the proinflammatory cytokines concentration. In acute oral toxicity study, this derivative was well tolerated and found to be safe up to 1000 mg/kg dose. To the best of our knowledge, this is the first report on curcumin mimics as synergistic agent via inhibition of efflux pump.

Development of an Orally Bioavailable Isoliquiritigenin Self-Nanoemulsifying Drug Delivery System to Effectively Treat Ovalbumin-Induced Asthma.

PURPOSE: Isoliquiritigenin (ILQ), an important component of Anti-Asthma Herbal Medicine Intervention (ASHMI), had shown potent anti-asthma effect in vitro in our previous study. However, poor solubility and low bioavailability hindered in vivo application to treat asthma. This study was to develop a novel ILQ loaded self-nanoemulsifying drug delivery system (ILQ-SMEDDS) with enhanced bioavailability. METHODS: The optimized SMEDDS formulation was composed of ethyl oleate (oil phase), Tween 80 (surfactant) and PEG400 (co-surfactant) at a mass ratio of 3:6:1. The physiochemical properties of ILQ-SMEDDS, including drug content, globule size, zeta potential, scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, were characterized. And the in vitro release profile, in situ intestinal absorption, in vivo pharmacokinetic parameters and the anti-asthma effect of ILQ suspension and ILQ-SMEDDS were evaluated. RESULTS: The ILQ-SMEDDS had an average globule size of 20.63 ± 1.95 nm with a polydispersity index (PDI) of 0.11 ± 0.03, and its zeta potential was -12.64 ± 2.12 mV. The cumulative release rate of ILQ from ILQ-SMEDDS to the simulated gastrointestinal tract was significantly higher than that of free ILQ suspension. And area under curve with ILQ-SMEDDS was found to be 3.95 times higher than that of ILQ suspension indicating improved bioavailability by SMEDDS. Although ILQ-SMEDDS showed a slight less effective inhibitory effect on eotaxin-1 in human lung fibroblast (HFL-1) cells than free ILQ, in an ovalbumin-induced asthma model, ILQ-SMEDDS exhibited more efficacy than ILQ suspension in improving asthma-associated inflammation, including eosinophil production, ovalbumin-specific immunoglobulin E (OVA-sIgE), interleukin 4 (IL 4), interleukin 5 (IL 5) and interferon-γ (IFN-γ). Even the low dose of ILQ-SMEDDS group (10 mg/kg) showed better anti-asthma effect than that of the ILQ suspension group (20 mg/kg). CONCLUSION: Compared with ILQ suspension, ILQ-SMEDDS showed significantly improved bioavailability and anti-asthma effect, revealing its potential as a favorable pharmaceutical agent for treating asthma.

Inhibitory functions of cardamonin against particulate matter-induced lung injury through TLR2,4-mTOR-autophagy pathways.

Particulate matter with an aerodynamic diameter equal to or less than 2.5 µm (PM2.5) is a form of air pollutant that causes significant lung damage when inhaled. Cardamonin, a flavone found in Alpinia katsumadai Heyata seeds, has been reported to have anti-inflammatory and anticoagulative activity. The aim of this study was to determine the protective effects of cardamonin on PM2.5-induced lung injury. Mice were treated with cardamonin via tail-vein injection 30 min after the intratracheal instillation of PM2.5. The results showed that cardamonin markedly reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM2.5. Cardamonin also significantly inhibited PM2.5-induced myeloperoxidase (MPO) activity in lung tissue, decreased the levels of PM2.5-induced inflammatory cytokines and effectively attenuated PM2.5-induced increases in the number of lymphocytes in the bronchoalveolar lavage fluid (BALF). And, cardamonin increased the phosphorylation of mammalian target of rapamycin (mTOR) and dramatically suppressed the PM2.5-stimulated expression of toll-like receptor 2 and 4 (TLR 2,4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1. In conclusion, these findings indicate that cardamonin has a critical anti-inflammatory effect due to its ability to regulate both the TLR2,4-MyD88 and mTOR-autophagy pathways and may thus be a potential therapeutic agent against PM2.5-induced lung injury.

PPAR-Gamma as putative gene target involved in Butein mediated anti-diabetic effect.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder caused due to varied genetic and lifestyle factors. The search for a potential natural compound to enhance the treatment of diabetes is the need of the hour. Butein, a flavonoid, found sufficiently in Faba bean, is said to possess an anti-diabetic property. In-silico analysis, Butein is predicted as a potential anti-diabetic compound, due to its regulatory action on PPAR-Gamma. Based on this evidence, the Butein's anti-diabetic action is studied in diabetic induced rat models. The drug property of Butein is studied through in-silico analysis to determine the metabolic properties. In animal models, the biochemical analysis, histopathological and gene expression against PPAR-Gamma were studied comparatively. Butein being a hydrophobic compound, the bioavailability is said to be minimum. Hence, Butein formulation was made using biopolymer Chitosan for the synergistic anti-diabetic action. The Butein Chitosan formulation was optimized and characterized using analytical techniques. Further, the anti-diabetic activity of Butein and Butein Chitosan formulation was studied in diabetic induced rats. The obtained in-silico analysis results showed that Butein is the most favorable drug. Apparently, in the rat model, Butein and Butein Chitosan formulation effectively controlled the blood glucose levels without any side effects. The histopathological observations of the tissue samples showed nontoxic activity. Additionally, the gene expression analysis predicted the possible mechanism of anti-diabetic action exhibited through the down regulation of PPAR-Gamma. Whereas, the Butein Chitosan formulation failed, to show synergetic anti-diabetic activity as expected. This study is vital in introducing Butein as a safe anti-diabetic compound, which can be used in the treatment of T2DM.

Protective effect of isoliquiritigenin on experimental diabetic nephropathy in rats: Impact on Sirt-1/NFκB balance and NLRP3 expression.

The prevalence of diabetes mellitus (DM) drastically increases worldwide. Persistent hyperglycemia affects body microvasculature causing injuries to kidney producing diabetic nephropathy (DNE). Manifestation of these microvascular complications is associated with disturbed redox homeostasis. The current study evaluated the effect of isoliquiritigenin (ISLQ), a bioactive chalcone found in licorice which is known for its antioxidant effect, on diabetes-induced renal injury. DM was prompted in male rats by streptozotocin (STZ, 50 mg/kg, intraperitoneally). ISLQ was administrated by oral gavage for 8 weeks at a dose (20 mg/kg/day). Features of renal injury were observed in kidneys of diabetic rats including, albuminuria and deteriorated renal function. Renal dysfunction was associated with reduced sirtuin-1 (Sirt-1) expression, increased renal oxidative stress, nucleotide-binding domain and leucine-rich repeat containing protein-3 (NLRP3), nuclear factor-κB (NFκB) and inflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). Moreover, there was significant downregulation of anti-inflammatory cytokine interleukin-10 (IL-10), glomerular and tubular injury and collagen accumulation. ISLQ administration preserved renal function and architecture, restored Sirt1 and renal oxidant-antioxidant balance, dampened inflammation and attenuated collagen accumulation. It can be inferred that ISLQ possess a protective effect and could have a potential as a food supplement to halt development and progression of DNE.

Echinatin suppresses esophageal cancer tumor growth and invasion through inducing AKT/mTOR-dependent autophagy and apoptosis.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with poor survival. It is urgent to search for new efficient drugs with good stability and safety for clinical therapy. This study aims to identify potential anticancer drugs from a compound library consisting of 429 natural products. Echinatin, a compound isolated from the Chinese herb Glycyrrhiza uralensis Fisch, was found to markedly induce apoptosis and inhibit proliferation and colony-formation ability in ESCC. Confocal fluorescence microscopy data showed that echinatin significantly induced autophagy in ESCC cells, and autophagy inhibitor bafilomycinA1 attenuated the suppressive effects of echinatin on cell viability and apoptosis. Mechanistically, RNA sequencing coupled with bioinformatics analysis and a series of functional assays revealed that echinatin induced apoptosis and autophagy through inactivation of AKT/mTOR signaling pathway, whereas constitutive activation of AKT significantly abrogated these effects. Furthermore, we demonstrated that echinatin had a significant antitumor effect in the tumor xenograft model and markedly suppressed cell migration and invasion abilities of ESCC cells in a dose-dependent manner. Our findings provide the first evidence that echinatin could be a novel therapeutic strategy for treating ESCC.