Unveiling the neuroprotective properties of isoflavones: current evidence, molecular mechanisms and future perspectives.

Neurodegenerative diseases encompass a wide range of debilitating and incurable brain disorders characterized by the progressive deterioration of the nervous system's structure and function. Isoflavones, which are naturally occurring polyphenolic phytochemicals, have been found to regulate various cellular signaling pathways associated with the nervous system. The main objective of this comprehensive review is to explore the neuroprotective effects of isoflavones, elucidate the underlying mechanisms, and assess their potential for treating neurodegenerative disorders. Relevant data regarding isoflavones and their impact on neurodegenerative diseases were gathered from multiple library databases and electronic sources, including PubMed, Google Scholar, Web of Science, and Science Direct. Numerous isoflavones, including genistein, daidzein, biochanin A, and formononetin, have exhibited potent neuroprotective properties against various neurodegenerative diseases. These compounds have been found to modulate neurotransmitters, which in turn contributes to their ability to protect against neurodegeneration. Both in vitro and in vivo experimental studies have provided evidence of their neuroprotection mechanisms, which involve interactions with estrogenic receptors, antioxidant effects, anti-inflammatory properties, anti-apoptotic activity, and modulation of neural plasticity. This review aims to provide current insights into the neuroprotective characteristics of isoflavones and shed light on their potential therapeutic applications in future clinical scenarios.

Ononin triggers ferroptosis-mediated disruption in the triple negative breast cancer both in vitro and in vivo.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is difficult to treat due to a lack of targeted therapies. In this study, we aimed to investigate whether a natural flavonoid compound called ononin could be effective in treating TNBC by triggering ferroptosis in MDA-MB-231 and 4 T1 cell lines, and MDA-MB-231-xenograft nude mice model. Ononin inhibited TNBC through ferroptosis, which was determined by MTT assay, flow cytometry, RT-PCR, immunofluorescence, transmission electron microscopy, histological analysis, western blot and bioluminescence assay. Our results showed that treatment with ononin led to increased levels of malondialdehyde and reactive oxygen species and decreased activity of superoxide dismutase, which are indicatives of ferroptosis. We also found that ononin downregulated two key markers of ferroptosis, SLC7A11 and Nrf2, at both the transcriptional and translational level. Additionally, the administration of ononin resulted in a notable decrease in tumor size and weight in the mouse model. Furthermore, it was observed to enhance the rate of apoptosis in TNBC cells. Importantly, ononin did not induce any histological changes in the kidney, liver, and heart. Taken together, our findings suggest that ononin could be a promising therapeutic strategy for TNBC, and that it works by disrupting the Nrf2/SLC7A11 axis through ferroptosis. These results are encouraging and may lead to the development of new treatments for this challenging cancer subtype.

Nepetin Attenuates Atopic Dermatitis in HaCaT Cells and BALB/c Mice Through MyD88-MKK3/6-Akt Signaling.

Nepetin is a type of O-methylated flavone (6-hydroxy luteolin) and has been found in many herbal medicines that exhibit various pharmacological properties, including anti-inflammatory responses. Here, we aimed to investigate the efficacy of nepetin in attenuating inflammatory responses in cultured keratinocytes and 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD) in BALB/c mice. Various assay methods including cell viability, flow cytometry, fluorometry, confocal microscopy, western blot, ELISA techniques, staining methods, score and scratch frequency assessment, etc. were employed to explore the mechanisms. LPS-treated keratinocytes showed a significant increase in inflammatory mediators (iNOS, COX-2, PGES2, and NO) and cytokines (IL-1ß, IL-6, and TNF-α) in a dose-dependent manner. Treatment with nepetin prevented LPS-induced cell death and inhibited inflammatory mediators and the production of cytokines in cultured keratinocytes. This inhibition was achieved by nepetin, which inhibited LPS-induced ROS production and the translocation of NF-κB in the cultures, thereby inhibiting the generation of inflammatory mediators and/or cytokines. In a mouse model of AD, treatment with nepetin reduced skin inflammation symptoms in a dose-dependent manner, as evidenced by the significant reduction of inflammation- related cytokines, skin lesions, and behavior scores. Based on the present in vitro and in vivo study, nepetin is the safest bioactive compound with potential therapeutic applications for AD-related skin lesions and adverse skin reactions.

Danggui Buxue Tang improves therapeutic efficacy of doxorubicin in triple negative breast cancer via ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Danggui Buxue Tang (DBT) has been used for over 800 years to enhance Qi and nourish Blood, and it is particularly beneficial for cancer patients. Recent research has shown that combining DBT with chemotherapy agents leads to superior anti-cancer effects, thereby enhancing therapeutic efficacy. AIM OF THE STUDY: The aim of this study was to evaluate the effectiveness of a combination therapy involving doxorubicin (DOX) and Danggui Buxue Tang (DBT) in the treatment of triple-negative breast cancer (TNBC) and to elucidate the underlying mechanisms of action. MATERIALS AND METHODS: In vitro experiments were performed using MDA-MB-231 and 4T1 cells, while in vivo experiments were carried out using MDA-MB-231 xenograft mice. The therapeutic effects of the combination therapy were evaluated using various techniques, including MTT assay, colony formation assay, flow cytometry, transwell assay, immunofluorescence, transmission electron microscopy (TEM), histological analysis, western blotting, and bioluminescence assay. RESULTS: DBT was found to enhance DOX's anti-TNBC activity in vitro by promoting ferroptosis, as evidenced by the observed mitochondrial morphological changes using TEM. The combination therapy was also found to reduce the expression of Nrf2, HO-1, and GPX4, which are all targets for ferroptosis induction, while simultaneously increasing ROS production. Additionally, the combination therapy reduced nuclear accumulation and constitutive activation of Nrf2, which is a significant cause of chemotherapy resistance and promotes cancer growth. In vivo experiments using an MDA-MB-231 xenograft animal model revealed that the combination therapy significantly reduced tumor cell proliferation and accelerated TNBC deaths by modulating the Nrf2/HO-1/GPX4 axis, with no evidence of tissue abnormalities. Moreover, the combination therapy exhibited a liver protective effect, and administration of Fer-1 was able to reduce the ROS formation produced by the DBT + DOX combination therapy. CONCLUSION: This study provides evidence that the combination therapy of DOX and DBT has the potential to treat TNBC by promoting ferroptosis through the Nrf2/HO-1/GPX4 axis.

Spatholobus suberectus inhibits lipogenesis and tumorigenesis in triple-negative breast cancer via activation of AMPK-ACC and K-Ras-ERK signaling pathway.

Background and aim: Triple-negative breast cancer (TNBC) is a highly invasive type of breast cancer with a poor prognosis. Currently, there are no effective management strategies for TNBC. Earlier, our lab reported the percolation of Spatholobus suberectus for the treatment of breast cancer. Lipid metabolic reprogramming is a hallmark of cancer. However, the anti-TNBC efficiency of S. suberectus extract and its causal mechanism for preventing lipogenesis have not been fully recognized. Hence, the present study aimed to investigate the inhibitory role of S. suberectus extract on lipogenesis and tumorigenesis in TNBC in vitro and in vivo by activating AMPK-ACC and K-Ras-ERK signaling pathways using lipidomic and metabolomic techniques. Experimental procedure: Dried stems of S. suberectus extract inhibited lipogenesis and tumorigenesis and promoted fatty acid oxidation as demonstrated by the identification of the metabolites and fatty acid markers using proteomic and metabolomic analysis, qPCR, and Western blot. Results and conclusion: The results indicated that S. suberectus extract promotes fatty acid oxidation and suppresses lipogenic metabolites and biomarkers, thereby preventing tumorigenesis via the AMPK-ACC and K-Ras-ERK signaling pathways. On the basis of this preclinical evidence, we suggest that this study represents a milestone and complements Chinese medicine. Further studies remain underway in our laboratory to elucidate the active principles of S. suberectus extract. This study suggests that S. suberectus extract could be a promising therapy for TNBC.

Danggui Buxue Tang: A Review of its Major Components.

Context: Danggui Buxue Tang (DBT) is a classical Chinese medicine that practitioners have used for thousands of years. Historically, those practitioners have used 16 prescriptions of DBT but currently are using only three prescriptions. Objective: The review intended to summarize pharmacological profiles of DBT and also clarify the major active chemicals found within it to provide a better understanding of the significance of DBT clinically. Design: The research team performed a narrative review by searching Pubmed databases. The search used the keywords Danggui Buxue Tang, bioactive chemcials, pharmacological functions. Setting: The databases setting were done by Gong Guowei and Zhou Xuan in the Zunyi Medical University, Zhuhai campus. Results: There are multiple results related to the crude fractions isolated from Danggui Buxue Tang, and also included the clinical trails. Conclusions: Thousands of years of clinical experience have ensured the efficacy of TCM treatments, which can determine the direction of basic research. That research can modify formulas at the molecular level to improve targeting and specificity in the treatment of specific diseases. As a result, the discovery and identification of new compounds within the herbal complex can provide useful research ideas and ensure the viability of new drug development.

Danggui Buxue Tang potentiates the cytotoxicity of 5-fluorouracil on colorectal adenocarcinoma cells: A signaling mediated by c-Jun N-terminal kinase.

Danggui Buxue Tang (DBT) is a well-known Chinese herbal recipe often prescribed in clinical treatment for menopausal and cardiovascular symptoms. 5-Fluorouracil (5-FU) is a chemotherapy drug that treats several cancers; however, it causes severe adverse effects and multidrug resistance. Combining natural medications can reduce the side effects of 5-FU use. Hence, we aimed to determine the role of DBT in strengthening the anticancer capabilities of 5-FU in a cultured colorectal adenocarcinoma cell line (HT-29 cell) and xenograft nude mice. HT-29 cells cultured with DBT did not exhibit cytotoxicity. However, co-administration of DBT with 5-FU significantly increased apoptosis and the expression of apoptotic markers. The inhibition of proliferation induced by DBT and 5-FU was shown to be mediated by c-Jun N-terminal kinase signaling. In addition, the potentiation effect of 5-FU and DBT was demonstrated in reducing tumor size, expressions of Ki67 and CD34 in HT-29 xenograft mice. This finding suggests that DBT can work with 5-FU as a novel chemotherapeutic strategy for treating colon cancer.

Anti-Invasive and Anti-Migratory Effects of Ononin on Human Osteosarcoma Cells by Limiting the MMP2/9 and EGFR-Erk1/2 Pathway.

Osteosarcoma is a common malignancy of the bone. Due to its high metastatic properties, osteosarcoma becomes the leading cause of cancer death worldwide. Ononin is an isoflavone glycoside known to have various pharmacological properties, including antioxidant and anti-inflammatory activities. In the present study, we aimed to investigate the efficacy of ononin on osteosarcoma cell migration, invasion, and the underlying mechanisms. The in vitro anti-tumorigenic and anti-migratory properties of ononin were determined by MTT, colony formation, invasion, and migration in MG-63 and U2OS osteosarcoma cell lines. The results were compared with the standard chemotherapeutic drug, doxorubicin (DOX), as a positive control. The dose-dependent manners of ononin treatment increased the expression of apoptosis and inhibition of cell proliferation through the EGFR-Erk1/2 signaling pathways. Additionally, ononin significantly inhibited the invasion and migration of human osteosarcoma cells. For consistency, we used the MG-63-xenograft mice model to confirm the in vivo anti-tumorigenic and anti-migratory efficacy of ononin by inhibiting the protein expressions of EGFR-Erk1/2 and MMP2/9. According to the histological study, ononin had no adverse effect on the liver and kidney. Overall, our findings suggested that ononin could be a potentially effective agent against the development and metastasis of osteosarcoma.

Identification of (S)-1-(2-(2,4-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)urea as a potential anti-colorectal cancer agent.

In our previous study, 1-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)urea (1) was obtained as a potent tyrosine kinase inhibitor. Further structural optimization was performed in this investigation, and a series of novel quinoline derivates were designed, synthesized and evaluated for their biological activity. Among them, compound 8m possessed nanomolar c-Met and Ron inhibitory activity, with IC50 values of 4.32 nM and 2.39 nM, respectively. Kinase profile study demonstrated that it could also inhibit ABL, PDGFRß, AXL, RET, and FLT3 with submicromolar potency. It also exhibited moderate to excellent cytotoxic activity against different types of human cancer cell lines, especially against COLO 205 cells (IC50 = 0.035 µM) which was remarkably superior to that of Cabozantinib (IC50 = 6.6 µM) and Fruquintinib (IC50 > 10.0 µM). Compared to ( ± )-8m, isomer (S)-8m and (R)-8m showed similar kinase inhibitory activity against c-Met/RON and in vitro anticancer activity against COLO 205 cells. Differently, compound (S)-8m showed an over 238-fold selectivity toward COLO 205 (IC50 = 0.042 µM) cells to FHC cells (IC50 > 10.0 µM), which indicated its low cytotoxicity against human normal tissue cells. Flow cytometry study demonstrated that compound (S)-8m could significantly induce apoptosis in COLO 205 cells in a dose-dependent manner. Cell cycle arrest assays showed that compound (S)-8m could not arrest the cell-cycle progression due to the massive dead cells.

Acrocalyenes A and B, Two New Diterpenoids from Sinomenium acutum Associated Fungus Acrocalymma sp.

We identified two new diterpenoidal acrocalyenes A (1) and B (2) through chemical investigation on Acrocalymma sp., a plant-associated fungus from the tender stem isolates of Sinomenium acutum collected from the Qinling Mountains, along with seven already-recognized compounds (3-9). The HR-ESI-TOF-MS and 1D/2D NMR data were utilized for structural elucidation of these compounds, and the single-crystal X-ray diffraction was employed for absolute configuration clarification of the novel acrocalyenes 1 and 2. Bioassays revealed that the cytotoxicities of compounds 2, 4, 6, 7, and 8 against three human carcinoma cells (RKO, HeLa and HCC-1806) were moderate to strong, with IC50 between 6.70-38.82 µM. These isolates were also evaluated for their fungal resistant potentials against Botrytis cinerea, Fusarium culmorum and Fusarium solani, in which 3 displayed significant inhibitory effects on all three phytopathogenic fungi, showing respective MIC of 50, 25 and 25 µM.

Antitumor Effects of Ononin by Modulation of Apoptosis in Non-Small-Cell Lung Cancer through Inhibiting PI3K/Akt/mTOR Pathway.

Lung cancer is a leading global cause of cancer-related death in both males and females. Non-small-cell lung cancer (NSCLC) is the most commonly diagnosed cancer type that can be difficult to control with conventional chemotherapeutic and surgical approaches resulting in a poor prognosis. Paclitaxel (PTX) is a commonly used chemotherapeutic drug for NSCLC, which can cause tissue injury in healthy cells and affect the quality of life in patients with cancer. In order to treat NSCLC, alternative medications with minimal or no side effects are highly needed. Ononin is an isoflavone glycoside extracted from Astragali Radix (AR) that has various pharmacological activities. Therefore, this study investigated whether ononin inhibits NSCLC progression and promotes apoptosis synergistically with PTX both in vitro and in vivo. Antitumorigenic properties of ononin were determined by MTT assay, colony formation assay, migratory capacity, and apoptotic marker expression in A549 and HCC827 cells. The combination of ononin with PTX increased the expression of apoptotic markers and ROS generation and inhibited cell proliferation through the PI3K/Akt/mTOR signaling pathways. Furthermore, ononin prevented the translocation of NF-κB from cytosol to the nucleus. Also, we used the xenograft NSCLC mice model to confirm the in vivo antitumorigenic efficacies of ononin by reduction of CD34 and Ki67 expressions. Based on the histological analysis, the cotreatment of PTX and ononin reduced PTX-induced liver and kidney damage. Overall, our findings suggested that the therapeutic index of PTX-based chemotherapy could be improved by reducing toxicity with increasing antitumor capabilities when combined with ononin.

Pharmaceutical Values of Calycosin: One Type of Flavonoid Isolated from Astragalus.

Astragalus is a popular Materia Medica in China, and it could be applied in the treatment of various diseases. It contains a variety of chemically active ingredients, such as saponins, flavonoids, and polysaccharides. Plant-derived bioactive chemicals are considered natural, safe, and beneficial. Among the infinite plant-identified and isolated molecules, flavonoids have been reported to have positive effects on human health. Calycosin is the most important active flavonoid substance identified predominantly within this medicinal plant. In recent years, calycosin has been reported to have anticancer, antioxidative, immune-modulatory, and estrogenic-like properties. This review collected recent relevant literatures on calycosin and summarized its potential pharmaceutical properties and working mechanism involved, which provided solid basis for future clinical research.

Anti-angiogenesis Function of Ononin via Suppressing the MEK/Erk Signaling Pathway.

Angiogenesis is a complicated pathological process and plays an important role in modulating tumor development. Flavonoids, sharing the basic functional group with estrogen, have been utilized as chemopreventive agents to inhibit endothelial cell angiogenesis and also suppress tumor cell proliferation. Ononin, also referred to as formononetin-7-O-ß-d-glucoside, is one of the bioactive chemicals found within many functional food or plants. The anticancer functions of ononin have been reported both in vitro and in vivo. However, the anti-angiogenetic properties of ononin have not been reported. The possible efficacies of ononin against angiogenesis was verified in cultured endothelial cells. Ononin suppressed vascular endothelial growth factor (VEGF)-induced HUVEC migration, invasion. and tube formation activity after 48 h. The apoptosis rate and specific markers, i.e., Bax/Bc-2 ratio, cleaved caspase 3/9 (Cl-caspase 3/9), and cytochrome c (Cyto c), were enhanced in the ononin-treated group. On the other hand, the protein expressions levels of hypoxia-inducible factor 1α (HIF-1α), mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), and vascular endothelial growth factor receptor 2 (VEGFR2) were restricted after ononin treatment for 2 days in VEGF-pretreated endothelial cells. In summary, ononin acts as a candidate for angiogenetic-related disease prevention and treatment.

Insights into non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction: Development and perspective.

The development of immune checkpoint inhibitors has become a research hotspot in cancer immunotherapy in recent years. Anti-PD-1/PD-L1 monoclonal antibodies (mAbs), such as pembrolizumab and nivolumab have been approved for treating different types of cancer. Many peptides, peptidomimetics and non-peptide small-molecule inhibitors targeting the PD-1/PD-L1 axis have been published so far. In comparison with mAbs, small-molecule inhibitors have the potential to overcome inherent shortcomings of mAbs, such as poor oral bioavailability, low tumor penetration, and high manufacturing costs. In this article, we mainly review non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction, their cocrystal structures, docking studies, and biological activities are also included to guide future study. In addition, we propose several strategies for designing more effective small-molecule modulators of the PD-1/PD-L1 pathway.

The anti-UV properties of Saussurea involucrate Matsum. & Koidz. Via regulating PI3K/Akt pathway in B16F10 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Ultra Violet (UV) radiation is the major reason for reactive oxygen species (ROS) forming, skin cell damage, melanin production, and could horribly cause skin cancer. Saussureae Involucratae Herba (SIH) is the aerial part of Saussurea involucrata Matsum. & Koidz. This Material Medica is popular with both in Uyghur and Chinese medicines filed. SIH is one of the famous species of the Asteraceae family and which prescribed for skin protection from UV-induced damage according to China Pharmacopeia (2020). However, the detailed working mechanism involved is still not elucidated. AIM OF THE STUDY: We would like to probe the potential transduction pathway of SIH against UV-induced skin cell damages in cultured B16F10 cells. METHODS: Western blot, luciferase assay, laser confocal, RT-PCR and flow cytometer were employed here to verify the protective pharmaceutical value of SIH in cultured B16F10 cells after UV pre-treatment. RESULTS: Our result revealed that SIH attenuates ROS formation after UV-induced damage in B16F10 cells in a dose-dependent manner. Moreover, the transcriptional and translational anti-oxidative encoding genes were up-regulated under the presence of SIH. Further studies showed that SIH activated transcriptional activity of anti-oxidant response element (ARE). Moreover, we found that SIH dramatically stimulates PI3K/Akt phosphorylation in cultured B16F10 cells, this result was further verified by its specific inhibitors, LY294002 and Tocris. CONCLUSION: Our findings concluded that SIH protect melanoma cells from UV damages via activating PI3K/Akt signaling and which could provide scientific evidence for anti-UV pharmaceutical values of this herbal extract.

Astragaloside IV, a saponin from Astragalus membranaceus var. mongholicus, induces expressions of heme recycle proteins via signaling of Nrf2/ARE in cultured macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine (TCM) theory, "Qi" is classified as energetic essence supporting the life activities in human. "Blood" is categorized as nourishing essence and circulating in the body. "Blood" and "Qi" have an intimate relationship. Astragali Radix (AR; root of Astragalus membranaceus (Fisch.) Bge. Var. mongholicus (Bge.) Hsiao) has a broad spectrum of application for "Qi-Blood" enrichment. Astragaloside IV, a major saponin in AR, has therapeutic functions in erythropoietic, cardiovascular and immune systems. However, the efficacy of astragaloside IV in erythrophagocytosis has not been elucidated. AIM OF THE STUDY: The possible functions of astragaloside IV in heme iron recycling during erythrophagocytosis in cultured macrophage were elucidated. METHODS: The translational and transcriptional expressions of heme recycling enzymes were determined after incubating of astragaloside IV for 24 h in cultured macrophage. RESULTS: In astragaloside IV-treated macrophage, the expressions, both RNA and protein levels, of regulators of heme recycling, e.g. heme oxygenase-1 (HO-1), ferroportin (FPN), biliverdin reductase A and B (BVRA, BVRB), were markedly induced in dose-dependent manners. In parallel, the transcriptional activity of antioxidant response element, cloned within an expression vector as pARE-Luc and transfected in cultured macrophages, was markedly induced after a challenge with astragaloside IV in a dose-dependent manner. Moreover, the translocation of Nrf2, a transcriptional factor in regulating expression of heme recycling protein, was induced by astragaloside IV, leading to an enrichment at nucleus fraction. CONCLUSION: Astragaloside IV shed lights in enhancing the expression of heme recycle proteins via Nrf2/ARE signaling pathway.

Evaluation of Anti-Inflammatory Components of Guizhi Fuling Capsule, an Ancient Chinese Herbal Formula, in Human Umbilical Vein Endothelial Cells.

BACKGROUND: Guizhi Fuling capsule (GFC), a well-known formula composed of five medicinal herbs, is commonly prescribed to treat primary dysmenorrhea, as well as to achieve good clinical efficacy in China. However, the active components of GFC have not been identified. Here, the anti-inflammatory functions of GFC, as well as its major ingredients, were evaluated in human umbilical vein endothelial cells (HUVECs). METHODS: Lipopolysaccharide (LPS) was used in HUVECs to imitate the cellular inflammation. Then, GFC-triggered mRNA expressions of cyclooxygenase-1 (COX-1) and COX-2 were determined by real-time PCR, while the expression of COX-2 protein was revealed by western blotting. Besides, nine components of GFC were evaluated for their contribution value in the anti-dysmenorrhea effects. RESULTS: The application of GFC downregulated the mRNA expressions of COX-1 and COX-2 mRNAs. Nine major components of GFC were tested in the inflammatory system, and three compounds, including paeoniflorin, benzoylpaeoniflorin, and amygdalin, exhibited robust activation in HUVECs. The combination of paeoniflorin, benzoylpaeoniflorin, and amygdalin showed over 80% of the anti-inflammatory activation. CONCLUSION: Our study supports that GFC plays a promising role in anti-dysmenorrhea function by decreasing COXs' expression. Besides, paeoniflorin, benzoylpaeoniflorin, and amygdalin could be considered as major regulators for the anti-dysmenorrhea effects of GFC.

Antidepressant-like effects of Schisandrin on lipopolysaccharide-induced mice : Gut microbiota, short chain fatty acid and TLR4/NF-κB signaling pathway.

Growing evidence shows that gut microbiota and neuroinflammatory responses play a critical role in the pathogenesis of depression. Our previous study demonstrated that schisandrin (SCH) could reduce proinflammatory factors of depressive mice. Therefore, our present study is to research the potential connection between gut microbial and anti-inflammatory effects of SCH on a depressive mouse model induced by lipopolysaccharide (LPS). We found that SCH pre-treatment could decrease the immobility time of forced swimming test (FST) and tail suspension test (TST). And the results of 16S rRNA demonstrated that SCH pre-administration attenuated the dysbiosis of gut microbiota of depressive mice, along with altered fecal short-chain fatty acids (SCFAs). Furthermore, SCH reduced the levels of proinflammatory factors of depressive mice and the expression of TLR4/NF-κB signaling pathway in the hippocampus. Overall, our study indicated that SCH might recover the gut microbial disorder of depressive mice through suppressing the expression of TLR4/NF-κB signaling pathway.

Identification of novel quinoline analogues bearing thiazolidinones as potent kinase inhibitors for the treatment of colorectal cancer.

In this investigation, a novel series of quinoline analogues bearing thiazolidinones were designed and synthesized based on our previous study. Among them, the most potent compound 11k, 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ureido)phenoxy)-6-methoxyquinolin-7-yl)oxy)-N-isopropylpiperidine-1-carboxamide, possessed submicromolar c-Met and Ron inhibitory activities. In addition, enzymatic assays against a mini-panel of kinases (c-Kit, B-Raf, c-Src, IGF1R, PDGFRα and AXL) were performed, the results showed that compound 11k exhibited moderate inhibitory activity against PDGFRα, c-Src and AXL. MTT assay revealed in vitro antitumor activities against HT-29 cells of compound 11k with an IC50 value of 0.31 µM which was 9.3- and 34.2-fold more potent than that of Regorafenib (IC50 = 2.87 µM) and Cabozantinib (IC50 = 10.6 µM). Preliminary antitumor mechanisms were also investigated by cellular assays. Considerable cytotoxicity, antiproliferation and induction of apoptosis of compound 11k in a dose- and time-dependent manner were confirmed by IncuCyte live-cell imaging assays. Treatment with compound 11k caused slight G2-or M-phase arrest in HT-29 cells. Further cell selectivity of compound 11k showed that it was not active against human normal colorectal mucosa epithelial cell FHC at 10.0 µg/mL. The above results support further structural modification of compound 11k to improve its inhibitory activity, which will lead to more potent anticancer agents.

Purification, structural characterization, and cognitive improvement activity of a polysaccharides from Schisandra chinensis.

The present study aimed to evaluate structural characteristics of a polysaccharides, SCP2-1, isolated from Schisandra chinensis (Turcz.) Baill (S. chinensis) and to assess its improvement on cognitive dysfunction caused by excessive neuroinflammation. Structural characterization indicated that SCP2-1 was composed of glucose and galactose in a molar ratio of 8.78:1.23 with molecular weight of 5.388 kDa. The main linkages of the glycosidic bonds of SCP2-1were 1,4-linked-Glcp, 1,4-linked-Galp, 1-linked-Galp and 1,4,6-linked-Galp. The evaluation of behavioral pharmacology and the detection of biochemical markers exhibited that SCP2-1 could improve LPS-induced cognitive dysfunction in mice, ameliorate excessive inflammatory response. The results showed that SCP2-1 could ameliorated the animals' exploration time of novel arm in Y maze test, shortened the escape latency of mice in MWM test, and increased the exploration time of new object in NOR test. What's more, mice could improve histopathological changes induced by LPS, suppress the over-activation of glial cells, decrease the expression of proinflammatory cytokines, increase the levels of anti-inflammatory cytokines, reduce the levels of NLRP3, M-caspaes-1, which may further induce the decrease of excessive deposition of Aß. Furthermore, SCP2-1 could inhibit the over-activation of NF-κB and the hyperphosphorylation of P38 MAPK pathway.