A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT.

The tumor suppressor protein p53 is central to cancer biology, with its pathway reactivation emerging as a promising therapeutic strategy in oncology. This study introduced LZ22, a novel compound that selectively inhibits the growth, migration, and metastasis of tumor cells expressing wild-type p53, demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant p53. LZ22's mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 protein. This interaction disrupted the MDM2-p53 binding, consequently stabilizing p53 by shielding it from proteasomal degradation. LZ22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling pathway. Moreover, LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT, effectively reducing tumor cell migration and distal metastasis. Importantly, LZ22 administration in tumor-bearing mice did not manifest notable side effects. The findings position LZ22 as a structurally unique reactivator of p53, offering therapeutic promise for the management of human cancers with wild-type TP53.

[Effect of nanoparticles of different stiffness combined with menthol/curcumol on mechanical properties of bEnd.3 cells].

This study aimed to investigate the effects of nanoparticles PLGA-NPs and mesoporous silicon nanoparticles(MSNs) of different stiffness before and after combination with menthol or curcumol on the mechanical properties of bEnd.3 cells. The particle size distributions of PLGA-NPs and MSNs were measured by Malvern particle size analyzer, and the stiffness of the two nanoparticles was quantified by atomic force microscopy(AFM). The bEnd.3 cells were cultured in vitro, and the cell surface morphology, roughness, and Young's modulus were examined to characterize the roughness and stiffness of the cell surface. The changes in the mechanical properties of the cells were observed by AFM, and the structure and expression of cytoskeletal F-actin were observed by a laser-scanning confocal microscope. The results showed that both nanoparticles had good dispersion. The particle size of PLGA-NPs was(98.77±2.04) nm, the PDI was(0.140±0.030), and Young's modulus value was(104.717±8.475) MPa. The particle size of MSNs was(97.47±3.92) nm, the PDI was(0.380±0.016), and Young's modulus value was(306.019±8.822) MPa. The stiffness of PLGA-NPs was significantly lower than that of MSNs. After bEnd.3 cells were treated by PLGA-NPs and MSNs separately, the cells showed fine pores on the cell surface, increased roughness, decreased Young's modulus, blurred and broken F-actin bands, and reduced mean gray value. Compared with PLGA-NPs alone, PLGA-NPs combined with menthol or curcumol could allow deepened and densely distributed surface pores of bEnd.3 cells, increase roughness, reduce Young's modulus, aggravate F-actin band breakage, and diminish mean gray value. Compared with MSNs alone, MSNs combined with menthol could allow deepened and densely distributed surface pores of bEnd.3 cells, increase roughness, reduce Young's modulus, aggravate F-actin band breakage, and diminish mean gray value, while no significant difference was observed in combination with curcumol. Therefore, it is inferred that the aromatic components can increase the intracellular uptake and transport of nanoparticles by altering the biomechanical properties of bEnd.3 cells.

Tao-Hong-Si-Wu decoction improves depressive symptoms in model rats via amelioration of BDNF-CREB-arginase I axis disorders.

CONTEXT: The traditional Chinese medicine formula Tao-Hong-Si-Wu decoction (TSD), used for treating ischaemic stroke, has the potential to treat depressive disorder (DD). OBJECTIVE: To explore the effective targets of TSD on DD animal models. MATERIALS AND METHODS: Sprague-Dawley (SD) rats were modelled by inducing chronic unpredictable mild stress (CUMS) during 35 days and treated with three dosages of TSD (2.5, 5 and 10 g/kg) or fluoxetine (10 mg/kg) by oral gavage for 14 days. Bodyweight measurements and behavioural tests were performed to observe the effect of TSD on the CUMS animals. A gas chromatography coupled with mass spectrometry (GC-MS)-based metabolomic analysis was conducted to reveal the metabolic characteristics related to the curative effect of TSD. Levels of the proteins associated with the feature metabolites were analysed. RESULTS: Reduced immobile duration and crossed squares in the behavioural tests were raised by 48.6% and 32.9%, on average, respectively, by TSD treatment (ED50=3.2 g/kg). Antidepressant effects of TSD were associated with 13 decreased metabolites and the restorations of ornithine and urea in the serum. TSD (5 g/kg) raised serum serotonin by 54.1 mg/dL but suppressed arginase I (Arg I) by 47.8 mg/dL in the CUMS rats. Proteins on the brain-derived neurotrophic factor (BDNF)-cAMP response element-binding protein (CREB) axis that modulate the inhibition of Arg I were suppressed in the CUMS rats but reversed by the TSD intervention. DISCUSSION AND CONCLUSIONS: TSD improves depression-like symptoms in CUMS rats. Further study will focus on the antidepressant-like effects of effective compounds contained in TSD.

Norlignans and phenolics from genus Curculigo protect corticosterone-injured neuroblastoma cells SH-SY5Y by inhibiting endoplasmic reticulum stress-mitochondria pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The plants of genus Curculigo are divided into the Section Curculigo and the Section Capitulata, which are mainly distributed in southeastern and southwestern China. Various ancient chinese books record that these plants were used as an important herb for tonifying kidney yang. Traditional Chinese medicine often draws on this property to treat depression syndrome. Thus genus Curculigo has potential for the treatment of neurodegenerative diseases (ND). The study showed that phenolics were the main characteristic components of plants in the Section Curculigo, represented by orcinol glucoside and curculigoside; the norlignans, with Ph-C5-Ph as the basic backbone, were the main characteristic components of the Section Capitulata. However, there is a lack of sufficient scientific evidence as to whether these two types of ingredients have neuroprotective effects. AIM OF THE STUDY: To determine the neuroprotective effects of phenolics and norlignans in genus Curculigo on human neuroblastoma cells SH-SY5Y. To discuss their structure-activity relationship and screen for compounds with high activity and neuroprotective effects. To reveal that the amelioration of endoplasmic reticulum (ER) stress by two classes of compounds is mediated by the PERK/eIF2α/ATF4 pathway. MATERIALS AND METHODS: The cytotoxicity of 17 compounds was assayed by MTT. SH-SY5Y cells were damaged by corticosterone (Cort) (200 µM) for 24 h and then co-administered with 17 compounds (0.1-100 µM) and Cort (200 µM) for 24 h. Cell survival was determined by MTT assay. Apoptosis rate, mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) levels were detected using flow cytometry. Intracellular Ca2+ levels were detected using a fluorescent probe. Cellular mitochondrial and ER damage was observed using transmission electron microscopy (TEM). ER stress and apoptotic pathway-related proteins (BiP, CHOP, cleaved caspase-3, cleaved caspase-9, Bax/Bcl-2), and the expression level of PERK/eIF2α/ATF4 pathway was measured via western blot (WB). RESULTS: The experimental data showed that Cort treatment of SH-SY5Y cells resulted in decreased cell survival and increased apoptosis, mitochondrial depolarization, ROS, and intracellular Ca2+ levels. The co-action of 17 compounds and Cort for a period of time significantly increased cell survival. Compounds 3, 7, 12, 13 also reduced apoptosis rate, mitochondrial depolarization, ROS and intracellular Ca2+ levels in the subsequent experiments. In addition, TEM observed that Cort caused mitochondrial and ER damage, and the damage was improved after treatment. WB analysis obtained that Cort increased the expression of apoptotic and ER stress-related proteins and activated pathway expression. However, in the presence of compounds 3, 7, 12, 13, the expression of BiP, CHOP, cleaved caspase-3, cleaved caspase-9, and Bax/Bcl-2 was significantly reduced, and the phosphorylation of PERK and eIF2α and the expression of ATF4 were inhibited. CONCLUSION: This study found that one phenolic (3) and three norlignans (7, 12, 13) from genus Curculigo have significant neuroprotective effects. The results of the structure-activity relationship indicated that the glucosyl polymeric norlignans and the phenolics with benzoic acid as the parent nucleus were more active. The neuroprotective effect of three norlignans is the latest discovery. This finding has important research value in the field of prevention and treatment of neurodegenerative diseases.

Erxian Decoction, a Famous Chinese Medicine Formula, Ameliorate Depression- Like Behavior in Perimenopausal Mice.

AIMS: The present study was performed in order to find out the anti-depression effect of Erxian Decoction in perimenopausal mice. BACKGROUND: Erxian Decoction (EXD) has been used in folk medicine for the treatment of perimenopausal syndrome, but it has not been researched on perimenopausal depression. OBJECTIVE: The present study aimed to evaluate the effect of extraction of Erxian Decoction on perimenopausal depressive mice. METHODS: In this study, female ICR mice were randomly divided into 6 groups: Low, medium and high dose of EXD groups (0.5, 1.5, and 4.5 g/kg), soy isoflavones group (250 mg/kg) and Sham group. The mice in the Sham group received sham surgery (within ovaries), and the others were excised with bilateral ovaries and exerted by 28-day chronic mild unpredictable stimulation for the establishment of a perimenopausal depression model. RESULTS: Behavioral tests showed that EXD could relieve depression symptoms and improve spatial memory in mice. Western blotting showed that EXD significantly up-regulated the expression of brain-derived neurotrophic factor (BDNF) and Bcl-2 in hippocampus and estrogen receptors (ERs) in the uterus and adrenals, protecting hippocampal tissue and antagonizing the symptoms of estrogen deficiency in mice, which was further proved within a uterine morphology test. In addition, EXD reduced the serum levels of follicle-stimulating hormone, luteinizing hormone, and interleukin- 6. CONCLUSION: These results indicated that EXD can regulate hormone secretion and recover hippocampal damage in perimenopausal depressed mice. Besides, it can antagonize the symptoms of ovarian hormone deficiency as well as relieve perimenopausal syndrome.

Evaluation of Anti-Diabetic Potential of Corn Silk in High-Fat Diet/ Streptozotocin-Induced Type 2 Diabetes Mice Model.

BACKGROUND: Corn silk is the elongated stigma of the female flower of Zea mays and traditionally used to treat diabetes mellitus (DM). OBJECTIVE: To investigate the beneficial effects of corn silk extract (CSE) on HFD/STZ-induced diabetic C56BL/6J mice. METHODS: Establishment of a T2DM model through feeding HFD combined with STZ. T2DM was randomly divided into 5 groups: diabetic control mice treated with vehicle (model group, n=10), metformin- treated group (metformin: 150 mg/kg.d, n=10), three CS-treated groups (CS: 300, 600 and 1200 mg/kg.d, n=10). After four weeks of CS treatment, the body weight, FBG, IR, TC, TG, LDL-C, MDA and SOD levels of mice were measured. In addition, the liver tissue was histomorphologically analyzed by HE stain followed a light microscopy observation. RESULTS: 4-week CSE treatment significantly reduced FBG and enhanced the glucose tolerance; improved IR indicated by decreased HOMA-IR and elevated ISI; alleviated hyperlipidemia indicated by decreased TC, TG, LDL-C, and increased HDL-C; reduced oxidative stress by decreased MDA and elevated SOD activity; decreased hepatic lipid accumulation and prevented liver tissue morphological change in T2DM. In addition, CSE treatments effectively prevent the weight gain loss of diabetic mice. CONCLUSION: These results confirmed the traditionally claimed benefits of corn silk on DM, which suggested that the corn silk possessed the anti-diabetic potential and could be further developed as a cheap and plant-derived agent for the treatment of type 2 diabetes mellitus.

Erxian decoction, a famous Chinese medicine formula, antagonizes corticosterone-induced injury in PC12 cells, and improves depression-like behaviours in mice.

Context: In folk medicine, erxian decoction (EXD) is used to treat perimenopausal syndrome in women. It is also used clinically to treat depression, but the mechanism remains unknown.Objectives: To investigate the neuroprotective effect of EXD, and its antidepressant potential.Materials and methods: ICR mice were treated with EXD (0.5, 1.5 and 4.5 g/kg i.g.) and fluoxetine (6.0 mg/kg i.g.) for 10 days. On day 10 of the treatment, depression-like behaviour was induced by reserpine (2.5 mg/kg injected i.p.), and after 24 h of reserpine administration, it was assessed using the tail suspension and forced swimming tests. MTT assay, lactate dehydrogenase test, flow cytometry analysis, Hoechst staining and western blotting were used to assess the apoptosis of PC12 cells. Apoptosis proteins and neurotransmitter were tested in vitro and in vivo, respectively.Results: MTT assay results showed corticosterone prevented cell growth, but EXD at concentrations of 100, 200 and 400 µg/mL restored cell viability (EC50: 204.016 µg/mL). EXD decreased lactate dehydrogenase leakage from 63.48 to 43.60 U/L, and upregulated expression of Bcl-2 while the expression of Bax, caspase-3 and caspase-8 were decreased in vivo and in vitro. Moreover, EXD improved depression-like behaviour in mice, and 4.5 g/kg EXD treatment increased the secretion of serotonin, dopamine and norepinephrine by 67.44, 28.12 and 42.12 pg/mg, respectively, in hypothalamus compared to that of reserpine group.Discussion and conclusions: EXD demonstrated neuroprotective effects and improved depression-like behaviour in mice. Further research should be focussed on the mechanism of the active components in EXD.

Chemical constituents with cytotoxic and anti-inflammatory activity in Hypericum sampsonii and the antitumor potential under the view of cancer-related inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic inflammation has an important role in the development of cancers. Hypericum sampsonii, known as "Yuanbao Cao", is mainly distributed in the southwest of China. As a folk medicinal plant, "Yuanbao Cao" is traditionally used for treatment of various inflammation-related diseases including swelling, burns, arthritis, and dermatitis, etc. The plant is a promising anticancer herb. However, there is no research on the antitumor potential of this plant from the view of cancer-related inflammation strategy. AIM OF THE STUDY: To explore the H. sampsonii in relation to cancer-related chemical constituents with anti-inflammatory and cytotoxic activity in cancer-related inflammation. MATERIALS AND METHODS: The chemical constituents of H. sampsonii were isolated by repeated chromatography techniques, and their structures were identified mainly by spectroscopic methods and compared to published data. The chemical profile of the herb was analyzed using HPLC. The cytotoxicities of compounds against five cancer cell lines: human melanoma cell (A375), human breast cancer cell (MDA-MB-231), human gastric cancer cell (SGC-7901), human colon cancer cell (SiHa), and human bone marrow neuroblastoma cell (SHSY-5Y), were tested using MTT assay; their anti-inflammatory activities were evaluated by inhibition on NO production in LPS-stimulated RAW 264.7, THP-1 and BV-2 microglial cells. RESULTS: Twenty-five compounds, including four phenols (1-4), two anthraquinonoids (5 and 6), six xanthones (7-12), one benzophenone (13), one phloroglucinol (14), nine flavonoids (15-23), one sterol (24) and one alkaloid (25), were isolated from the EtOH extract of H. sampsonii. Of them, compounds 3, 4, 6, 7, 10-14, 17, 19, 22 and 23 were reported in H. sampsonii for the first time. HPLC analysis showed that flavonoids were the main constituents in the herb. MTT assay revealed that compounds 1, 2, 5-14, 15, 17, 18, 20, 21, 22 and 25 had selective cytotoxic activities (IC50: 7.52-158.90 µM) against tested cancer cells, in which compound 5, 6, 13 and 14 displayed high activities against A375, MDA-MB-231, SiHa and SHSY-5Y. In the screening experiment of anti-inflammatory activity, most compounds (1-2, 5-23) showed considerable high anti-inflammatory activities (IC50: 10.59-42.75 µM), in which compounds 5, 6, 13, 14, and 15 exhibited high anti-inflammatory activities in LPS-stimulated RAW264.7, THP-1 and BV-2 microglial cells. CONCLUSIONS: Compounds 3, 4, 6, 7, 10-14, 17, 19, 22 and 23 were isolated for the first time from H. sampsonii. Compound 5, 6, 13 and 14 displayed high cytotoxic activities against the tested cancer cell lines. Compounds (1-2, 5-23) showed anti-inflammatory activities, of them, compounds 5, 6, 13, 14 and 15 exhibited the high activity. From the view of cancer-related inflammation point, not only the compounds with high cytotoxicity, but those compounds with anti-inflammatory activities, especially the flavonoids, contribute to the antitumor potential of H. sampsonii. The results and viewpoint of present study provide a different insight to better understand the antitumor potential of H. sampsonii, and may also promote the reasonable usage of this folk medical herb.

Nucleoside and N-acetyldopamine derivatives from the insect Aspongopus chinensis.

Two new nucleoside derivatives, named asponguanosines A and B (1 and 2), three new N-acetyldopamine analogues, aspongamides C-E (3-5), one new sesquiterpene, aspongnoid D (6), and three known compounds were isolated from the medicinal insect Aspongopus chinensis. Their structures including absolute configurations were assigned by using spectroscopic methods and ECD and 13C NMR calculations. Biological activities of compounds 3-7 towards human cancer cells, COX-2, ROCK1, and JAK3 were evaluated.

Renoprotective meroterpenoids from the fungus Ganoderma cochlear.

Nine multifarious new meroterpenoids, cochlearols E-M (1-9), along with seven known meroterpenoids 10-16, were isolated from the fruiting bodies of Ganoderma cochlear. Racemic 1, 6-8, 10 and 13 were separated by chiral HPLC. The structures were elucidated based on detailed spectroscopic analyses (HRESIMS, 1D/2D-NMR) and calculated electronic circular dichroism (ECD). Their biological activities against renal fibrosis were evaluated by using rat normal and diseased renal interstitial fibroblast cells (NRK49F). The results show that compounds 7a, 7b, and 10a exhibit potent proliferation inhibition in TGF-ß1-induced NRK-49F cells.

Medicinal plants of Chinese Pharmacopoeia and Daodi: Insights from phylogeny and biogeography / 中草药·英文版

Objective: The Chinese Pharmacopoeia (2015) includes 584 plant medicines, of which 284 also contain high quality subsets, so called “Daodi” components, where Daodi denotes superior clinical properties compared to non-Daodi counterparts despite being sourced from the same species. Commercial and clinical drivers of selection for Daodi have been described elsewhere. Our objective is to investigate the overall composition of Daodi to determine in what ways medicines with Daodi as a whole differ from the other plants of the Chinese Pharmacopoeia. A further objective is to characterise the Chinese Pharmacopoeia and Daodi in terms of the plant species including their traits and distribution. Methods: We used trait analysis to identify whether Daodi species were significantly different from the remaining Chinese Pharmacopoeia plant species in any traits. We used biogeographic methods and an existing classification of Daodi into 10 regions to identify spatial patterns amongst the species. Regression and binomial analyses were used to test for over- and under-use of plant families and endemic species. Preferences for lineages were visualized using phylogenetic mapping. Results: We found that Daodi species (species with any Daodi subset) were more likely to be roots that are “hot” or “warm” and less likely to be “oxic” according to traditional Chinese medicine (TCM) concepts. Roots were over-represented in the Bei region, and whole plants over-represented in Guang. Both the Chinese Pharmacopoeia and Daodi indicated preferences for families not common in previously studied ethnopharmacopoeias, and fewer endemic species were represented than expected by chance. Conclusion: Using the phylogenetic and biogeographical methods, we highlighted patterns of plant use, and the biological characters of Daodi medicinal plants. Our study points towards cultural preferences in need of scientific explanation.

Two new neolignans from Patrinia scabra with potent cytotoxic activity against HeLa and MNK-45 cells.

Two new neolignans, patrineolignan A (1) and patrineolignan B (2), together with seven known lignans, were isolated from the 90 % aqueous EtOH extract of the roots of Patrinia scabra. Their structures were elucidated on the basis of spectroscopic data (HRESIMS, IR, 1D and 2D NMR) and comparison with literature data. The two new neolignans were evaluated in vitro for cytotoxic properties against human cervical carcinoma HeLa cell line and gastric carcinoma MNK-45 cell line using the microculture tetrazolium assay, and both 1 and 2 exhibited strongly cytotoxic activity against the two tumor cell lines.

New norlignan derivatives from Curculigo capitulata.

Two new norlignan derivatives, crassifoside I (1) and sinensigenin C (2), were isolated from the rhizomes of Curculigo capitulate, along with six known norlignan derivatives, 1,1-bis(3,4-dihydroxyphenyl)-1-(2-furan)-methane (3), crassifogenin B (4), crassifoside A (5), breviscaside A (6), crassifoside D (7), and curcapital (8). Their structures were elucidated on the basis of spectral evidence and comparisons with literature data. The 1H and 13C NMR data of compound 3 was first assigned. Compounds 3-7 were isolated from this plant for the first time.

Chemical constituents from the leaves of Ilex pernyi / 药学学报

A new compound and five known compounds were isolated from the ethanolic extract of the leaves of Ilex pernyi Franch. Their structures were established on the basis of spectral analysis and identified as trans-isoeugenyl-alpha-L-arabinopynosyl (1 --> 6) -beta-D-glucopyranoside (1) , kaempferol-3-O-sambubioside (2), quercetin-3-O-sambubioside (3), isoquercitrin (4), (+) -syringaresinol-O-beta-D-glucopyranoside (5), amarantholidoside IV (6). Among them, compound 1 is a new phenolic glycoside, named as ilexperphenoside A, and compounds 2-6 were isolated from this plant for the first time.

Studies on chemical constituents of aerial parts of Ammopiptanthus mongolicus / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the chemical constituents of the aerial parts of Ammopiptanthus mongolicus.</p><p><b>METHOD</b>The chemical constituents were isolated by various column chromatographic methods. The structures were identified by spectral data.</p><p><b>RESULT</b>Ten compounds were isolated and identified as m-hydroxybenzoic acid (1), 1-(4-hydroxyphenyl) ethanone (2), beta-sitosterol (3), (-)-syringaresinol (4), (+)-lariciresinol (5), blumenol A (6), blumenol B (7), beta-daucosterol (8), coniferin (9), syringin (10).</p><p><b>CONCLUSION</b>The ten compounds were obtained from the genus Ammopiptanthus for the first time.</p>

Studies on triterpenoid constituents in leaf of Ilex pernyi / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the chemical constituents of Ilex pernyi.</p><p><b>METHOD</b>The chemical constituents were isolated by various column chromatographic methods. The structures were identified by spectral data.</p><p><b>RESULT</b>Eight triterpenoid compounds were isolated and identified as ursolic acid (1), lupeol (2), alpha-amyrin (3), uvaol (4), 3beta-hydroxyurs-11-ene-13beta-olide (5), pomolic acid (6), lup-20 (29)-ene-3beta, 24-diol (7), 3beta, 23-dihydroxy-urs-12-en-28-oic acid (8).</p><p><b>CONCLUSION</b>The eight compounds were obtained from this plant for the first time.</p>