A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer

Breast cancer (BC) is the second leading cause of death among women, and it has become a global health issue due to the increasing number of cases. Different treatment options, including radiotherapy, surgery, chemotherapy and anti-estrogen therapy, aromatase inhibitors, anti-angiogenesis drugs, and anthracyclines, are available for BC treatment. However, due to its high occurrence and disease progression, effective therapeutic options for metastatic BC are still lacking. Considering this scenario, there is an urgent need for an effective therapeutic strategy to meet the current challenges of BC. Natural products have been screened as anticancer agents as they are cost-effective, possess low toxicity and fewer side effects, and are considered alternative therapeutic options for BC therapy. Natural products showed anticancer activities against BC through the inhibition of angiogenesis, cell migrations, proliferations, and tumor growth; cell cycle arrest by inducing apoptosis and cell death, the downstream regulation of signaling pathways (such as Notch, NF-κB, PI3K/Akt/mTOR, MAPK/ERK, and NFAT-MDM2), and the regulation of EMT processes. Natural products also acted synergistically to overcome the drug resistance issue, thus improving their efficacy as an emerging therapeutic option for BC therapy. This review focused on the emerging roles of novel natural products and derived bioactive compounds as therapeutic agents against BC. The present review also discussed the mechanism of action through signaling pathways and the synergistic approach of natural compounds to improve their efficacy. We discussed the recent in vivo and in vitro studies for exploring the overexpression of oncogenes in the case of BC and the current status of newly discovered natural products in clinical investigations.     

可溶性鸟苷酸环化酶介导NO信号转导的结构基础及其分子机制研究

可溶性鸟苷酸环化酶(sGC)是NO信号转导通路中的核心金属酶,是NO的敏感器和受体.sGC含有?和?两个亚基,每个亚基分别具有3个结构域,包括血红素结构域、中心结构域和催化结构域,两个亚基的血红素结构域共享有一个血红素,NO结合到sGC的血红素后,激活sGC,催化其底物GTP转化为二级信号分子cGMP,开启PKG信号通路,导致血管舒张.NO信号转导通路异常将导致多种疾病的发生,如多种心血管疾病、肺动脉高血压、心力衰竭及神经退行性疾病等.近20年来,关于sGC的结构、功能、激活机制及其在生理与病理中的作用有了很多进展.本文重点对sGC的结构、功能及其活化/失活机制研究进展进行综述.     

The Signaling Pathways and Targets of Natural Compounds from Traditional Chinese Medicine in Treating Ischemic Stroke

Ischemic stroke (IS) is a common neurological disorder associated with high disability rates and mortality rates. At present, recombinant tissue plasminogen activator (r-tPA) is the only US(FDA)-approved drug for IS. However, due to the narrow therapeutic window and risk of intracerebral hemorrhage, r-tPA is currently used in less than 5% of stroke patients. Natural compounds have been widely used in the treatment of IS in China and have a wide range of therapeutic effects on IS by regulating multiple targets and signaling pathways. The keywords “ischemia stroke, traditional Chinese Medicine, Chinese herbal medicine, natural compounds” were used to search the relevant literature in PubMed and other databases over the past five years. The results showed that JAK/STAT, NF-κB, MAPK, Notch, Nrf2, and PI3K/Akt are the key pathways, and SIRT1, MMP9, TLR4, HIF-α are the key targets for the natural compounds from traditional Chinese medicine in treating IS. This study aims to update and summarize the signaling pathways and targets of natural compounds in the treatment of IS, and provide a base of information for the future development of effective treatments for IS.     

Elucidation of Pathways for NO Electroreduction on Pt(111) from First Principles

The mechanism of nitric oxide electroreduction on Pt(111) is investigated using a combination of first principles calculations and electrokinetic rate theories. Barriers for chemical cleavage of N? O bonds on Pt(111) are found to be inaccessibly high at room temperature, implying that explicit electrochemical steps, along with the aqueous environment, play important roles in the experimentally observed formation of ammonia. Use of explicit water models, and associated determination of potential‐dependent barriers based on Bulter–Volmer kinetics, demonstrate that ammonia is produced through a series of water‐assisted protonation and bond dissociation steps at modest voltages (<0.3 V). In addition, the analysis sheds light on the poorly understood formation mechanism of nitrous oxide (N₂O) at higher potentials, which suggests that N₂O is not produced through a Langmuir–Hinshelwood mechanism; rather, its formation is facilitated through an Eley–Rideal‐type process.     

An in vitro Study on Transition from NO-Hemoglobin to Methemoglobin： Oxygen Effect

The nitrosyl-hemoglobin (HbNO) is the carrier of nitric oxide (NO) which is the important messenger molecule displaying multiple physiologic and pathophysiologic roles. However it is still not clear for the fate of HbNO molecules during the venous-arterial transit. In this letter, the HbNO transition in vitro was studied by using the electron paramagnetic resonance (EPR) spectra. It was found that HbNO molecules were stable when oxygen did not exist in the system but not stable in aerobic conditions. The absorption spectra further revealed that the methemoglobin (metHb) was the product of HbNO in aerobic environment, showing that the HbNO changed to metHb when there were enough oxygen molecules in the system.     

用分子筛修饰制备的NO传感器的电化学性能研究

采用层层组装方法(LBL),将纳米方钠石分子筛进一步修饰到经镍(Ⅱ)四磺酸基酞菁(NiTSPc)和全氟磺酸离子交联聚合物(NafionR)修饰的玻碳电极(GCE/NiTSPc/NafionR)表面上,制得一新型NO传感器GCE/NiTSPc/NafionR/(PDDA/Zeolite)5 (PDDA即聚二甲基二烯丙基氯化铵),并对其电化学性能进行了研究.结果表明,纳米方钠石分子筛修饰膜不仅可提高电极检测NO的灵敏度(由26 Ma/(mol·L-1)升至29 Ma/(mol·L-1)),还可提高电极抵抗共存物干扰的能力.Nafion修饰层可使电极对抗坏血酸、多巴胺、肾上腺素及亚硝酸钾的响应分别降低19%、0%、11%、33%,而进一步修饰纳米方钠石分子筛后,电极对上述干扰物质的响应分别降低了68%、51%、52%和39%.     

Study on patterns and chemical features of NO effect on marine phytoplankton growth

With supernatural bioactivation, nitric oxide (NO), which was first regarded as an endothelium- derived relaxing factor, was recognized by Science as the “Molecule of the Year” in 1992. The Nobel Prize of Physiology & Medicine in 1998 was awarded jointly to Furchgatt, Ignarro, and Murad for their discoveries concerning the NO effects in the cardiovascular sys- tem. From then on, researchers have paid more and more attention to the special and diverse functions of NO in organism[1―18].…     

An isoindole alkaloid from Portulaca oleracea L.

A novel isoindole alkaloid named oleraisoindole (1), together with six known compounds, 7′-ethoxy-trans-feruloyltyramine (2), N-trans-feruloyltyramine (3), N-trans-feruloyl-3-methoxytyramine (4), N-trans-p-coumaroyltyramine (5) aurantiamide (6) and ferulic acid methyl ester (7) were isolated from Portulaca oleracea L. Compounds 2 and 7 were isolated for the first time from this plant. Compound 1 was identified using spectroscopic methods including HR-ESI-TOF-MS, 1D-NMR, 2D-NMR. It was tested in a nitric oxide (NO) inhibition assay and was shown to inhibit NO production in RAW 264.7 cells induced by LPS.     

From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.     

Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways

Drug resistance is still an obstacle in cancer therapy, leading to the failure of tumor treatment. The emergence of tumor drug resistance has always been a main concern of oncologists. Therefore, overcoming tumor drug resistance and looking for new strategies for tumor treatment is a major focus in the field of tumor research. Natural products serve as effective substances against drug resistance because of their diverse chemical structures and pharmacological effects. We reviewed the signaling pathways involved in the development of tumor drug resistance, including Epidermal growth factor receptor (EGFR), Renin-angiotensin system (Ras), Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), Wnt, Notch, Transforming growth factor-beta (TGF-β), and their specific signaling pathway inhibitors derived from natural products. This can provide new ideas for the prevention of drug resistance in cancer therapy.     

新型甲氨蝶呤衍生物的合成

设计合成了新的甲氨蝶呤(methotrexate, MTX)衍生物1～4, 在这些新化合物中, 将MTX分子中10-位对氨基苯甲酰谷氨酸砌块移植到4-位, 同时在6-位引入苯环芳香基以及甲基等基团. 生物活性测试结果显示, 化合物1～4具有与MTX相似的抑制iNOS活性的作用; 相对于MTX, 选测的化合物2和4明显地增强了抑制K-562白血病细胞株生长的活性. 本研究为进行MTX的结构修饰开辟了新途径, 2-氨基-4-[N-(对氨基苯甲酰谷氨酸)-基]-6-取代基蝶啶衍生物可成为潜在的抗肿瘤候选药物被进一步研究.     

Nanomolar Nitric Oxide Concentrations in Living Cells Measured by Means of Fluorescence Correlation Spectroscopy

Measurement of the nitric oxide (NO) concentration in living cells in the physiological nanomolar range is crucial in understanding NO biochemical functions, as well as in characterizing the efficiency and kinetics of NO delivery by NO-releasing drugs. Here, we show that fluorescence correlation spectroscopy (FCS) is perfectly suited for these purposes, due to its sensitivity, selectivity, and spatial resolution. Using the fluorescent indicators, diaminofluoresceins (DAFs), and FCS, we measured the NO concentrations in NO-producing living human primary endothelial cells, as well as NO delivery kinetics, by an external NO donor to the immortal human epithelial living cells. Due to the high spatial resolution of FCS, the NO concentration in different parts of the cells were also measured. The detection of nitric oxide by means of diaminofluoresceins is much more efficient and faster in living cells than in PBS solutions, even though the conversion to the fluorescent form is a multi-step reaction.     

NO的催化氧化

采用傅里叶变换红外光谱定量分析方法研究了γ－Ａｌ２Ｏ３,ＴｉＯ２和硅胶负载的金属氧化物和贵金属催化剂对ＮＯ催化氧化反应的活性,考察了反应温度、活性组分负载量、空速及预氧化还原处理等因素对催化剂活性的影响,并以ＮＯ的催化氧化机理为基础,对各种因素影响机理进行了分析,实验结果表明,ＭｎＯ,Ｃｒ２Ｏ３和Ｃｏ３Ｏ４催化剂的活性较好：预处理条件对贵金属催化剂Ｐｔ／Ａｌ２Ｏ３的活性影响较大,不同载体及不同的活     

What Flow Injection has to Offer in the Environmental Analytical Field

NO plays an important role in the regulation of physiological and pathophysiological mechanisms, and quite a lot of investigations have been focused on this kind of special molecule. It is difficult to achieve reliable ex vivo NO measurements with the existing analytical methods, and developing a reliable in vivo monitoring method for NO is still an urgent task. In this review, the techniques utilized for the determination of endogenous NO formed by enzymatic action and its reactions with other biological substances found in living organisms are discussed with respect to applications both in vivo or in vitro. In addition, various NO (micro)sensors and trap probes based on different principles are presented with their respective advantages and limitations. Finally, an NO monitoring system based on the combination of microdialysis sampling and chemiluminescence is introduced which is considered to be a prospective method for in vivo monitoring.     

Anti-Aging Effect of Momordica charantia L. on d-Galactose-Induced Subacute Aging in Mice by Activating PI3K/AKT Signaling Pathway

Anti-aging is a challenging and necessary research topic. Momordica charantia L. is a common edible medicinal plant that has various pharmacological activities and is often employed in daily health care. However, its anti-aging effect on mice and the underlying mechanism thereof remain unclear. Our current study mainly focused on the effect of Momordica charantia L. on d-galactose-induced subacute aging in mice and explored the underlying mechanism. UHPLC-Q-Exactive Orbitrap MS was applied to qualitatively analyze the chemical components of Momordica charantia L. ethanol extract (MCE). A subacute aging mice model induced by d-galactose (d-gal) was established to investigate the anti-aging effect and potential mechanism of MCE. The learning and memory ability of aging mice was evaluated using behavioral tests. The biochemical parameters, including antioxidant enzyme activity and the accumulation of lipid peroxides in serum, were measured to explore the effect of MCE on the redox imbalance caused by aging. Pathological changes in the hippocampus were observed using hematoxylin and eosin (H&E) staining, and the levels of aging-related proteins in the PI3K/AKT signaling pathway were assessed using Western blotting. The experimental results demonstrated that a total of 14 triterpenoids were simultaneously identified in MCE. The behavioral assessments results showed that MCE can improve the learning and memory ability of subacute mice. The biochemical parameters determination results showed that MCE can improve the activity of antioxidant enzymes and decrease the accumulation of lipid peroxides in aging mice significantly. Furthermore, aging and injury in the hippocampus were ameliorated. Mechanistically, the results showed a significant upregulation in the protein expression of P-PI3K/PI3K and P-AKT/AKT (p < 0.01), as well as a significant reduction in cleaved caspase-3/caspase-3, Bax and P-mTOR/mTOR (p < 0.01). Our results confirm that MCE could restore the antioxidant status and improve cognitive impairment in aging mice, inhibit d-gal-induced apoptosis by regulating the PI3K/AKT signaling pathway, and rescue the impaired autophagy caused by mTOR overexpression, thereby exerting an anti-aging effect.     

An Approach for the Selective Detection of Nitric Oxide in Biological Systems: An in vitro and in vivo Perspective

A naphthalimide‐based fluorescent probe, LyNP‐NO , was designed and synthesized for the selective detection of exogenously and endogenously generated nitric oxide (NO) in C6 glial cells. In addition, LyNP‐NO was also explored for monitoring endogenous NO levels in rat hippocampus at various tissue depths by stimulating the brain with N‐methyl‐d ‐aspartate (NMDA).     

Theoretical study of NO adsorption/dissociation on Pd (100) and (111) surfaces

Both adsorption and dissociation of the diatomic molecular NO on Pd (100) and (111) surfaces are studied using the extended London‐Eyring‐Polyani‐Sato (LEPS) method constructed by means of 5‐MP (the 5‐parameter Morse potential). All critical characteristics of the system that we obtain, such as adsorption geometry, binding energy, eigenvalues for vibration, are in good agreement with the experimental results. On Pd (100) surface, NO prefers to adsorb in fourfold hollow site (H) uprightly at low coverage. With increase in the coverage NO gradually tilts in fourfold hollow and bridge sites. For NO? Pd (111) system, two adsorption states are found at low coverage, of which one adsorption state is the B(tilt) state that the centroid of NO projects at bridge site, another (H? B? H state) that NO almost parallels to the (111) surface with the vibration frequency of 610 cm^?1, but the frequency is near to that of the atoms, which is easy to be ignored in experiments. At high coverage, two transitional states (BH and HT) are found. NO is difficult to dissociate on Pd (100) and (111) surfaces. Especially for NO? Pd (111) system, the three‐well‐potential dissociation mode is initially put forward to show the remarkable dissociation process with two dissociation transitional states of NO on Pd (111). Copyright © 2008 John Wiley & Sons, Ltd.