Recent advances and future directions on small molecule VEGFR inhibitors in oncological conditions.

"A journey of mixed emotions" is a quote that best describes the progress chart of vascular endothelial growth factor receptor (VEGFR) inhibitors as cancer therapeutics in the last decade. Exhilarated with the Food and Drug Administration (FDA) approvals of numerous VEGFR inhibitors coupled with the annoyance of encountering the complications associated with their use, drug discovery enthusiasts are on their toes with an unswerving determination to enhance the rate of translation of VEGFR inhibitors from preclinical to clinical stage. The recently crafted armory of VEGFR inhibitors is a testament to their growing dominance over other antiangiogenic therapies for cancer treatment. This review perspicuously underscores the earnest attempts of the researchers to extract the antiproliferative potential of VEGFR inhibitors through the design of mechanistically diverse structural assemblages. Moreover, this review encompasses sections on structural/molecular properties and physiological functions of VEGFR, FDA-approved VEGFR inhibitors, and hurdles restricting the activity range/clinical applicability of VEGFR targeting antitumor agents. In addition, tactics to overcome the limitations of VEGFR inhibitors are discussed. A clear-cut viewpoint transmitted through this compilation can provide practical directions to push the cart of VEGFR inhibitors to advanced-stage clinical investigations in diverse malignancies.

Small molecule tractable PARP inhibitors: Scaffold construction approaches, mechanistic insights and structure activity relationship.

Diverse drug design strategies viz. molecular hybridization, substituent installation, scaffold hopping, isosteric replacement, high-throughput screening, induction and separation of chirality, structure modifications of phytoconstituents and use of structural templates have been exhaustively leveraged in the last decade to load the chemical toolbox of PARP inhibitors. Resultantly, numerous promising scaffolds have been pinpointed that in turn have led to the resuscitation of the credence to PARP inhibitors as cancer therapeutics. This review briefly presents the physiological functions of PARPs, the pharmacokinetics, and pharmacodynamics, and the interaction profiles of FDA-approved PARP inhibitors. Comprehensively covered is the section on the drug design strategies employed by drug discovery enthusiasts for furnishing PARP inhibitors. The impact of structural variations in the template of designed scaffolds on enzymatic and cellular activity (structure-activity relationship studies) has been discussed. The insights gained through the biological evaluation such as profiling of physicochemical properties andin vitroADME properties, PK assessments, and high-dose pharmacology are covered.

Prudent tactics to sail the boat of PARP inhibitors as therapeutics for diverse malignancies.

INTRODUCTION: PARP inhibitors block the DNA-repairing mechanism of PARP and represent a promising class of anti-cancer therapy. The last decade has witnessed FDA approvals of several PARP inhibitors, with some undergoing advanced-stage clinical investigation. Medicinal chemists have invested much effort to expand the structure pool of PARP inhibitors. Issues associated with the use of PARP inhibitors that make their standing disconcerting in the pharmaceutical sector have been addressed via the design of new structural assemblages. AREA COVERED: In this review, the authors present a detailed account of the medicinal chemistry campaigns conducted in the recent past for the construction of PARP1/PARP2 inhibitors, PARP1 biased inhibitors, and PARP targeting bifunctional inhibitors as well as PARP targeting degraders (PROTACs). Limitations associated with FDA-approved PARP inhibitors and strategies to outwit the limitations are also discussed. EXPERT OPINION: The PARP inhibitory field has been rejuvenated with numerous tractable entries in the last decade. With numerous magic bullets in hand coupled with unfolded tactics to outwit the notoriety of cancer cells developing resistance toward PARP inhibitors, the dominance of PARP inhibitors as a sagacious option of targeted therapy is highly likely to be witnessed soon.

Ascophyllum nodosum and Fucus vesiculosus Extracts Improved Lipid Metabolism and Inflammation in High-Energy Diet-Induced Hyperlipidemia Rats.

Ascophyllum nodosum and Fucus vesiculosus both contain unique polyphenols called phlorotannins. Phlorotannins reportedly possess various pharmacological activities. A previous study reported that the activity of phlorotannin is strongly correlated with the normalization of metabolic function, and phlorotannins are extremely promising nutrients for use in the treatment of metabolic syndrome. To date, no study has explored the antihyperlipidemic effects of phlorotannins from A. nodosum and F. vesiculosus in animal models. Therefore, in the present study, we investigated the effects of phlorotannins using a rat model of high-energy diet (HED)-induced hyperlipidemia. The results showed that the rats that were fed an HED and treated with phlorotannin-rich extract from A. nodosum and F. vesiculosus had significantly lower serum fasting blood sugar (FBS), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triacylglyceride (TG) and free fatty acids (FFAs) levels and hepatic TG level and had higher serum insulin, high-density lipoprotein cholesterol (HDL-C) levels and lipase activity in their fat tissues than in the case with the rats that were fed the HED alone. A histopathological analysis revealed that phlorotannin-rich extract could significantly reduce the size of adipocytes around the epididymis. In addition, the rats treated with phlorotannin-rich extract had significantly lowered interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels and increased superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities than did those in the HED group. These results suggested that the phlorotannin-rich extract stimulated lipid metabolism and may have promoted lipase activity in rats with HED-induced hyperlipidemia. Our results indicated that A. nodosum and F. vesiculosus, marine algae typically used as health foods, have strong antihyperlipidemic effects and may, therefore, be useful for preventing atherosclerosis. These algae may be incorporated into antihyperlipidemia pharmaceuticals and functional foods.

Accommodation of ring C expanded deoxyvasicinone in the HDAC inhibitory pharmacophore culminates into a tractable anti-lung cancer agent and pH-responsive nanocarrier.

A fragment recruitment process was conducted to pinpoint a suitable fragment for installation in the HDAC inhibitory template to furnish agents endowed with the potential to treat lung cancer. Resultantly, Ring C expanded deoxyvasicinone was selected as an appropriate surface recognition part that was accommodated in the HDAC three-component model. Delightfully, fused quinazolinone 6 demonstrating a magnificent anticancer profile against KRAS and EGFR mutant lung cancer cell lines (IC50 = 0.80-0.96 µM) was identified. Results of the mechanistic studies confirmed that the cell growth inhibitory effects of compound 6 stems for HDAC6 (IC50 = 12.9 nM), HDAC1 (IC50 = 49.9 nM) and HDAC3 inhibition (IC50 = 68.5 nM), respectively. Compound 6 also suppressed the colony formation ability of A549 cells, induced apoptosis, and increased autophagic flux. Key interactions of HDAC inhibitor 6 within the active site of HDAC isoforms were figured out through molecular modeling studies. Furthermore, a pH-responsive nanocarrier (Hyaluronic acid - fused quinazolinone 6 nanoparticles) was designed and assessed using a dialysis bag approach under both normal and acidic circumstances that confirmed the pH-sensitive nature of NPs. Delightfully, the nanoparticles demonstrated selective cell viability reduction potential towards the lung cancer cell lines (A549 lung cancer cell lines) and were found to be largely devoid of cell growth inhibitory effects under normal settings (L929, mouse fibroblast cells).

Probiotic supplementation attenuates age-related sarcopenia via the gut-muscle axis in SAMP8 mice.

BACKGROUND: Age-related muscle dysfunctions are common disorders resulting in poor quality of life in the elderly. Probiotic supplementation is a potential strategy for preventing age-related sarcopenia as evidence suggests that probiotics can enhance muscle function via the gut-muscle axis. However, the effects and mechanisms of probiotics in age-related sarcopenia are currently unknown. In this study, we examined the effects of Lactobacillus casei Shirota (LcS), a probiotic previously reported to improve muscle function in young adult mice. METHODS: We administered LcS (1 × 108 or 1 × 109  CFU/mouse/day) by oral gavage to senescence-accelerated mouse prone-8 mice for 12 weeks (16- to 28-week-old). Sixteen-week-old and 28-week-old SMAP8 mice were included as non-aged and aged controls, respectively. Muscle condition was evaluated using dual-energy X-ray absorptiometry for muscle mass, holding impulse and grip strength tests for muscle strength, and oxygen consumption rate, gene expressions of mitochondrial biogenesis, and mitochondrial number assays for mitochondria function. Inflammatory cytokines were determined using enzyme-linked immunosorbent assay. Gas chromatography-mass spectrometry was utilized to measure the short-chain fatty acid levels. The gut microbiota was analysed based on the data of 16S rRNA gene sequencing of mouse stool. RESULTS: The LcS supplementation reduced age-related declines in muscle mass (>94.6%, P < 0.04), strength (>66% in holding impulse and >96.3% in grip strength, P < 0.05), and mitochondrial function (P < 0.05). The concentration of short-chain fatty acids (acetic, isobutyric, butyric, penic, and hexanoic acid) was recovered by LcS (>65.9% in the mice given high dose of LcS, P < 0.05) in the aged mice, and LcS attenuated age-related increases in inflammation (P < 0.05) and reactive oxygen species (>89.4%, P < 0.001). The high dose of LcS supplementation was also associated with distinct microbiota composition as indicated by the separation of groups in the beta-diversity analysis (P = 0.027). LcS supplementation altered predicted bacterial functions based on the gut microbiota. Apoptosis (P = 0.026), p53 signalling (P = 0.017), and non-homologous end-joining (P = 0.031) were significantly reduced, whereas DNA repair and recombination proteins (P = 0.043), RNA polymerase (P = 0.008), and aminoacyl-tRNA biosynthesis (P = 0.003) were increased. Finally, the genera enriched by high-dose LcS [linear discriminant analysis (LDA) score > 2.0] were positively correlated with healthy muscle and physiological condition (P < 0.05), while the genera enriched in aged control mice (LDA score > 2.0) were negatively associated with healthy muscle and physiological condition (P < 0.05). CONCLUSIONS: Lactobacillus casei Shirota represents an active modulator that regulates the onset and progression of age-related muscle impairment potentially via the gut-muscle axis.

Pathological Role of Phosphoglycerate Kinase 1 in Balloon Angioplasty-Induced Neointima Formation.

Restenosis is a common vascular complication after balloon angioplasty. Catheter balloon inflation-induced transient ischemia (hypoxia) of local arterial tissues plays a pathological role in neointima formation. Phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate (ATP)-generating glycolytic enzyme, has been reported to associate with cell survival and can be triggered under hypoxia. The purposes of this study were to investigate the possible role and regulation of PGK1 in vascular smooth muscle cells (VSMCs) and balloon-injured arteries under hypoxia. Neointimal hyperplasia was induced by a rat carotid artery injury model. The cellular functions and regulatory mechanisms of PGK1 in VSMCs were investigated using small interfering RNAs (siRNAs), chemical inhibitors, or anaerobic cultivation. Our data indicated that protein expression of PGK1 can be rapidly induced at a very early stage after balloon angioplasty, and the silencing PGK1-induced low cellular energy circumstance resulted in the suppressions of VSMC proliferation and migration. Moreover, the experimental results demonstrated that blockage of PDGF receptor-ß (PDGFRB) or its downstream pathway, the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis, effectively reduced hypoxia-induced factor-1 (HIF-1α) and PGK1 expressions in VSMCs. In vivo study evidenced that PGK1 knockdown significantly reduced neointima hyperplasia. PGK1 was expressed at the early stage of neointimal formation, and suppressing PGK1 has a potential beneficial effect for preventing restenosis.

Lacticaseibacillus paracasei PS23 Effectively Modulates Gut Microbiota Composition and Improves Gastrointestinal Function in Aged SAMP8 Mice.

Probiotics are reported to improve gastrointestinal (GI) function via regulating gut microbiota (GM). However, exactly how probiotics influence GM and GI function in elders is poorly characterized. Therefore, in this study, we assessed the effect of the probiotic Lacticaseibacillus paracasei PS23 (LPPS23) on the GM and GI function of aged mice. There were four groups of senescence-accelerated mouse prone-8 (SAMP8) mice (n = 4): a non-treated control group, a saline control group, a low dose LPPS23 group (1 × 108 colony-forming unit (CFU)/mouse/day), and a high dose LPPS23 group (1 × 109 CFU/mouse/day). Non-treated mice were euthanized at 16 weeks old, and others were euthanized at 28 weeks old. The next-generation sequencing results revealed that LPPS23 enriched Lactobacillus and Candidatus_Saccharimonas, while the abundance of Lachnospiraceae_UCG_001 decreased in aged mice given LPPS23. The abundance of Lactobacillus negatively correlated with the abundance of Erysipelotrichaceae. Moreover, LPPS23 improved the GI function of aged mice due to the longer intestine length, lower intestinal permeability, and higher phagocytosis in LPPS23-treated mice. The ELISA results showed that LPPS23 attenuated the alterations of pro-inflammatory factors and immunoglobulins. The abundance of LPPS23-enriched Lactobacillus was positively correlated with healthy GI function, while Lachnospiraceae_UCG_001, which was repressed by LPPS23, was negatively correlated with a healthy GI function in the aged mice according to Spearman's correlation analysis. Taken together, LPPS23 can effectively modulate GM composition and improve GI function in aged SAMP8 mice.

Circulating level of microRNA-142-5p is a potential biomarker for predicting in-stent restenosis: a case-control study.

BACKGROUND: Patients who receive percutaneous coronary intervention (PCI) have different chances of developing in-stent restenosis (ISR). To date, no predictable biomarker can be applied in the clinic. MicroRNAs (miRNAs or miRs) play critical roles in transcription regulation, and their circulating levels were reported to have potential as clinical biomarkers. METHODS: In total, 93 coronary stent-implanted patients without pregnancy, liver or renal dysfunction, malignancy, hemophilia, or autoimmune diseases were recruited in this clinical study. All recruited participants were divided into an ISR group (n = 45) and a non-ISR group (n = 48) based on their restenotic status as confirmed by cardiologists at the first follow-up visit (6 months after surgery). Blood samples of all participants were harvested to measure circulating levels of miRNA candidates (miR-132, miR-142-5p, miR-15b, miR-24-2, and miR-424) to evaluate whether these circulating miRNAs can be applied as predictive biomarkers of ISR. RESULTS: Our data indicated that circulating levels of miR-142-5p were significantly higher in the ISR population, and results from the receiver operating characteristic (ROC) curve analysis also demonstrated superior discriminatory ability of miR-142-5p in predicting patients' restenotic status. In addition, circulating levels of miR-15b, miR-24-2, and miR-424 had differential expressions in participants with diabetes, hyperlipidemia, and hypertension, respectively. CONCLUSIONS: The current study revealed that the circulating level of miR-142-5p has potential application as a clinical biomarker for predicting the development of ISR in stent-implanted patients.

Sclareol ameliorated ERCC1-mediated cisplatin resistance in A549 human lung adenocarcinoma cells and a murine xenograft tumor model by suppressing AKT-GSK3ß-AP1/Snail and JNK-AP1 pathways.

Cisplatin-based chemotherapy is a common first-line regimen for treating non-small cell lung cancer (NSCLC). However, drug resistance is still a major problem. The purposes of this study were to evaluate whether sclareol can reverse cisplatin resistance and to investigate its possible mechanisms. A549 cells, the human NSCLC cells with inherent cisplatin resistance, were used to investigate synergistic effect of sclareol with cisplatin in cell proliferation and migration as well as its regulatory mechanisms in expression of excision repair cross-complementation group 1 (ERCC1), a cisplatin resistance-associated molecule. Nude mice bearing subcutaneous A549 tumors were applied to investigate synergistic activity of sclareol in anti-tumor. As comparing to the cisplatin alone group, the treatment of cisplatin combined with sclareol significantly suppressed survival rate and cell migration of A549 cells. Besides, sclareol also exhibited suppression in ERCC1 expression by inhibiting AKT-GSK3ß-AP1/Snail and JNK-AP1 pathways. Furthermore, the experimental data from in vivo study also demonstrated that the combination group of cisplatin and sclareol showed the greatest anti-tumor activity, whose effect could be partially attributed to sclareol-mediated decrease in intratumoral level of ERCC1 protein. Accordingly, sclareol has potential as an adjuvant for the treatment in NSCLC patients with cisplatin resistance.

Edible Mushrooms: Novel Medicinal Agents to Combat Metabolic Syndrome and Associated Diseases.

Metabolic syndrome is an aggregation of conditions and associated with an increased risk of developing diabetes, obesity and cardiovascular diseases (CVD). Edible mushrooms are widely consumed in many countries and are valuable components of the diet because of their attractive taste, aroma, and nutritional value. Medicinal mushrooms are higher fungi with additional nutraceutical attributes having low-fat content and a transisomer of unsaturated fatty acids along with high fiber content, biologically active compounds such as polysaccharides or polysaccharide ß-glucans, alkaloids, steroids, polyphenols and terpenoids. In vitro experiments, animal models, and even human studies have demonstrated not only fresh edible mushroom but also mushroom extract that has great therapeutic applications in human health as they possess many properties such as antiobesity, cardioprotective and anti-diabetic effect. They are considered as the unmatched source of healthy foods and drugs. The focus of this report was to provide a concise and complete review of the novel medicinal properties of fresh or dry mushroom and extracts, fruiting body or mycelium and its extracts, fiber, polysaccharides, beta-glucan, triterpenes, fucoidan, ergothioneine from edible mushrooms that may help to prevent or treat metabolic syndrome and associated diseases.

Lactobacillus plantarum PS128 Improves Physiological Adaptation and Performance in Triathletes through Gut Microbiota Modulation.

A triathlon is an extremely high-intensity exercise and a challenge for physiological adaptation. A triathlete's microbiome might be modulated by diet, age, medical treatments, lifestyle, and exercise, thereby maintaining aerobiosis and optimum health and performance. Probiotics, prebiotics, and synbiotics have been reported to have health-promoting activities (e.g., immunoregulation and cancer prevention). However, few studies have addressed how probiotics affect the microbiota of athletes and how this translates into functional activities. In our previous study, we found that Lactobacillus plantarum PS128 could ameliorate inflammation and oxidative stress, with improved exercise performance. Thus, here we investigate how the microbiota of triathletes are altered by L. plantarum PS128 supplementation, not only for exercise performance but also for possible physiological adaptation. The triathletes were assigned to two groups: an L. plantarum 128 supplement group (LG, 3 × 1010 colony-forming units (CFU)/day) and a placebo group (PG). Both groups continued with their regular exercise training for the next 4 weeks. The endurance performance, body composition, biochemistries, blood cells, microbiota, and associated metabolites were further investigated. PS128 significantly increased the athletes' endurance, by about 130% as compared to the PG group, but there was no significant difference in maximal oxygen consumption (VO2max) and composition between groups. The PS128 supplementation (LG) modulated the athlete's microbiota with both significant decreases (Anaerotruncus, Caproiciproducens, Coprobacillus, Desulfovibrio, Dielma, Family_XIII, Holdemania, and Oxalobacter) and increases (Akkermansia, Bifidobacterium, Butyricimonas, and Lactobacillus), and the LG showed lower diversity when compared to the PG. Also, the short-chain fatty acids (SCFAs; acetate, propionate, and butyrate) of the LG were significantly higher than the PG, which might be a result of a modulation of the associated microbiota. In conclusion, PS128 supplementation was associated with an improvement on endurance running performance through microbiota modulation and related metabolites, but not in maximal oxygen uptake.

Suppression of Cell Growth, Migration and Drug Resistance by Ethanolic Extract of Antrodia cinnamomea in Human Lung Cancer A549 Cells and C57BL/6J Allograft Tumor Model.

The purpose of this study was to investigate the inhibitory activities of ethanolic extracts from Antrodia cinnamomea (EEAC) on lung cancer. Cell proliferation and cell cycle distribution were analyzed using (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay and flow cytometry, respectively. Wound-healing assay, Western blotting, and a murine tumor model were separately used to examine cell migration, protein expression, and tumor repression. Our results showed that EEAC induced cell cycle arrest at the G0/G1 phase resulting decreased cell viability in A549 cells. Moreover, EEAC up-regulated the growth-suppressing proteins, adenosine 5'-monophosphate-activated protein kinase (AMPK), p21 and p27, but down-regulated the growth-promoting proteins, protein kinase B (Akt), mammalian tarfet of rapamycin (mTOR), extracellular signal-regulating kinase 1/2 (ERK1/2), retinoblastoma protein (Rb), cyclin E, and cyclin D1. EEAC also inhibited A549 cell migration and reduced expression of gelatinases. In addition, our data showed that tumor growth was suppressed after treatment with EEAC in a murine allograft tumor model. Some bioactive compounds from EEAC, such as cordycepin and zhankuic acid A, were demonstrated to reduce the protein expressions of matrix metalloproteinase (MMP)-9 and cyclin D1 in A549 cells. Furthermore, EEAC enhanced chemosensitivity of A549 to paclitaxel by reducing the protein levels of caveolin-1. Our data suggests that EEAC has the potential to be an adjuvant medicine for the treatment of lung cancer.

Suppressive activities and mechanisms of ugonin J on vascular smooth muscle cells and balloon angioplasty-induced neointimal hyperplasia.

Neointimal hyperplasia (or restenosis) is primarily attributed to excessive proliferation and migration of vascular smooth muscle cells (VSMCs). In this study, we investigated the inhibitory effects and mechanisms of ugonin J on VSMC proliferation and migration as well as neointimal formation. Cell viability and the cell-cycle distribution were, respectively, analyzed using an MTT assay and flow cytometry. Cell migration was examined using a wound-healing analysis and a transwell assay. Protein expressions and gelatinase activities were, respectively, measured using Western blot and gelatin zymography. Balloon angioplasty-induced neointimal formation was induced in a rat carotid artery model and then examined using immunohistochemical staining. Ugonin J induced cell-cycle arrest at the G0 /G1 phase and apoptosis to inhibit VSMC growth. Ugonin J also exhibited marked suppressive activity on VSMC migration. Ugonin J significantly reduced activations of focal adhesion kinase, phosphoinositide 3-kinase, v-akt murine thymoma viral oncogene homolog 1, and extracellular signal-regulated kinase 1/2 proteins. Moreover, ugonin J obviously reduced expressions and activity levels of matrix metalloproteinase-2 and matrix metalloproteinase-9. In vivo data indicated that ugonin J prevented balloon angioplasty-induced neointimal hyperplasia. Our study suggested that ugonin J has the potential for application in the prevention of balloon injury-induced neointimal formation.

Toxicological effects of NCKU-21, a phenanthrene derivative, on cell growth and migration of A549 and CL1-5 human lung adenocarcinoma cells.

BACKGROUND: Chemotherapy insensitivity continues to pose significant challenges for treating non-small cell lung cancer (NSCLC). The purposes of this study were to investigate whether 3,6-dimethoxy-1,4,5,8-phenanthrenetetraone (NCKU-21) has potential activity to induce effective toxicological effects in different ethnic NSCLC cell lines, A549 and CL1-5 cells, and to examine its anticancer mechanisms. METHODS: Mitochondrial metabolic activity and the cell-cycle distribution were analyzed using an MTT assay and flow cytometry in NCKU-21-treated cells. NCKU-21-induced cell apoptosis was verified by Annexin V-FITC/propidium iodide (PI) double-staining and measurement of caspase-3 activity. Western blotting and wound-healing assays were applied to respectively evaluate regulation of signaling pathways and cell migration by NCKU-21. Molecular interactions between target proteins and NCKU-21 were predicted and performed by molecular docking. A colorimetric screening assay kit was used to evaluate potential regulation of matrix metalloproteinase-9 (MMP-9) activity by NCKU-21. RESULTS: Results indicated that NCKU-21 markedly induced cytotoxic effects that reduced cell viability via cell apoptosis in tested NSCLC cells. Activation of AMP-activated protein kinase (AMPK) and p53 protein expression also increased in both NSCLC cell lines stimulated with NCKU-21. However, repression of PI3K-AKT activation by NCKU-21 was found in CL1-5 cells but not in A549 cells. In addition, increases in phosphatidylserine externalization and caspase-3 activity also confirmed the apoptotic effect of NCKU-21 in both NSCLC cell lines. Moreover, cell migration and translational levels of the gelatinases, MMP-2 and MMP-9, were obviously reduced in both NSCLC cell lines after incubation with NCKU-21. Experimental data obtained from molecular docking suggested that NCKU-21 can bind to the catalytic pocket of MMP-9. However, the in vitro enzyme activity assay indicated that NCKU-21 has the potential to increase MMP-9 activity. CONCLUSIONS: Our results suggest that NCKU-21 can effectively reduce cell migration and induce apoptosis in A549 and CL1-5 cells, the toxicological effects of which may be partly modulated through PI3K-AKT inhibition, AMPK activation, an increase in the p53 protein, and gelatinase inhibition.

Anti-Restenotic Roles of Dihydroaustrasulfone Alcohol Involved in Inhibiting PDGF-BB-Stimulated Proliferation and Migration of Vascular Smooth Muscle Cells.

Dihydroaustrasulfone alcohol (DA), an active compound firstly isolated from marine corals, has been reported to reveal anti-cancer and anti-inflammation activities. These reported activities of DA raised a possible application in anti-restenosis. Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) and the stimulation of platelet-derived growth factor (PDGF)-BB play major pathological processes involved in the development of restenosis. Experimental results showed that DA markedly reduced balloon injury-induced neointima formation in the rat carotid artery model and significantly inhibited PDGF-BB-stimulated proliferation and migration of VSMCs. Our data further demonstrated that translational and active levels of several critical signaling cascades involved in VSMC proliferation, such as extracellular signal-regulated kinase/ mitogen-activated protein kinases (ERK/MAPK), phosphatidylinositol 3-kinase (PI3K)/AKT, and signal transducer and activator of transcription (STAT), were obviously inhibited. In addition, DA also decreased the activation and expression levels of gelatinases (matrix metalloproteinase (MMP)-2 and MMP-9) involved in cell migration. In conclusion, our findings indicate that DA can reduce balloon injury-neointimal hyperplasia, the effect of which may be modulated through suppression of VSMC proliferation and migration. These results suggest that DA has potential application as an anti-restenotic agent for the prevention of restenosis.

K20E, an oxidative-coupling compound of methyl caffeate, exhibits anti-angiogenic activities through down-regulations of VEGF and VEGF receptor-2.

Anti-angiogenesis is one of the most popular clinical interventions for cancer chemotherapy. A series of synthesized derivative of methyl caffeate were used to evaluate the anti-angiogenic activity and to investigate possible pharmacological mechanisms in the present study. The most potent anti-angiogenic compound was evaluated in the experiments of murine allograft tumor model and Matrigel plug assay as well as cell models in the human umbilical vascular endothelial cells (HUVECs) and the LLC1 lung cancer cells. Our results suggested that K20E suppressed the tumor growth in the allograft tumor model and exhibited anti-angiogenic activity in Matrigel plug assay. Besides, HUVEC viability was found to be significantly reduced by arresting cell cycle at G2/M phase and apoptosis. Cell migration, invasion, and tube formation of the HUVECs were also markedly suppressed by K20E treatment. K20E largely down-regulated the intracellular and secreted vascular endothelial growth factor (VEGF) in the LLC1 cancer cells. Besides, VEGF receptor-2 (VEGFR-2) and its downstream signaling cascades (AKT-mTOR and MEK1/2-ERK1/2) as well as gelatinases were all evidently reduced in the HUVECs treated with K20E. Inversely, K20E can up-regulate the expression levels of p53 and p21 proteins in the HUVECs. Based on these results, our study suggested that K20E possessed inhibiting angiogenesis through regulation of VEGF/VEGFR-2 and its downstream signaling cascades in the vascular endothelial cells (VECs).

Inhibitory effect of dihydroaustrasulfone alcohol on the migration of human non-small cell lung carcinoma A549 cells and the antitumor effect on a Lewis lung carcinoma-bearing tumor model in C57BL/6J mice.

There are many major causes of cancer death, including metastasis of cancer. Dihydroaustrasulfone alcohol, which is isolated from marine coral, has shown antioxidant activity, but has not been reported to have an anti-cancer effect. We first discovered that dihydroaustrasulfone alcohol provided a concentration-dependent inhibitory effect on the migration and motility of human non-small cell lung carcinoma (NSCLC) A549 cells by trans-well and wound healing assays. The results of a zymography assay and Western blot showed that dihydroaustrasulfone alcohol suppressed the activities and protein expression of matrix metalloproteinase (MMP)-2 and MMP-9. Further investigation revealed that dihydroaustrasulfone alcohol suppressed the phosphorylation of ERK1/2, p38, and JNK1/2. Dihydroaustrasulfone alcohol also suppressed the expression of PI3K and the phosphorylation of Akt. Furthermore, dihydroaustrasulfone alcohol markedly inhibited tumor growth in Lewis lung cancer (LLC)-bearing mice. We concluded that dihydroaustrasulfone alcohol is a new pure compound with anti-migration and anti-tumor growth activity in lung cancer and might be applied to clinical treatment in the future.

NSC746364, a G-quadruplex-stabilizing agent, suppresses cell growth of A549 human lung cancer cells through activation of the ATR/Chk1-dependent pathway.

The telomere is considered to be a potential target for cancer therapy. NSC746364, a novel G-quadruplex-stabilizing agent, has been found to have cytotoxic effects on various cancer cells. To date, its pharmacological mechanisms are still unknown. The goal of this study was to investigate the molecular mechanisms of NSC746364 on the A549 human lung adenocarcinoma cell line. For this, we used a wide variety of in vitro assays. The intracellular signaling pathways including DNA damage sensing and response proteins, cell cycle regulatory proteins, and some key executors involved in apoptosis were evaluated in this study. Our study suggested that NSC746364 induced cell cycle arrest at the G2/M phase and triggers programming cell death on A549 human lung cancer cells, whose effects are modulated through the activation of the ATR/Chk1 pathway, the downregulation of cyclin B1 expression, and the activation of caspase-3. Consequently, our results indicated that NSC746364 may have therapeutic potential as a chemotherapy for non-small-cell lung cancers.

Deep sea water modulates blood pressure and exhibits hypolipidemic effects via the AMPK-ACC pathway: an in vivo study.

Deep sea water (DSW), originally pumped from the Pacific Rim off the coast of Hualien County (Taiwan), and its mineral constituents, were concentrated by a low-temperature vacuum evaporation system to produce a hardness of approximately 400,000 mg/L of seawater mineral concentrate. The primary composition of this seawater mineral concentrate was ionic magnesium (Mg²âº), which was approximately 96,000 mg/L. Referring to the human recommended daily allowance (RDA) of magnesium, we diluted the mineral concentrate to three different dosages: 0.1 × DSW (equivalent to 3.75 mg Mg²âº/kg DSW); 1 × DSW (equivalent to 37.5 mg Mg²âº/kg DSW); and 2 × DSW (equivalent to 75 mg Mg²âº/kg DSW). Additionally, a magnesium chloride treatment was conducted for comparison with the DSW supplement. The study indicated that 0.1 × DSW, 1 × DSW and 2 × DSW decreased the systolic and diastolic pressures in spontaneous hypertensive rats in an eight-week experiment. DSW has been shown to reduce serum lipids and prevent atherogenesis in a hypercholesterolemic rabbit model. Our results demonstrated that 1 × DSW and 2 × DSW significantly suppressed the serum cholesterol levels, reduced the lipid accumulation in liver tissues, and limited aortic fatty streaks. These findings indicated that the antiatherogenic effects of DSW are associated with 5'-adenosine monophosphate-activated protein kinase (AMPK) stimulation and the consequent inhibition of phosphorylation of acetyl-CoA carboxylase (ACC) in atherosclerotic rabbits. We hypothesize that DSW could potentially be used as drinking water because it modulates blood pressure, reduces lipids, and prevents atherogenesis.