The Mechanisms of Zinc Action as a Potent Anti-Viral Agent: The Clinical Therapeutic Implication in COVID-19.

The pandemic of COVID-19 was caused by a novel coronavirus termed as SARS-CoV2 and is still ongoing with high morbidity and mortality rates in the whole world. The pathogenesis of COVID-19 is highly linked with over-active immune and inflammatory responses, leading to activated cytokine storm, which contribute to ARDS with worsen outcome. Currently, there is no effective therapeutic drug for the treatment of COVID-19. Zinc is known to act as an immune modulator, which plays an important role in immune defense system. Recently, zinc has been widely considered as an anti-inflammatory and anti-oxidant agent. Accumulating numbers of studies have revealed that zinc plays an important role in antiviral immunity in several viral infections. Several early clinical trials clearly indicate that zinc treatment remarkably decreased the severity of the upper respiratory infection of rhinovirus in humans. Currently, zinc has been used for the therapeutic intervention of COVID-19 in many different clinical trials. Several clinical studies reveal that zinc treatment using a combination of HCQ and zinc pronouncedly reduced symptom score and the rates of hospital admission and mortality in COVID-19 patients. These data support that zinc might act as an anti-viral agent in the addition to its anti-inflammatory and anti-oxidant properties for the adjuvant therapeutic intervention of COVID-19.

The Short-Chain Fatty Acids Propionate and Butyrate Augment Adherent-Invasive Escherichia coli Virulence but Repress Inflammation in a Human Intestinal Enteroid Model of Infection.

Short-chain fatty acids (SCFAs), which consist of six or fewer carbons, are fermentation products of the bacterial community that inhabits the intestine. Due to an immunosuppressive effect on intestinal tissue, they have been touted as a therapeutic for inflammatory conditions of the bowel. Here, we study the impact of acetate, propionate, and butyrate, the three most abundant SCFAs in the intestine, on gene expression in the intestinal pathobiont adherent-invasive Escherichia coli. We pair this with adherence, invasion, and inflammation in Caco-2 and human intestinal enteroid (HIE)-derived monolayer models of the intestinal epithelium. We report that propionate and butyrate upregulate transcription of adherent-invasive Escherichia coli (AIEC) flagellar synthesis genes and decrease expression of capsule assembly and transport genes. These changes are predicted to augment AIEC invasiveness. In fact, SCFA supplementation increases AIEC adherence to and invasion of the Caco-2 monolayer but has no effect on these parameters in the HIE model. We attribute this to the anti-inflammatory effect of propionate and butyrate on HIEs but not on Caco-2 cells. We conclude that the potential of SCFAs to increase the virulence of intestinal pathogens should be considered in their use as anti-inflammatory agents. IMPORTANCE The human terminal ileum and colon are colonized by a community of microbes known as the microbiota. Short-chain fatty acids (SCFAs) excreted by bacterial members of the microbiota define the intestinal environment. These constitute an important line of communication within the microbiota and between the microbiota and the host epithelium. In inflammatory conditions of the bowel, SCFAs are often low and there is a preponderance of a conditionally virulent bacterium termed adherent-invasive Escherichia coli (AIEC). A connection between SCFA abundance and AIEC has been suggested. Here, we study AIEC in monoculture and in coculture with human intestinal enteroid-derived monolayers and show that the SCFAs propionate and butyrate increase expression of AIEC virulence genes while concurrently bolstering the intestinal epithelial barrier and reducing intestinal inflammation. While these SCFAs have been promoted as a therapy for inflammatory bowel conditions, our findings demonstrate that their effect on bacterial virulence must be considered.

Fabrication of Chinese Traditional Medicines incorporated collagen biomaterials for human bone marrow mesenchymal stem cells.

Chinese Traditional Medicines (CTMs) are very popular for therapeutic applications to cure several chronic diseases. Many researchers are trying to discover the potential application and actual mechanism of CTMs in order to scientifically prove their effects for commercial use. One of the main functions of CTMs is to aid stem cell regeneration. Since, this study was focused to fabricate CTMs incorporated fish collagen film, which has good biocompatibility in mammalian cell growth and thus investigated the effect on human Mesenchymal stem cells (hMSCs) proliferation and differentiation. In this study, three types of CTMs such as Genistein, Icariin, and Naringin were used for film fabrication. Mechanical properties of collagen films were improved by the addition of CTMs, especially in Collagen-Naringin films. Solubility and In-vitro biodegradation of collagen films were enhanced by the hydrophobicity and chemical interaction of CTMs with collagen. The proliferation rate was accelerated in hMSCs cultured on CTMs incorporated collagen films in a dose- and time-dependent manner. Proliferation biomarkers such as Ki-67 and BrdU levels were higher in hMSCs cultured on CTMs incorporated collagen films. The proliferative and differentiation effect of CTMs was further confirmed by higher gene expression of Collagen I, Runx2, c-Fos, SMAD3 and TGF-ß1 in hMSCs. Overall, this study provides a new insight on novel biomaterial fabrication using CTMs and fish collagen for making a compatible platform for in-vitro stem cell culture.

Recent advances on bioactive polysaccharides from mulberry.

Mulberry (Moraceae family), commonly considered as a folk remedy, has a long history of usage in many regions of the world. Polysaccharides regarded as one of the major components in mulberry plants, and they possess antioxidant, antidiabetic, hepatoprotective, prebiotic, immunomodulatory and antitumor properties, among others. In recent decades, mulberry polysaccharides have been widely studied for their multiple health benefits and potential economic value. However, there are few reviews providing updated information on polysaccharides from mulberry. In this review, recent advances in the study of isolation, purification, structural characterization, biological activity and the structure-activity relationship of mulberry polysaccharides are summarized and discussed. Furthermore, a thorough analysis of the current trends and perspectives on mulberry polysaccharides is also proposed. Hopefully, these findings can provide a useful reference value for the development and application of natural polysaccharides in the field of functional food and medicine in the future.

Natural Triterpenoids Isolated from Akebia trifoliata Stem Explants Exert a Hypoglycemic Effect via α-Glucosidase Inhibition and Glucose Uptake Stimulation in Insulin-Resistant HepG2 Cells.

The inhibition of α-glucosidase activity is a prospective approach to attenuate postprandial hyperglycemia in the treatment of type 2 diabetes mellitus (T2DM). Herein, the inhibition of α-glucosidase by three compounds T1 -T3 of Akebia trifoliata stem, namely hederagenin (T1 ), 3-epiakebonoic acid (T2 ), and arjunolic acid (T3 ) were investigated using enzyme kinetics and molecular docking analysis. The three triterpenoids exhibited excellent inhibitory activities against α-glucosidase. T1 -T3 showed the strongest inhibition with IC50 values of 42.1±5.4, 19.6±3.2, and 11.2±2.3 µM, respectively, compared to the acarbose positive control (IC50 =106.3±8.2). Enzyme inhibition kinetics showed that triterpenoids T1 -T3 demonstrated competitive, mixed, and noncompetitive-type inhibition against α-glucosidase, respectively. The inhibition constant (Ki ) values were 21.21, 7.70, and 3.18 µM, respectively. Docking analysis determined that the interaction of ligands T1 -T3 and α-glucosidase was mainly forced by hydrogen bonds and hydrophobic interactions, which could result in improved binding to the active site of the target enzyme. The insulin resistant (IR)-HepG2 cell model used in this study (HepG2 cells exposed to 10-7  M insulin for 24 h) and glucose uptake assays showed that compounds T1 -T3 had no cytotoxicity with concentrations ranging from 6.25 to 25 µM and displayed significant stimulation of glucose uptake in IR-HepG2 cells. Thus, triterpenoids T1 -T3 showed dual therapeutic effects of α-glucosidase inhibition and glucose uptake stimulation and could be used as potential medicinal resources to investigate new antidiabetic agents for the prevention or treatment of diabetes.

Resveratrol and Celastrol Loaded Collagen Dental Implants Regulate Periodontal Ligament Fibroblast Growth and Osteoclastogenesis of Bone Marrow Macrophages.

Collagen is widely used for dental therapy in several ways such as films, 3D matrix, and composites, besides traditional Chinese medicine (TCM), has been used in tissue regeneration and wound healing application for centuries. Hence, the present study was targeted for the first time to fabricate collagen film with TCM such as resveratrol and celastrol in order to investigate the human periodontal ligament fibroblasts (HPLF) growth and bone marrow macrophages (BMM) derived osteoclastogenesis. Further, the physicochemical, mechanical and biological activities of collagen-TCM films crosslinked by glycerol and EDC-NHS (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-N-hydroxysulfosuccinimide) were investigated. Collagen film characterization was significantly regulated by the nature of plasticizers like hydrophobic and degree of polarity. Interestingly, the collagen film's denaturation temperature was increased by EDC-NHS than glycerol. FT-IR data confirmed the functional group changes due to chemical interaction of collagen with TCM. Morphological changes of HPLF cells cultured in control and collagen films were observed by SEM. Importantly, the addition of resveratrol upregulated the proliferation of HPLF cells, while osteoclastogenesis of BMM cells treated with mCSF-RANKL was significantly downregulated by celastrol. Accordingly, the collagen-TCM film could be an interesting material for dental regeneration, and especially it is a therapeutic target to restrain the elevated bone resorption during osteoporosis.

Evaluation of Marine Diindolinonepyrane in Vitro and in Vivo: Permeability Characterization in Caco-2 Cells Monolayer and Pharmacokinetic Properties in Beagle Dogs.

A marine fibrinolytic compound was studied for use in thrombolytic therapy. Firstly, the absorption and transportation characteristics of 2,5-BHPA (2,5-BHPA:2,5-Bis-[8-(4,8-dimethyl-nona-3,7-dienyl)-5,7-dihydroxy-8-methyl-3-keto-1,2,7,8-tertahydro-6H-pyran[a]isoindol-2-yl]-pentanoic acid, a novel pyran-isoindolone derivative with bioactivity isolated from a rare marine microorganism in our laboratory) in the human Caco-2 cells monolayer model were investigated. We collected 2,5-BHPA in the cells to calculate the total recovery, and its concentration was analyzed by LC/MS/MS (Liquid Chromatography/ Mass Spectrum/ Mass Spectrum). The results showed that 2,5-BHPA has low permeability and low total recoveries in the Caco-2 cells membrane. Pharmacokinetics and tissue distribution of 2,5-BHPA were investigated in beagle dogs using HPLC (High Performance Liquid Chromatography) after intravenous administration of three different doses (7.5, 5.0, 2.5 mg·kg-1). Pharmacokinetic data indicated that 2,5-BHPA fitted well to a two-compartment model. Elimination half-lives (T1/2) were 49 ± 2, 48 ± 2, and 49 ± 2 min, respectively; the peak concentrations (Cmax) were 56.48 ± 6.23, 48.63 ± 5.53, and 13.64 ± 2.76 µg·mL-1, respectively; clearance rates (CL) were 0.0062 ± 0.0004, 0.0071 ± 0.0008, and 0.0092 ±0.0006 L·min-1·kg-1, respectively; mean retention times (MRT) were 28.17 ± 1.16, 26.23 ± 0.35, and 28.66 ± 0.84 min, respectively. The low penetrability of 2,5-BHPA indicated that the intravenous route of administration is more appropriate than the oral route. Meanwhile, 2,5-BHPA showed a good pharmacokinetic profile in beagle dogs. The tissue distribution showed that 2,5-BHPA could quickly distribute into the heart, intestines, liver, stomach, spleen, lungs, testicles, urine, intestine, kidneys, brain, and feces. The concentration of 2,5-BHPA was higher in the liver and bile. Interestingly, 2,5-BHPA was detected in the brain. Taken together, the above results suggested that our work might be beneficial in the development of agents for thrombolytic treatment.

Molecular Mechanisms of Zinc as a Pro-Antioxidant Mediator: Clinical Therapeutic Implications.

The essentiality of zinc as a trace mineral in human health has been recognized for over five decades. Zinc deficiency, caused by diet, genetic defects, or diseases, can cause growth retardation, delayed sexual maturation, depressed immune response, and abnormal cognitive functions in humans. Zinc supplementation in zinc-deficient individuals can overcome or attenuate these abnormalities, suggesting zinc is an essential micro-nutrient in the body. A large number of in vitro and in vivo experimental studies indicate that zinc deficiency also causes apoptosis, cellular dysfunction, deoxyribonucleic acid (DNA) damage, and depressed immune response. Oxidative stress, due to the imbalance of reactive oxygen species (ROS) production and detoxification in the anti-oxidant defense system of the body, along with subsequent chronic inflammation, is believed to be associated with many chronic degenerative diseases such as diabetes, heart diseases, cancers, alcohol-related disease, macular degenerative disease, and neuro-pathogenesis. A large number of experimental studies including cell culture, animal, and human clinical studies have provided supportive evidence showing that zinc acts as an anti-oxidative stress agent by inhibition of oxidation of macro-molecules such as (DNA)/ribonucleic acid (RNA) and proteins as well as inhibition of inflammatory response, eventually resulting in the down-regulation of (ROS) production and the improvement of human health. In this article, we will discuss the molecular mechanisms of zinc as an anti-oxidative stress agent or mediator in the body. We will also discuss the applications of zinc supplementation as an anti-oxidative stress agent or mediator in human health and disease.

Effect of IgY on Periodontitis and Halitosis Induced by Fusobacterium nucleatum.

Fusobacterium nucleatum is a morbific agent in periodontitis and halitosis. Egg yolk antibody (IgY) was obtained from egg yolks from chickens stimulated with F. nucleatum. This study was to assess the effectiveness of IgY on periodontitis and halitosis caused by F. nucleatum in vitro and in vivo. The growth of F. nucleatum was inhibited (p <0. 05) by different concentrations of IgY in vitro and the results of a Halimeter show volatile sulfur compounds (VSCs) were reduced to 904 ± 57 ppb at a concentration 40 mg/ml of IgY. The changes of fatty acids of F. nucleatum were determined using GC-MS. The scores for odor index of rat saliva were decreased. The major constituent of volatile organic compounds (VOCs) including short-chain acids decreased 46.2% in 10 mg/ml IgY, ammonia decreased 70% in 40 mg/ml IgY, while aldehydes and olefine ketones were almost unchanged. The ELISA assay revealed that IL-6 and TNF-α were decreased after 4 weeks' IgY treatment. Morphometric (X-ray) and histological analyses (HE) showed that IgY reduced alveolar bone loss and collagen fibers became orderly in rat models. As a result, IgY may have the potential to treat periodontitis and halitosis.

1H NMR-based metabolic study reveals the improvements of bitter melon (Momordica charantia) on energy metabolism in diet-induced obese mouse.

CONTEXT: Obesity can be ameliorated by some natural products such as polyphenol, flavones and saponin. As a typical medicinal plant, Momordica charantia L. (Cucurbitaceae) (bitter melon, BM) contains these natural chemicals and reduces diet-induced obesity in mice. OBJECTIVE: This study evaluates the metabolic effects of dietary BM supplement, investigates a global metabolic profile and determines associated perturbations in metabolic pathways. MATERIALS AND METHODS: Male C57BL/6 mice were fed with low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with 5% BM based on 37.6 g/kg body weight in average for 12 weeks, respectively. Then energy metabolism was quantified using PhenoMaster/LabMaster. The spectroscopy of urine was acquired by nuclear magnetic resonance and latent biomarkers were identified. Pattern recognition analysis was used to discriminate associated metabolic profiles. RESULTS: Dietary BM supplement reduced body weight gain (-0.15-fold, p < 0.01) and blood glucose levels (-0.19-fold, p < 0.01) in HFD-fed mice. Meanwhile, the levels of energy metabolism were enhanced (0.08-0.11-fold, p < 0.01). According to pattern recognition analysis, dietary BM supplement changed metabolic profiles in HFD-fed mice and the modified profiles were similar to those in LFD-fed mice. Finally, the mapping of metabolic pathways showed that dietary BM supplement primarily affected glucose metabolism-associated pathways. DISCUSSION AND CONCLUSION: The results indicated that BM improves weight loss in diet-induced obesity and elevate energy expenditure in HFD-fed mice. The pattern recognition with metabolic study may be used as a noninvasive detection method to assess the effects of dietary BM supplement on mouse energy metabolism.

Inhibition of HMG-CoA reductase by MFS, a purified extract from the fermentation of marine fungus Fusarium solani FG319, and optimization of MFS production using response surface methodology.

The present study was designed to isolate and characterize a purified extract from Fusarium solani FG319, termed MFS (Metabolite of Fusarium solani FG319) that showed anti-atherosclerosis activity by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Response surface methodology (RSM) was employed to achieve an improved yield from the fermentation medium. The inhibiting effect of the isolate, MFS, on HMG-CoA reductase was greater than that of the positive control, lovastatin. The average recovery of MFS and the relative standard deviation (RSD) ranged between 99.75% to 101.18%, and 0.31% to 0.74%, respectively. The RSDs intra- and inter-assay of the three samples ranged from 0.288% to 2.438%, and from 0.934% to 2.383%, respectively. From the RSM, the concentration of inducer, cultivation time, and culture temperatures had significant effects on the MFS production, with the effect of inducer concentration being more pronounced that other factors. In conclusion, the optimal conditions for the MFS production were achieved using RSM and that MFS could be explored as an anti-atherosclerosis agent based on its ability to inhibit HMG-CoA reductase.

Structure characterization of an arabinogalactan from green tea and its anti-diabetic effect.

A water-soluble polysaccharide, 7WA, with an average molecular mass of 7.1×10(4)Da, was isolated from the leaves of green tea. Monosaccharide composition analysis indicated that 7WA mainly contained Arabinose and Galactose in the molar ratio of 1.0:0.96. By using the methods of methylation analysis, partial hydrolysis, and NMR, 7WA was characterized to possess a backbone consisting of 1,3- and 1,6-linked galactopyranosyl residues, with branches attached to O-3 of 1,6-linked galactose residues, and O-4 and O-6 of 1,3-linked galactose residues. The results of glucose-stimulated insulin secretion (GSIS) showed that 7WA significantly augmented insulin secretion at high glucose level (25mM), however, such effect was not seen at low glucose level (5mM). The mechanism study results indicated 7WA, a type II arabinogalactan from Green Tea, enhances GSIS through cAMP-PKA pathway.

Low-dose diet supplement of a natural flavonoid, luteolin, ameliorates diet-induced obesity and insulin resistance in mice.

SCOPE: Mast cells play important roles in diet-induced obesity and diabetes, and some synthetic mast cell stabilizers can improve related metabolic disturbances in mice. Luteolin (LU) is a potent natural mast cell stabilizer. However, a direct correlation between LU and these common metabolic diseases is not established. METHODS AND RESULTS: Male C57BL/6 mice were fed low-fat diet, high-fat diet (HFD), HFD with 0.002 and 0.01% LU for 12 wk, respectively. Dietary LU suppressed HFD-induced body weight gain, fat deposition, and adipocyte hypertrophy. Meanwhile, glucose intolerance and insulin sensitivity was also improved. Interestingly, dietary LU ameliorated angiogenesis and associated cell apoptosis and cathepsin activity in epididymis adipose tissues, which is a critical mechanism that mast cells are involved in diet-induced obesity and diabetes. Further, we showed dietary LU reduced mast cell and macrophage infiltrations and inflammatory cytokine levels in epididymis adipose tissues. Finally, LU inhibited mast cell-derived IL-6 expression, which is a key cytokine that contributes to mast cell-associated metabolic derangements, and protein kinase C activator phorbol myristoyl acetate reversed the inhibitory effects. CONCLUSIONS: As a natural flavonoid, low-dose diet supplement of LU ameliorates diet-induced obesity and insulin resistance in mice, suggesting a new therapeutic and interventional approach for these diseases.

Quercetin reduces obesity-associated ATM infiltration and inflammation in mice: a mechanism including AMPKα1/SIRT1.

Adipose tissue macrophage (ATM) plays a central role in obesity-associated inflammation and insulin resistance. Quercetin, a dietary flavonoid, possesses anti-inflammation and anti-insulin resistance properties. However, it is unclear whether quercetin can alleviate high-fat diet (HFD)-induced ATM infiltration and inflammation in mice. In this study, 5-week-old C57BL/6 mice were fed low-fat diet, HFD, or HFD with 0.l% quercetin for 12 weeks, respectively. Dietary quercetin reduced HFD-induced body weight gain and improved insulin sensitivity and glucose intolerance in mice. Meanwhile, dietary quercetin enhanced glucose transporter 4 translocation and protein kinase B signal in epididymis adipose tissues (EATs), suggesting that it heightened glucose uptake in adipose tissues. Histological and real-time PCR analysis revealed that quercetin attenuated mast cell and macrophage infiltration into EATs in HFD-fed mice. Dietary quercetin also modified the phenotype ratio of M1/M2 macrophages, lowered the levels of proinflammatory cytokines, and enhanced adenosine monophosphate-activated protein kinase (AMPK) α1 phosphorylation and silent information regulator 1 (SIRT1) expression in EATs. Further, using AMPK activator 5-aminoimidazole-4-carboxamide-1-ß4-ribofuranoside and inhibitor Compound C, we found that quercetin inhibited polarization and inflammation of mouse bone marrow-derived macrophages through an AMPKα1/SIRT1-mediated mechanism. In conclusion, dietary quercetin might suppress ATM infiltration and inflammation through the AMPKα1/SIRT1 pathway in HFD-fed mice.

Epigenetic regulation of miRNA-cancer stem cells nexus by nutraceuticals.

Nutraceuticals, the bioactive food components represented by many naturally occurring dietary compounds, have been investigated for a few decades for their numerous beneficial effects, including their anticancer properties. The initial interest in the cancer-preventing/therapeutic ability of these agents was based on their ability to affect multiple signaling pathways that are deregulated in cancer cells. With a shift in the focus of cancer research to the emerging areas such as epigenetic regulation, microRNAs (miRNAs) and the cancer stem cells (CSCs), nutraceuticals initially appeared out of place. However, research investigations over the last several years have slowly but firmly presented evidence that supports a relevance of these agents in modern day research. While nutraceuticals are increasingly being realized to alter miRNA/CSCs expression and function, the molecular mechanism(s) are not very clearly understood. Epigenetic regulation is one mechanism by which these agents exert their anticancer effects. In this focused mini review, we summarize our current understanding of epigenetic regulation of miRNAs and CSCs by nutraceuticals. We discuss both direct and indirect evidences that support such an activity of these compounds.

Recent progress on nutraceutical research in prostate cancer.

Recently, nutraceuticals have received increasing attention as the agents for cancer prevention and supplement with conventional therapy. Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer-related death in men in the US. Growing evidences from epidemiological studies, in vitro experimental studies, animal studies, and clinical trials have shown that nutraceuticals could be very useful for the prevention and treatment of PCa. Several nutraceuticals including isoflavone, indole-3-carbinol, 3,3'-diindolylmethane, lycopene, (-)-epigallocatechin-3-gallate, and curcumin are known to downregulate the signal transductions in AR, Akt, NF-κB, and other signal transduction pathways which are vital for the development of PCa and the progression of PCa from androgen-sensitive to castrate-resistant PCa. Therefore, nutraceutical treatment in combination with conventional therapeutics could achieve better treatment outcome in prostate cancer therapy. Interestingly, some nutraceuticals could regulate the function of cancer stem cell (CSC)-related miRNAs and associated molecules, leading to the inhibition of prostatic CSCs which are responsible for drug resistance, tumor progression, and recurrence of PCa. Hence, nutraceuticals may serve as powerful agents for the prevention of PCa progression and they could also be useful in combination with chemotherapeutics or radiotherapy. Such strategy could become a promising newer approach for the treatment of metastatic PCa with better treatment outcome by improving overall survival.

Homogalacturonans from preinfused green tea: structural characterization and anticomplementary activity of their sulfated derivatives.

Two homogeneous water-soluble polysaccharides (TPSR4-2B and TPSR4-2C) were obtained from preinfused green tea. Their average molecular weights were estimated to be 41 kDa and 28 kDa, respectively. A combination of composition, methylation, and configuration analysis, as well as NMR spectroscopy, indicated that both TPSR4-2B and TPSR4-2C were poly-(1-4)-α-d-galactopyranosyluronic acid in which 30.5 ± 0.3% and 28.3 ± 0.5%, respectively, of uronic acid existed as methyl ester. Two sulfated derivatives (Sul-R4-2B and Sul-R4-2C) from TPSR4-2B and TPSR4-2C were prepared after sulfation with a 2:1 chlorosulfonic acid-pyridine ratio. The anticomplementary assay showed that Sul-R4-2B and Sul-R4-2C demonstrated a stronger inhibitory effect on the complement activation through the classic pathway, compared to that of heparin. Preliminary mechanism studies by using complement component depleted-sera indicated that both Sul-R4-2B and Sul-R4-2C selectively interact with C1q, C1r, C1s, C2, C5, and C9 but not with C3 and C4. The relationship between DS and the anticomplementary activity of sulfated derivatives of homogalacturonans showed that low sulfated derivatives of homogalacturonans also exhibited potent anticomplementary effect, which might greatly reduce the side effects related to heparin and oversulfated chondroitin sulfate, such as anticoagulant activity and allergic-type reaction. These results suggested that sulfated derivatives of homogalacturonans might be promising drug candidates for therapeutic complement inhibition.

The discovery and optimization of novel dual inhibitors of topoisomerase II and histone deacetylase.

A novel class of podophyllotoxin derivatives have been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities towards histone deacetylases and Topo II and their cytotoxicities in cancer cell lines were evaluated. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure-activity relationships are discussed. Among all of the synthesized hybrid compounds, compound 24 d showed the most potent HDAC inhibitory activity at a low nanomolar level and exhibited powerful antiproliferative activity towards HCT116 colon carcinoma cells at a low micromolar level. Further exploration of this series led to the discovery of potent dual inhibitor 32, which exhibited the strongest in vitro cytotoxic activity.

Perspectives on the role of isoflavones in prostate cancer.

Isoflavones have been investigated in detail for their role in the prevention and therapy of prostate cancer. This is primarily because of the overwhelming data connecting high dietary isoflavone intake with reduced risk of developing prostate cancer. A number of investigations have evaluated the mechanism(s) of anticancer action of isoflavones such as genistein, daidzein, biochanin A, equol, etc., in various prostate cancer models, both in vitro and in vivo. Genistein quickly jumped to the forefront of isoflavone cancer research, but the initial enthusiasm was followed by reports on its contradictory prometastatic and tumor-promoting effects. Use of soy isoflavone mixture has been advocated as an alternative, wherein daidzein can negate harmful effects of genistein. Recent research indicates a novel role of genistein and other isoflavones in the potentiation of radiation therapy, epigenetic regulation of key tumor suppressors and oncogenes, and the modulation of miRNAs, epithelial-to-mesenchymal transition, and cancer stem cells, which has renewed the interest of cancer researchers in this class of anticancer compounds. This comprehensive review article summarizes our current understanding of the role of isoflavones in prostate cancer research.

Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment.

Hypoxia is known to play critical roles in cell survival, angiogenesis, tumor invasion, and metastasis. Hypoxia mediated over-expression of hypoxia-inducible factor (HIF) has been shown to be associated with therapeutic resistance, and contributes to poor prognosis of cancer patients. Emerging evidence suggest that hypoxia and HIF pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and also maintains the vicious cycle of inflammation-all which lead to therapeutic resistance. However, the precise molecular mechanism(s) by which hypoxia/HIF drives these events are not fully understood. Here, we show, for the first time, that hypoxia leads to increased expression of VEGF, IL-6, and CSC signature genes Nanog, Oct4 and EZH2 consistent with increased cell migration/invasion and angiogenesis, and the formation of pancreatospheres, concomitant with increased expression of miR-21 and miR-210 in human pancreatic cancer (PC) cells. The treatment of PC cells with CDF, a novel synthetic compound inhibited the production of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 and miR-210 under hypoxia. CDF also led to decreased cell migration/invasion, angiogenesis, and formation of pancreatospheres under hypoxia. Moreover, CDF decreased gene expression of miR-21, miR-210, IL-6, HIF-1α, VEGF, and CSC signatures in vivo in a mouse orthotopic model of human PC. Collectively, these results suggest that the anti-tumor activity of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become a novel, and effective anti-tumor agent for PC therapy.