Therapeutic Potential of Polyphenols and their Nanoformulations in the Treatment of Colorectal Cancer.

BACKGROUND: Colorectal Cancer (CRC) ranks third among all cancer-related deaths around the globe. Chemotherapy may prolong the survival of CRC patients to some extent, but its clinical use is associated with grave side effects on overall health. Contrary to chemotherapy, the use of plant-derived therapeutic molecules offered advantages because of their reduced toxicity. Polyphenol is a group of phytochemicals that impart many therapeutic benefits in the treatment of diabetes, cardiovascular disease and cancer. Various signaling pathways, including Wnt/ß-catenin, MAPK/PI3K and TGF-ß/Smad, play very important roles in the development and progression of CRC. Polyphenols inhibit CRC progressions by modulating these signaling pathways e.g. curcumin and resveratrol impede cancer cell proliferation by inhibiting Wnt signaling. Because of their lower aqueous solubility, the therapeutic efficacy of polyphenols is not fully exploited. In order to increase their bioavailability and efficacy, the nanoformulations of polyphenols have been formulated and investigated against various CRC test models. The main objective of this review is to explore the potential roles of polyphenols and their nanoformulations in the treatment of colorectal cancer. METHODS: We used PubMed, Web of Science, ScienceDirect, Google Scholar and Scopus electronic databases by searching the keywords: nanoparticles, polyphenols, colorectal cancer, cell signaling pathways. Mostly, the articles were retrieved directly from the journals licensed to the library of Qassim University, Saudi Arabia. RESULTS: Literature analysis has shown that the polyphenols contain several important bioactive compounds, which showed potential effectiveness against CRC. Incorporating polyphenols into nanoparticles further enhanced their bioavailability and efficacy. The findings from various studies demonstrated that polyphenol-nanoformulations accelerated the apoptosis in CRC cells by upregulating the levels of caspases and Bax, whereas inhibiting the CRC cell proliferation by downregulating the expression of Bcl-2 and ERK1/2. CONCLUSION: This review provides a valuable resource on the important anti-CRC role of polyphenols and their nanoformulations. This review will expand our knowledge about the anti-CRC roles of polyphenols and their mechanisms of action through the multiple cell signaling pathways.

Potential of Methylglyoxal-Conjugated Chitosan Nanoparticles in Treatment of Fluconazole-Resistant Candida albicans Infection in a Murine Model.

BACKGROUND: Fungal infections are becoming more prevalent and threatening because of the continuous emergence of azole-resistant fungal infections. The present study was aimed to assess the activity of free Methylglyoxal (MG) or MG-conjugated chitosan nanoparticles (MGCN) against fluconazole-resistant Candida albicans. MATERIALS AND METHODS: A novel formulation of MGCN was prepared and characterized to determine their size, shape and polydispersity index. Moreover, the efficacy of fluconazole or MG or MGCN was determined against intracellular C. albicans in macrophages and the systematic candidiasis in a murine model. The safety of MG or MGCN was tested in mice by analyzing the levels of hepatic and renal toxicity parameters. RESULTS: Candida albicans did not respond to fluconazole, even at the highest dose of 20 mg/kg, whereas MG and MGCN effectively eliminated C. albicans from the macrophages and infected mice. Mice in the group treated with MGCN at a dose of 10 mg/kg exhibited a 90% survival rate and showed the lowest fungal load in the kidney, whereas the mice treated with free MG at the same dose exhibited 50% survival rate. Moreover, the administration of MG or MGCN did not induce any liver and kidney toxicity in the treated mice. CONCLUSION: The findings of the present work suggest that MGCN may be proved a promising therapeutic formulation to treat azole-resistant C. albicans infections.

Enhancement in the Catalytic Activity of Human Salivary Aldehyde Dehydrogenase by Alliin from Garlic: Implications in Aldehyde Toxicity and Oral Health.

BACKGROUND: Lower human salivary aldehyde dehydrogenase (hsALDH) activity increases the risk of aldehyde mediated pathogenesis including oral cancer. Alliin, the bioactive compound of garlic, exhibits many beneficial health effects. OBJECTIVE: To study the effect of alliin on hsALDH activity. METHODS: Enzyme kinetics was performed to study the effect of alliin on the activity of hsALDH. Different biophysical techniques were employed for structural and binding studies. Docking analysis was done to predict the binding region and the type of binding forces. RESULTS: Alliin enhanced the dehydrogenase activity of the enzyme. It slightly reduced the Km and significantly enhanced the Vmax value. At 1 µM alliin concentration, the initial reaction rate increased by about two times. Further, it enhanced the hsALDH esterase activity. Biophysical studies indicated a strong complex formation between the enzyme and alliin (binding constant, Kb: 2.35 ± 0.14 x 103 M-1). It changes the secondary structure of hsALDH. Molecular docking study indicated that alliin interacts to the enzyme near the substrate binding region involving some active site residues that are evolutionary conserved. There was a slight increase in the nucleophilicity of active site cysteine in the presence of alliin. Ligand efficiency metrics values indicate that alliin is an efficient ligand for the enzyme. CONCLUSION: Alliin activates the catalytic activity of the enzyme. Hence, consumption of alliincontaining garlic preparations or alliin supplements and use of alliin in pure form may lower aldehyde related pathogenesis including oral carcinogenesis.

Thymoquinone Shows the Diverse Therapeutic Actions by Modulating Multiple Cell Signaling Pathways: Single Drug for Multiple Targets.

Thymoquinone (TQ), derived from the seeds of Nigella sativa, has lately been shown as a miracle drug because of its wide range of therapeutic effects against various diseases, including cancer, asthma, diabetes, colitis and infectious diseases. In the present review, we aimed to decipher the molecular mechanisms of therapeutic action of TQ by modulating the cell signaling pathways. Many in vivo and in vitro studies have demonstrated the therapeutic efficacy of TQ against a wide range of ailments. TQ possesses potent anti-inflammatory and immunomodulatory effects by specifically targeting the NF-kB, IL-1ß and TNF-α signaling pathways. The anticancer activity of TQ has been primarily shown by altering the expression of signal transducers and activator transcription (STAT3), PTEN and p53 genes. TQ alleviates the hyperglycemia-associated complications, the hepatic or renal ailments through its potent antioxidant and anti-inflammatory properties. Interestingly, the liposome- or nanoparticle-based TQ formulations have shown greater effectiveness against various diseases in animal models. Thus, the understanding of the molecular mechanisms of TQ action may lead to the development of its therapeutic formulations to cure a wide variety of diseases.

Inhibitory effect of alliin from Allium sativum on the glycation of superoxide dismutase.

Inhibition of glycation is an important approach for alleviating diabetic complications. Alliin, the most abundant sulphur compound in garlic has been demonstrated to possess antidiabetic activity. However, there is no scientific evidence supporting its antiglycating activity. The objective of this study was to determine the inhibitory effect of alliin on glucose and methyglyoxal (MG)-induced glycation of an important antioxidant enzyme, superoxide dismutase (SOD). Glycation of SOD resulted in a decrease in enzyme activity, fragmentation/cross-linking, reduced cross-reactivity with anti-SOD antibodies, both tertiary and secondary structural changes, and formation of AGEs and fibrils. Alliin offered protection against glucose or MG induced glycation of SOD. The antiglycating potential of alliin appears to be comparable with that of quercetin which is reported to be a potent natural inhibitor of glycation. Alliin has a good antiglycating effect and hence is expected to have therapeutic potential in the prevention of glycation-mediated diabetic complications.

Thymoquinone, an active constituent of Nigella sativa seeds, binds with bilirubin and protects mice from hyperbilirubinemia and cyclophosphamide-induced hepatotoxicity.

Some reports indicate that thymoquinone (TQ), the main constituent of Nigella sativa seeds, is hepatoprotective. The aim of this study was to determine whether TQ is able to bind directly to bilirubin, and whether TQ or liposomal formulation of TQ (Lip-TQ) can reduce cyclophosphamide (CYP)-induced liver toxicity, serum bilirubin level in mice. The binding of TQ with bilirubin was studied by UV-VIS, fluorescence and Near-UV CD spectroscopy. Inhibition of binding of bilirubin to erythrocytes by TQ was also examined. To increase the in vivo efficacy, Lip-TQ was prepared and used against CYP-induced toxicity. The protective role of TQ or Lip-TQ against CYP-induced toxicity was assessed by determining the liver function parameters, the levels of superoxide dismutase (SOD) and catalase (CAT), and histological studies. It was found that TQ binds to bilirubin and significantly inhibits the binding of bilirubin to erythrocytes. Lip-TQ (10 mg/kg) significantly reduced the levels of aspartate transaminase (AST) from 254 ± 48 to 66 ± 18 IU/L (P < 0.001), alanine transaminase (ALT) from 142 ± 28 to 47.8 ± 16 IU/L (P < 0.05) and serum bilirubin from 2.8 ± 0.50 to 1.24 ± 0.30 mg/dl (P < 0.05). Treatment with Lip-TQ reduced the CYP-induced inflammation and hemorrhage in liver tissues. Moreover, treatment with free or Lip-TQ protected the activity of SOD and CAT in CYP-injected mice. Therefore, TQ can reduce the level of bilirubin in systemic circulation in disease conditions that lead to hyperbilirubinemia and liver toxicity and hence may be used as a supplement in the treatment of liver ailments.

Phospholipase D from Allium sativum bulbs: A highly active and thermal stable enzyme.

This is the first report on the identification and partial characterization of phospholipase D (EC 3.1.4.4) from Allium sativum (garlic) bulbs (PLD(GB)). The enzyme shares the phenomenon of interfacial activation with other lipolytic enzymes, i.e. the hydrolytic rate increases when the substrate changes to a more aggregated state. The enzyme activity is highly temperature tolerant and the temperature optimum was measured to be 70 degrees C. PLD(GB) unlike many plant PLDs exhibited high thermal stability. It was activated further after exposure to high temperatures, i.e. 80 degrees C, indicating that the enzyme refolds better upon cooling back to room temperature after short exposure to thermal stress. The activity of PLD(GB) is optimum in 70mM calcium ion concentration and the enzyme is activated further in the presence of phosphatidyl-4,5-bisphosphate (PIP(2)). PLD(GB) exhibited both hydrolytic and transphosphatidylation activities, both of which appear to be higher than those of PLD from cabbage leaves (PLD(CL)).

Stem bromelain: an enzyme that naturally facilitates oriented immobilization.

The lone oligosaccharide chain of stem bromelain was oxidized with periodic acid to generate aldehyde groups and the resulting oxidized enzyme coupled to amino-Sepharose in order to obtain an immobilized preparation with uniformly oriented enzyme. The immobilized bromelain exhibited high proteolytic activity and remarkably enhanced thermal stability as compared to soluble bromelain and that coupled to CNBr activated Sepharose.