Alkyl Gallates as Potential Antibiofilm Agents: A Review.

Biofilms, which consist of microorganisms embedded in a polymer-rich matrix, contribute to a variety of infections and increase antimicrobial resistance. Thus, there is a constant need to develop new chemotherapeutic agents to combat biofilms. This review article focuses on the use of alkyl gallates, gallic acid and its esters (methyl, ethyl, propyl, butyl, hexyl, octyl, and dodecyl gallate), most of which are found in plants, to inhibit biofilm formation. The studies under review reveal that alkyl gallates have the capacity to prevent biofilm development and eradicate mature biofilms through mechanisms that suppress the synthesis of the extracellular polymeric matrix, inhibit quorum-sensing signaling, and alter the microbial cell membrane. The effects are stronger the greater the length of the alkyl chain. Moreover, the alkyl gallates' preventive activity against biofilm formation occurs at doses below the minimum inhibitory concentration. More importantly, combining alkyl gallates with antimicrobials or blue-light irradiation produces a synergistic effect on the inhibition of biofilm formation that can be used to treat infections and overcome microbial resistance.

Inhibiting mutant KRAS G12D gene expression using novel peptide nucleic acid-based antisense: A potential new drug candidate for pancreatic cancer.

KRAS mutations, which are the main cause of the pathogenesis of lethal pancreatic adenocarcinomas, impair the functioning of the GTPase subunit, thus rendering it constitutively active and signaling intracellular pathways that end with cell transformation. In the present study, the AsPC-1 cell line, which has a G12D-mutated KRAS gene sequence, was utilized as a cellular model to test peptide nucleic acid-based antisense technology. The use of peptide nucleic acids (PNAs) that are built to exhibit improved hybridization specificity and have an affinity for complementary RNA and DNA sequences, as well as a simple chemical structure and high biological stability that affords resistance to nucleases and proteases, enabled targeting of the KRAS-mutated gene to inhibit its expression at the translation level. Because PNA-based antisense molecules should be capable of binding to KRAS mRNA sequences, PNAs were utilized to target the mRNA of the mutated KRAS gene, a strategy that could lead to the development of a novel drug for pancreatic cancer. Moreover, it was demonstrated that introducing new PNA to cells inhibited the growth of cancer cells and induced apoptotic death and, notably, that it can inhibit G12D-mutated KRAS gene expression, as demonstrated by RT-PCR and western blotting. Altogether, these data strongly suggest that the use of PNA-based antisense agents is an attractive therapeutic approach to treating KRAS-driven cancers and may lead to the development of novel drugs that target the expression of other mutated genes.

A Novel Docetaxel-Biotin Chemical Conjugate for Prostate Cancer Treatment.

A novel conjugate of docetaxel and biotin (designated as IDD-1010) was designed and chemically synthesized via an ester linkage at position 2' carbon in docetaxel. The synthesized pure IDD-1010 exhibits a potent anti-cancer activity in in vitro and in vivo studies. At 10 nM, IDD-1010 has induced increased apoptosis and mitotic arrest of PC3-Luc prostate cancer cells, causing aneuploidy and cell death at higher concentrations. Toxicology studies indicate that the maximal tolerated dose (MTD) of IDD-1010 is 150 mg/kg in mice; equivalent to about 12.2 mg/kg of body weight, or to about an 850 mg dose for a patient weighing 70 kg. The MTD-treated mice exhibited weight gain similar to that of the control group, with no gross pathological signs at 14 days post-dosing. At a lower dose, IDD-1010 treatment did not lead to any significant weight loss in mice, although decreased the tumor volume stemming from injecting cancer cells into the dorsal loop of mouse prostate, and it was found to be more potent than Paclitaxel (reference drug). Similarly, IDD-1010 treatment significantly reduced tumor weight and thereby increased the percentage of mice survival as compared to reference drug-treated and control groups. To summarize, the described experiments using IDD-1010, as compared to the reference drug, strongly suggest a potential treatment utility with a wider therapeutic window for prostate cancer. Henceforth, clinical research on such a novel drug candidate would be greatly worthwhile.

Forty-One Plant Extracts Screened for Dual Antidiabetic and Antioxidant Functions: Evaluating the Types of Correlation between -Amylase Inhibition and Free Radical Scavenging.

Dysregulation of glucose homeostasis followed by chronic hyperglycemia is a hallmark of diabetes mellitus (DM), a disease spreading as a worldwide pandemic for which there is no satisfactory dietary treatment or cure. The development of glucose-controlling drugs that can prevent complications of DM, such as hyperglycemia and oxidative stress, which contribute to the impairment of the key physiological processes in the body, is of grave importance. In pursuit of this goal, this study screened 41 plant extracts for their antidiabetic and antioxidant activities by employing assays to test for α-amylase inhibition and free radical scavenging activity (FRSA) and by measuring glucose uptake in L6-GLUT4myc cells. While extracts of Rhus coriaria, Punica granatum, Olea europaea, Pelargonium spp., Stevia rebaudiana, and Petroselinum crispum demonstrated significant α-amylase inhibition, the extracts of Rhus coriaria and Pelargonium spp. also demonstrated increased FRSA, and the extract of Rhus coriaria stimulated glucose uptake. These natural extracts, which are believed to have fewer side effects because they are prepared from edible plants, interfere with the process in the small intestine that breaks down dietary carbohydrates into monosaccharide and disaccharide derivatives, and thereby suppress increases in diet-induced blood glucose; hence, they may have clinical value for type 2 diabetes management. The Pelargonium spp. and Rhus coriaria extracts demonstrated the highest antidiabetic and antioxidant activities. Both plants may offer valuable medical benefits, especially because they can be taken as dietary supplements by patients with diabetes and can serve as sources of new, natural-based antidiabetic drug candidates. The enhancement of cellular glucose uptake stimulated by Rhus coriaria extract could lead to the development of clinical applications that regulate blood glucose levels from within the circulatory system. Isolating bioactive substances from these plant extracts and testing them in diabetic mice will significantly advance the development of natural drugs that have both antidiabetic and free radical-scavenging properties, likely with lesser side effects.

Lauryl Gallate Activity and Streptococcus mutans: Its Effects on Biofilm Formation, Acidogenicity and Gene Expression.

Streptococcus mutans bacterium is implicated in the pathogenesis of dental caries due to the production of biofilm and organic acids from dietary sucrose. Despite the availability of various means of prophylaxis, caries still has a high worldwide prevalence. Therefore, it is important to find new pharmaceuticals to inhibit S. mutans biofilm formation and acidogenicity. The aim of the current study was to evaluate the activity of lauryl gallate (dodecyl gallate) against S. mutans acidogenicity, the expression of biofilm-associated genes, and biofilm development on solid surfaces (polystyrene, glass). The biofilm quantities produced by S. mutans bacteria were assessed using colorimetric and optical profilometry techniques. Acidogenicity was evaluated by measuring the pH of the biofilm growth medium with microelectrode. Assessment of the expression of gene coding for glucan-binding protein B (gbpB), glucosyltranferases B, -C, -D (gtfB, -C, -D), and the F-ATPase ß subunit of F1 protein (atpD) was carried out using a quantitative reverse transcription-polymerase chain reaction (RT-qPCR). The results demonstrate the capacity of lauryl gallate to significantly inhibit S. mutans acidogenicity and biofilm development on solid surfaces, in a dose-dependent manner, compared to untreated bacteria (p < 0.05). The highest activity of lauryl gallate occurred at a concentration of 98.98 µM, at which it suppressed biofilm formation by 100% and lowered pH levels by 98%. The effect of lauryl gallate treatment on gene expression changes, as demonstrated by our RT-qPCR data, was limited to the gtfD gene only, was a significant (48%) decrease in gene expression, obtained for the biofilm-producing bacteria, while a 300% increase in fold change for the same gene occurred in the planktonic cells. It is important to note that in previous studies we showed a broader effect of related derivatives. However, a similar magnitude of difference in effects between biofilm and planktonic cells for the atpD gene was obtained after treatment with octyl gallate and reverse magnitude for the same gene after treatment with ethyl gallate. Therefore, to ascertain the possible direct or indirect effects of lauryl gallate, as well as octyl gallate and ethyl gallate, more research is needed to examine the effects on the amount of enzymes and on the enzymatic activity of the products of the affected genes that are involved in the production and maintenance of biofilm by S. mutans.

Correlation between cytotoxicity in cancer cells and free radical-scavenging activity: In vitro evaluation of 57 medicinal and edible plant extracts.

Cancer is a complex interaction among multiple signaling pathways involving a variety of target molecules. Cancer causes morbidity and mortality in millions of people worldwide, and due to its prevalence, the discovery of novel anticancer drugs is urgently required. Nature is considered an important source of the discovery of anticancer treatments, and many of the cytotoxic medicines in clinics today are derived from plants and other natural sources. Reactive oxygen species (ROS) induce a variety of human cancers, and antioxidants or scavengers are used to counteract them. The current study reports on the screening of extracts from 57 plants that are used in the galilee district as a food and/or for traditional medicine. Investigating the free radical scavenging capacity and these plants, and their cytotoxicity, may prove helpful to high-throughput screening projects that use antioxidants and cytotoxic natural products. The current study assessed the correlation between free radical scavenging and cytotoxicity. Correlational analysis is important for increasing the efficiency of the screening process. In the present study, free radical scavenging was assessed using a DPPH assay, while cytotoxicity was measured using a XTT assay. A total of 9 extracts were indicated to exhibit EC50 values <250 µg/ml, and 4 others exhibited a high antioxidant content, with EC50 values, for free radical scavenging, of <0.5 µg/ml. An in-depth analysis of the results revealed that the extracts of plants that exhibit an EC50 of free radical scavenging ≤10 µg/ml show a degree of enrichment toward increased cytotoxicity. It is recommended that future studies test the validity of the conclusions of the current study on other cancer cell-lines, and isolate and identify the bioactive agents that are found in the most cytotoxic extracts of plants.

A Novel Paclitaxel Conjugate with Higher Efficiency and Lower Toxicity: A New Drug Candidate for Cancer Treatment.

Paclitaxel-lipoate (IDD-1040) is a conjugate formed by the chemical joining of the two compounds, by condensing a lipoic acid moiety to the C2' of paclitaxel. IDD-1040 was evaluated for its anti-tumor activity and potential druggability, using an in vivo non-small-cell, lung cancer (NSCLC) xenograft mouse model. In the in vivo studies, IDD-1040 showed a maximum tolerated dose (MTD) of 250 mg/kg compared to paclitaxel (PTX), with an MTD of 20 mg/kg. Most interesting, IDD-1040 demonstrated higher anti-tumor activity, and its inhibitory activity on tumor volume (cell growth) was dose-dependent. That anti-tumor activity persisted for two weeks after cessation of IDD-1040 treatment, as opposed to PTX cessation, after which the tumor relapsed, confirming that IDD-1040 exhibits superior tumor inhibition. Similar to PTX treatment, no marked body weight decrease was observed during IDD-1040 treatment, indicating a low toxicity profile. The increase in animal body weight noted over time was due to the increasing weight of tumors, recorded in all the mouse test groups. The results also showed that mortality rate of mice was reduced by treatment with IDD-1040, more so than with PTX. Furthermore, in a preliminary study on the ex vivo distribution of IDD-1040, neutropenia was primarily concentrated in the liver 1 h after injection, and most of the drug was metabolized by the liver in 24 h. All of these results demonstrate IDD-1040's great potential as a candidate drug for cancer treatment.

Suppressive Effects of Octyl Gallate on Streptococcus mutans Biofilm Formation, Acidogenicity, and Gene Expression.

The accumulation of biofilm by Streptococcus mutans bacteria on hard tooth tissues leads to dental caries, which remains one of the most prevalent oral diseases. Hence, the development of new antibiofilm agents is of critical importance. The current study reports the results from testing the effectiveness of octyl gallate (C8-OG) against: (1) S. mutans biofilm formation on solid surfaces (polystyrene, glass), (2) acidogenicity, (3) and the expression of biofilm-related genes. The amount of biofilm formed by S. mutans bacteria was evaluated using the colorimetric method and optical profilometry. The pH of the biofilm growth medium was measured with microelectrode. A quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was used to assess the expression of genes encoding glucan binding protein B (gbpB), glucosyltransferases B, -C, -D (gtfB, -C, -D), and the F-ATPase ß subunit of the F1 protein (atpD). The results show that C8-OG significantly diminished biofilm formation by exposed S. mutans on solid surfaces and suppressed acidogenicity in a dose-dependent manner, compared to unexposed bacteria (p < 0.05). The C8-OG concentration of 100.24 µM inhibited S. mutans biofilm development on solid surfaces by 100% and prevented a decrease in pH levels by 99%. In addition, the RT-qPCR data demonstrate that the biofilm-producing bacteria treated with C8-OG underwent a significant reduction in gene expression in the case of the four genes under study (gbpB, gtfC, gtfD, and atpD), and there was a slight decrease in expression of the gtfB gene. However, C8-OG treatments did not produce significant expression change compared to the control for the planktonic cells, although there was a significant increase for the atpD gene. Therefore, C8-OG might be a potent antibiofilm and/or anticaries agent for oral formulations that aim to reduce the prevalence of dental caries.

Phytochemical Composition and Biological Activities of Wild Scolymus maculatus L.

Background: The wild population of spotted golden thistle, Scolymus maculatus, which belongs to the Compositae family, is believed to be one of the multi-curative wild plants mentioned in Flora Palaestina. This study aims to disclose the phytochemical composition, antioxidant potential, and antimicrobial activity of wild S. maculatus collected from the farms of Kabul, a village in northwest Galilee, for the first time. Methods: The phytochemical components of crude S. maculatus extracts from methanol, ethyl acetate, and n-hexane solvents were separated and identified using gas chromatography-mass spectrometry (GC-MS) in the electron impact (EI) mode. The free radical scavenging of the plant extracts was measured by DPPH assay. The microdilution test was used to determine the minimum inhibitory concentrations (MICs) of different S. maculatus extracts and to evaluate their antimicrobial activities. Results: Thirty-two phytochemicals were found in S. maculatus extracts including stigmasterol, γ-sitosterol, lupeol, lupeol acetate, and ß-amyrin. Phytochemicals, such as 2-linoleoylglycerol, γ-sitosterol, ß-amyrin, lupeol, (3α)-12-oleanen-3-yl acetate, and lupenyl acetate, were found to dominate the methanol extract. Most of these compounds were also observed in ethyl acetate and n-hexane extracts, but at different levels, in addition to some other minor compounds. The various extracts were investigated for their antioxidant and antimicrobial activity. The ethanolic and the methanolic extracts were shown to exhibit the highest free radical scavenging by DPPH assay with a half-maximally effective concentration (EC50) of 0.37 and 0.65 mg/mL respectively, while the other three extracts (aqueous, ethyl acetate and n-hexane) were less active and their EC50 (effective concentration at which DPPH radical was scavenged by 50%) were above 1.0 mg/mL. Moreover, MICs were determined to be effective against Staphylococcus aureus, Salmonella typhimurium, and Candida albicans microorganisms. Ethyl acetate and the ethanolic extracts are active against the three types of microorganisms at a minimum inhibitory concentration (MIC) of 0.5 mg/mL, while aqueous and the n-hexane extracts are inactive against Salmonella typhimurium. Conclusions: The results show that S. maculatus extracts are a rich source of compounds that can play an important role in human health, and in a broader context, in the treatment of various diseases, such antimicrobial and antioxidant-related ailments.

Discovering highly selective and diverse PPAR-delta agonists by ligand based machine learning and structural modeling.

PPAR-δ agonists are known to enhance fatty acid metabolism, preserving glucose and physical endurance and are suggested as candidates for treating metabolic diseases. None have reached the clinic yet. Our Machine Learning algorithm called "Iterative Stochastic Elimination" (ISE) was applied to construct a ligand-based multi-filter ranking model to distinguish between confirmed PPAR-δ agonists and random molecules. Virtual screening of 1.56 million molecules by this model picked ~2500 top ranking molecules. Subsequent docking to PPAR-δ structures was mainly evaluated by geometric analysis of the docking poses rather than by energy criteria, leading to a set of 306 molecules that were sent for testing in vitro. Out of those, 13 molecules were found as potential PPAR-δ agonist leads with EC50 between 4-19 nM and 14 others with EC50 below 10 µM. Most of the nanomolar agonists were found to be highly selective for PPAR-δ and are structurally different than agonists used for model building.

Inhibitory Effects of Ethyl Gallate on Streptococcus mutans Biofilm Formation by Optical Profilometry and Gene Expression Analysis.

This study aimed to test the effectiveness of ethyl gallate (EG) against S. mutans biofilm formation on solid surfaces (polystyrene, glass) and acidogenicity, and to examine the effect on expression of related genes. The biofilm that is formed by S. mutans bacteria was evaluated using colorimetric assay and optical profilometry, while the pH of the biofilm growth medium was measured with microelectrode. The expression of genes encoding glucan binding protein B (gbpB), glucosyltranferases B, -C, -D (gtfB, -C, -D) and F-ATPase (atpD, atpF) was assessed using a quantitative reverse transcription-polymerase chain reaction (RT-qPCR). It was revealed that all of the EG concentrations significantly suppressed S. mutans biofilm build-up on polystyrene and glass surfaces, and inhibited acidogenicity, in a dose-dependent manner, compared to the activity of untreated bacteria (p < 0.05). The highest concentration of EG (3.53 mM) reduced biofilm formation on polystyrene and glass surfaces by 68% and more than 91%, respectively, and prevented a decrease in pH levels by 95%. The RT-qPCR data demonstrate that the biofilm-producing bacteria treated with EG underwent significant gene expression changes involving the gtfC (a 98.6 increase in fold change), gtfB gene (a 47.5 increase in fold change) and the gbpB gene (a 13.8 increase in fold change). However, for the other genes tested (gtfD, atpD and atpF), the EG treatments did not produce significant expression change compared to the control. EG produced significant gene expression change in three genes-gtfC, gtfB, and gbpB; it has the capacity to inhibit S. mutans biofilm formation on solid surfaces (polystyrene, glass), as well as acidogenicity. Therefore, EG might be used as an antibiofilm and/or anticaries agent for oral formulations in order to reduce the prevalence of dental caries.

Anticancer activity and phytochemical composition of wild Gundelia tournefortii.

Artichoke-like wild thistles are often used in Palestinian cuisine. One of the most commercially recognized species of these wild edible thistles is Gundelia tournefortii, a common plant in the Mediterranean region. G. tournefortii, or 'Akoob' in Arabic, remains uncultivated, harvested wild by local populations and considered highly valuable due to its reputed health benefits. The present study aimed to investigate the anticancer effects of G. tournefortii on the human colon carcinoma HCT-116 cell line. Methanol and hexane extracts were identified to exert considerable antitumor activity against the HCT-116 cancer cell line, while the aqueous extract was inactive. The phytochemical profiles of the methanol and hexane extracts were investigated using gas chromatography-mass spectrometry. A total of 6 of the 27 natural compounds identified, including sitosterol, stigmasterol, lupeol, gitoxigenin, α-amyrin and artemisinin, have been previously validated as being active against cancerous cells. Therefore, the presence of these phytochemicals in G. tournefortii is of importance in its role in preventing and treating cancer.

Indexing Natural Products for their Antifungal Activity by Filters-based Approach: Disclosure of Discriminative Properties.

BACKGROUND: A considerable worldwide increase in the rate of invasive fungal infections and resistance toward antifungal drugs was witnessed during the past few decades. Therefore, the need for newer antifungal candidates is paramount. Nature has been the core source of therapeutics for thousands of years, and an impressive number of modern drugs including antifungals were derived from natural sources. In order to facilitate the recognition of potential candidates that can be derived from natural sources, an iterative stochastic elimination optimization technique to index natural products for their antifungal activity was utilized. METHODS: A set of 240 FDA-approved antifungal drugs, which represent the active domain, and a set of 2,892 natural products, which represent the inactive domain, were used to construct predictive models and to index natural products for their antifungal bioactivity. The area under the curve for the produced predictive model was 0.89. When applying it to a database that is composed of active/inactive chemicals, we succeeded to detect 42% of the actives (antifungal drugs) in the top one percent of the screened chemicals, compared with one-percent when using a random model. RESULTS AND CONCLUSION: Eight natural products, which were highly scored as likely antifungal drugs, are disclosed. Searching PubMed showed only one molecule (Flindersine) out of the eight that have been tested was reported as an antifungal. The other seven phytochemicals await evaluation for their antifungal bioactivity in a wet laboratory.

A New Approach for Indexing Honey for Its Heath/Medicinal Benefits: Visualization of the Concept by Indexing Based on Antioxidant and Antibacterial Activities.

Background: The goals of the current study were to address a new concept termed a health benefits' index (HBI) and to verify the type of correlation between the pricing of honey and its HBI/medicinal properties. Diverse types of honey from different origins and places were investigated for their antioxidant and antimicrobial activity. Methods: We have utilized a modified protocol of the DPPH assay for measuring free radical scavenging and the microdilution test for the determination of antibacterial/antifungal minimum inhibitory concentrations (MICs). MICs were determined against Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, and Candida albicans microorganisms. Employing a "combined benefits approach" enabled us to attach to each honey type a unique number of HBI that correlate with honey health and medicinal values. Results: The various types of honey demonstrated significant but variable antioxidant, antibacterial, and antifungal activities. Types of wildflower-labeled honey were found to have a wide range of HBI values and medicinal properties, probably due to their containing different nectar contents/phytochemicals. Moreover, an inconsiderable correlation was detected between the market prices of different types of honey and their HBIs. Conclusions: The proposed index of health benefits could be recalculated/updated following measurement of more and more medicinal properties, such as anti-inflammatory, antidiabetic, and anticancer activities. This index could be used as an effective tool for consumers of honey to evaluate the real value of the purchased product.

Capturing antibacterial natural products with in silico techniques.

The aim of the present study was to index natural products in order to facilitate the discovery of less expensive antibacterial therapeutic drugs. Thus, for modeling purposes, the present study utilized a set of 628 antibacterial drugs, representing the active domain, and 2,892 natural products, representing the inactive domain. In addition, using the iterative stochastic elimination algorithm, 36 unique filters were identified, which were then used to construct a highly discriminative and robust model tailored to index natural products for their antibacterial bioactivity. The area attained under the curve was 0.957, indicating a highly discriminative and robust prediction model. Utilizing the proposed model to virtually screen a mixed set of active and inactive substances enabled the present study to capture 72% of the antibacterial drugs in the top 1% of the sample, yielding an enrichment factor of 72. In total, 10 natural products that scored highly as antibacterial drug candidates with the proposed indexing model were reported. PubMed searches revealed that 2 molecules out of the 10 (caffeine and ricinine) have been tested and identified as showing antibacterial activity. The other 8 phytochemicals await experimental evaluation. Due to the efficiency and rapidity of the proposed prediction model, it could be applied to the virtual screening of large chemical databases to facilitate the drug discovery and development processes for antibacterial drug candidates.

Sesamin from Cuscuta palaestina natural plant extracts: Directions for new prospective applications.

The aim of this study is to disclose the potential bioactive components of Cuscuta palaestina, a native parasitic natural plant of flora palaestina and to open direction towards new prospective application. GC-MS analysis identified 18 components in the methanolic extract of C. palaestina for the first time. The most appealing among them are Sesamin and two other phytosterols (Campesterol and Stigmasterol), all of which are documented in the scientific literature for their anticancer activity. Quantitation of Sesamin extracted from C. palaestina by HPLC-PDA with the use of three organic solvents showed that the Sesamin content in the methanolic extract was the highest. Following the disclosure of Sesamin presence in C. palaestina, we raised the question of whether it is produced naturally in C. palaestina or acquired from the host plant. The quantitation of Sesamin in C. palaestina was performed while being with five different host plants, and was compared with the amount of Sesamin in C. palaestina grown alone. The findings reveal that Sesamin is an endogenous secondary metabolite in C. palaestina. Thus, further studies are required to prove if C. palaestina can be used as an alternative source of anticancer phytochemicals, mainly Sesamin, and if proteins in the Sesamin production pathway could be valid biological targets for the development of novel and selective pesticides for control/ eradication of C. palaestina and maybe some other Cuscuta species. As well, the findings from this study raise a big question of whether inferring Sesamin production in C. palaestina could reduce its attack ability to host plants.

Nature is the best source of anti-inflammatory drugs: indexing natural products for their anti-inflammatory bioactivity.

OBJECTIVES: The aim was to index natural products for less expensive preventive or curative anti-inflammatory therapeutic drugs. MATERIALS: A set of 441 anti-inflammatory drugs representing the active domain and 2892 natural products representing the inactive domain was used to construct a predictive model for bioactivity-indexing purposes. METHOD: The model for indexing the natural products for potential anti-inflammatory activity was constructed using the iterative stochastic elimination algorithm (ISE). ISE is capable of differentiating between active and inactive anti-inflammatory molecules. RESULTS: By applying the prediction model to a mix set of (active/inactive) substances, we managed to capture 38% of the anti-inflammatory drugs in the top 1% of the screened set of chemicals, yielding enrichment factor of 38. Ten natural products that scored highly as potential anti-inflammatory drug candidates are disclosed. Searching the PubMed revealed that only three molecules (Moupinamide, Capsaicin, and Hypaphorine) out of the ten were tested and reported as anti-inflammatory. The other seven phytochemicals await evaluation for their anti-inflammatory activity in wet lab. CONCLUSION: The proposed anti-inflammatory model can be utilized for the virtual screening of large chemical databases and for indexing natural products for potential anti-inflammatory activity.

Nature is the best source of anticancer drugs: Indexing natural products for their anticancer bioactivity.

Cancer is considered one of the primary diseases that cause morbidity and mortality in millions of people worldwide and due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. However, the traditional process of drug discovery and development is lengthy and expensive, so the application of in silico techniques and optimization algorithms in drug discovery projects can provide a solution, saving time and costs. A set of 617 approved anticancer drugs, constituting the active domain, and a set of 2,892 natural products, constituting the inactive domain, were employed to build predictive models and to index natural products for their anticancer bioactivity. Using the iterative stochastic elimination optimization technique, we obtained a highly discriminative and robust model, with an area under the curve of 0.95. Twelve natural products that scored highly as potential anticancer drug candidates are disclosed. Searching the scientific literature revealed that few of those molecules (Neoechinulin, Colchicine, and Piperolactam) have already been experimentally screened for their anticancer activity and found active. The other phytochemicals await evaluation for their anticancerous activity in wet lab.

Indexing Natural Products for Their Potential Anti-Diabetic Activity: Filtering and Mapping Discriminative Physicochemical Properties.

Diabetes mellitus (DM) poses a major health problem, for which there is an unmet need to develop novel drugs. The application of in silico techniques and optimization algorithms is instrumental to achieving this goal. A set of 97 approved anti-diabetic drugs, representing the active domain, and a set of 2892 natural products, representing the inactive domain, were used to construct predictive models and to index anti-diabetic bioactivity. Our recently-developed approach of 'iterative stochastic elimination' was utilized. This article describes a highly discriminative and robust model, with an area under the curve above 0.96. Using the indexing model and a mix ratio of 1:1000 (active/inactive), 65% of the anti-diabetic drugs in the sample were captured in the top 1% of the screened compounds, compared to 1% in the random model. Some of the natural products that scored highly as potential anti-diabetic drug candidates are disclosed. One of those natural products is caffeine, which is noted in the scientific literature as having the capability to decrease blood glucose levels. The other nine phytochemicals await evaluation in a wet lab for their anti-diabetic activity. The indexing model proposed herein is useful for the virtual screening of large chemical databases and for the construction of anti-diabetes focused libraries.

Inhibitory capacity of Rhus coriaria L. extract and its major component methyl gallate on Streptococcus mutans biofilm formation by optical profilometry: Potential applications for oral health.

Streptococcus mutans (S. mutans) bacterium is the most well recognized pathogen involved in pathogenesis of dental caries. Its virulence arises from its ability to produce a biofilm and acidogenicity, causing tooth decay. Discovery of natural products capable to inhibit biofilm formation is of high importance for developing health care products. To the best of our knowledge, in all previous scientific reports, a colorimetric assay was applied to test the effect of sumac and methyl gallate (MG) on S. mutans adherence. Quantitative assessment of the developed biofilm should be further performed by applying an optical profilometry assay, and by testing the effect on both surface roughness and thickness parameters of the biofilm. To the best of our knowledge, this is the first study to report the effect of sumac extract and its constituent MG on biofilm formation using an optical profilometry assay. Testing antibacterial activity of the sumac extract and its fractions revealed that MG is the most bioactive component against S. mutans bacteria. It reduced S. mutans biofilm biomass on the polystyrene surface by 68­93%, whereas 1 mg/ml MG was able to decrease the biofilm roughness and thickness on the glass surface by 99%. MG also prevented a decrease in pH level by 97%. These bioactivities of MG occurred in a dose­dependent manner and were significant vs. untreated bacteria. The findings are important for the development of novel pharmaceuticals and formulations of natural products and extracts that possess anti­biofilm activities with primary applications for oral health, and in a broader context, for the treatment of various bacterial infections.