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Tuberculosis (TB) continues to be a primary worldwide health concern due to relatively ineffective treatments. The prolonged duration of conventional antibiotic therapy warrants innovative approaches to shorten treatment courses. In response to challenges, the study explores potential of Ajoene, a naturally occurring garlic extract-derived compound, for potential TB treatment. Mycobacterium smegmatis as a model organism for M. tuberculosis (M. tb) to investigate Ajoene's efficiency. In vitro techniques like antimicrobial susceptibility, antibiofilm, EtBr accumulation assay, and ROS assay evaluate the potency of Ajoene and conventional TB drugs against Mycobacterium smegmatis. An in-silico study also investigated the interaction between Ajoene and quorum-sensing proteins, specifically regX3, MSMEG_5244, and MSMEG_3944, which are involved in biofilm formation and sliding activity. In vitro findings revealed that Ajoene exhibited significant antibacterial activity by inhibiting growth and showing bactericidal effects. It also demonstrated additive interactions with common antibiotics such as Isoniazid and Rifampicin. Furthermore, Ajoene demonstrated a comparative interaction with commonly used antibiotics, such as Isoniazid and Rifampicin, and reduced M. smegmatis motility, both alone and in combination with these antibiotics. In silico analysis shows that Ajoene exhibited a higher binding affinity with regX3, a protein orthologous to the regX3 gene in M.tb. Ajoene also demonstrated consistent antibiofilm effects, particularly when combined synergistically with Isoniazid and Rifampicin. Mechanistic investigations demonstrated Ajoene's potential to inhibit efflux pumps and promote ROS generation in bacteria, suggesting a potential direct killing mechanism. Collectively, the findings emphasize Ajoene's effectiveness as a novel antimycobacterial and antibiofilm molecule for TB treatment. [ABSTRACT FROM AUTHOR]

Abstract The emergence and spread of pathogenic bacterial resistance to many antibiotics are on the rise globally, thereby posing a significant threat to public health. In response, scientists are actively investigating alternative therapeutic agents to combat antibiotic‐resistant microorganisms. This review focuses on the antimicrobial effects of commonly consumed spices, namely garlic, chilli peppers, turmeric, ginger and black pepper, which have shown promising results in previous research. The review highlights the key phytochemicals, including allicin, ajoene, capsaicin, dihydrocapsaicin, curcumin, 6‐gingerol, 6‐shogaol and piperine, responsible for their antimicrobial activities. Various pharmacological experiments to elucidate the action mechanism and metabolism of those bioactive compounds are described. Moreover, the synergistic effects of these phytochemicals with conventional antibiotics are discussed, emphasizing the potential to reduce the required antibiotic dosage for effective microbial inhibition. The review also addresses the gaps in current research, such as the variations in antimicrobial assay results across different research groups and the incomplete understanding of the synergistic mechanisms between antibiotics and phytochemicals. Finally, future research directions and opportunities are suggested to further explore the antimicrobial potential of these spice‐derived phytochemicals and bridge the existing knowledge gaps.

Background: Allium sativum, the bulbous perennial plant of the Alliaceae family has been utilized as a very valuable remedy in the management of numerous diseases even from time immemorial. The plant exhibits antimicrobial activities over a wide range of microorganisms like parasites, fungi, virus and other pathogens. This broad- spectrum of antimicrobial activity coupled with the low toxicity of Allium sativum are an attraction to scientists and thus it has been vastly employed as a therapeutic cure in contemporary society. The therapeutic properties of Allium sativum (antibacterial, antiviral, fungicidal, anti-cardiovascular disease, anticancer, antidiabetic, anti-blood pressure, antiatherosclerosis, antirheumatic, hyperlipidemia) are linked to the sulphur compounds it contains (diallyl disulfide, allicin, diallyl trisulfide, ajoene's, vinyl-dithiin, micronutrient selenium and S-allylcystein. Objectives: This review considers some sulphur compounds contained in Allium sativum and the mechanisms by which they elicit their biological actions. Method: The journals for this review paper were retrieved from prominent database sources like Academia.edu (https://www.academia.edu), PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Web of science (https://access.clarivate.com). Both medical headings and free text keywords were employed in the search “biological activities of allicin”, “biosynthesis of sulphur compounds in garlic”, “sulphur compounds in garlic”, “mechanism of action of antibacterial action of ajoene”, “S-allylcystein in garlic”, “mechanism of neuroprotection by vinvyl-dithiin”, “anticancer actions of dially disulfide”, mechanism of anti-quorum sensing actions of ajoene, antihyperlipidemic activity of allicin, mechanism of anti-platelet actions of ajoene and other related information from related journals. Results: Allium sativum has many therapeutic properties; antibacterial, neuroprotection, antiviral, fungicidal, lipid metabolism, anti-cardiovascular disease, glucose metabolism, anticancer, antidiabetic, anti-blood pressure, antiatherosclerosis, antirheumatic, hyperlipidemia), these properties result from some sulphur compounds (diallyl disulfide, allicin, diallyl trisulfide, ajoene's, vinyl-dithiin, micronutrient selenium and S-allylcystein) which the plant contains. Conclusion: Within this paper, some sulphur containing phytonutrients in Allium sativum namely; allicin, ajoene, S-allylcystein, vinvyl-dithiin, dially disulfide, dially trisulfide and the mechanisms by which they carry out these actions are considered. The pharmaceutical and food industries have harnessed these phytochemicals in manufacturing both wellness and therapeutic products. Should more research be carried out on Allium sativum, safe and effective doses can be authenticated so that it can be safely included in the management of pathologies.

Background and aims: Amaryllidaceae is a family of monocotyledons belonging to the order Asparagales. Some species have extensive pharmacological properties as they produce alkaloids, with antiviral and antimicrobial activity. Within this family, in the Allioideae subfamily, it’s found garlic (Allium sativum L.). Investigations have been carried out on the phytochemical compounds, both of the isolated components of their bulbs and of various formulations. The objective of the present work was to carry out a bibliographical review of investigations made in this regard, with emphasis on those referred to fungal control. M&M: The methodology used consisted of an online search and subsequent review of specialized papers. The search engines Google and Google Scholar were used. A total of 31 scientific journals, 1 web page, 6 theses, 1 final degree project and 1 conference proceedings have been consulted. These investigations date from the end of the 20th century to the present. The following search guides were used: Garlic, garlic components, and garlic as an antifungal agent. The works consulted and search sites have been synthesized in a table. Results: The investigations surveyed in this review confirm the high potential of garlic as an antimicrobial and antifungal agent, both in isolated components of the bulbs and in different formulations. A synthesis with the results obtained in recent investigations applied to prevention and fungal control is presented. Conclusions: This review contributes to the updated knowledge of the antimicrobial and antifungal properties of garlic that are related to the variety of isolated compounds produced in the plant. [ABSTRACT FROM AUTHOR]

Introducción y objetivos: Amaryllidaceae es una familia de monocotiledóneas pertenecientes al orden Asparagales. Algunas especies poseen amplias propiedades farmacológicas ya que producen alcaloides, los cuales tienen actividad antiviral y antimicrobiana. Dentro de dicha familia, en la subfamilia Allioideae, se encuentra el ajo (Allium sativum L.). Se han realizado investigaciones sobre los compuestos fitoquímicos, tanto de los componentes aislados de sus bulbos como de diversas formulaciones. El objetivo del presente trabajo fue hacer una revisión bibliográfica de investigaciones realizadas al respecto, con énfasis en las referidas a control fúngico. M&M: La metodología utilizada consistió en la búsqueda online y posterior revisión de trabajos especializados. Se utilizaron los buscadores Google y Google Académico. Ha sido consultado un total de 31 revistas científicas, 1 página web, 6 tesis, 1 trabajo de fin de grado y 1 acta de congreso. Dichas investigaciones datan desde fines del siglo XX hasta la actualidad. Se utilizaron las siguientes guías de búsqueda: Ajo, componentes del ajo y ajo como agente antifúngico. Se han sintetizado en una tabla los trabajos consultados y sitios de búsqueda. Resultados: Las investigaciones relevadas en esta revisión, confirman el alto potencial del ajo como agente antimicrobiano y antifúngico, tanto en componentes aislados de los bulbos como en distintas formulaciones. Se presenta una síntesis con los resultados obtenidos en investigaciones recientes aplicadas a prevención y control fúngico. Conclusiones: Esta revisión aporta al conocimiento actualizado de las propiedades antimicrobianas y antifúngicas del ajo que se hallan relacionadas con la variedad de compuestos aislados, producidos en la planta.

An outbreak of pneumonia occurred on December 2019 in Wuhan, China, which caused a serious public health emergency by spreading around the globe. Globally, natural products are being focused on more than synthetic ones. So, keeping that in view, the current study was conducted to discover potential antiviral compounds from Allium sativum. Twenty-five phytocompounds of this plant were selected from the literature and databases including 3-(Allylsulphinyl)-L-alanine, Allicin, Diallyl sulfide, Diallyl disulfide, Diallyl trisulfide, Glutathione, L-Cysteine, S-allyl-mercapto-glutathione, Quercetin, Myricetin, Thiocysteine, Gamma-glutamyl-Lcysteine, Gamma-glutamylallyl-cysteine, Fructan, Lauricacid, Linoleicacid, Allixin, Ajoene, Diazinon Kaempferol, Levamisole, Caffeicacid, Ethyl linoleate, Scutellarein, and S-allylcysteine methyl-ester. Virtual screening of these selected ligands was carried out against drug target 3CL protease by CB-dock. Pharmacokinetic and pharmacodynamic properties defined the final destiny of compounds as drug or non-drug molecules. The best five compounds screened were Allicin, Diallyl Sulfide, Diallyl Disulfide, Diallyl Trisulfide, Ajoene, and Levamisole, which showed themselves as hit compounds. Further refining by screening filters represented Levamisole as a lead compound. All the interaction visualization analysis studies were performed using the PyMol molecular visualization tool and LigPlot+. Conclusively, Levamisole was screened as a likely antiviral compound which might be a drug candidate to treat SARS-CoV-2 in the future. Nevertheless, further research needs to be carried out to study their potential medicinal use. [ABSTRACT FROM AUTHOR]

Introduction: Use of natural products for management of diseases has increased widely due to the belief that natural products are less toxic than conventional medicines. Natural products have been utilised for management of chronic diseases such as diabetes and cancers. Respiratory infections have also been managed using natural products. Allium sativum is one of the natural products that has been utilised in the management of SARS-CoV infections, diabetes and cancer. Methods: This study was aimed at screening bioactive agents in Allium sativum using computational analysis. The targets of the bioactive agents were predicted using SwissTargetPrediction tools. Molecular docking followed, where the docking energies of the bioactive agents to the targets were generated. The bioactive agents were analysed for pharmacokinetics properties using SwissADME as well as toxicity profiles using the ProTox II webserver. The docking scores, toxicities and pharmacokinetics profiles of the bioactive agents in Allium sativum were compared with those of reference compounds. Results: All the bioactives showed lower docking scores than the reference compounds. The bioactives, however, showed some activity on specific receptors such as carbonic anhydrases, cyclooxygenase and ghrelin. All the bioactives showed high gastrointestinal tract absorption and none violated Lipinski’s rule of five. Diallyl trisulphide was predicted to be most lethal, with an LD50 of 100mg/kg, while was the safest, with 8000mg/kg. Conclusions: In conclusion, bioactives showed lower docking scores than the reference compounds, therefore overall pharmacological activity could be attributed to synergy between the bioactives for a particular receptor.

ABSTRACT Prenatal screening in pregnant women between 35 and 37 weeks of gestation and intrapartum antibiotic prophylaxis has successfully reduced the incidence of neonatal morbidity and mortality related to Streptococcus agalactiae. However, the contamination rates of newborns are still considerable. In traditional and folk medicines, it has been observed that garlic has been effective in treating S. agalactiae infection. The aim of this study was to isolate and identify the active compounds from garlic that have antimicrobial activity against S. agalactiae. In order to do this, SP80 (Sep-Pak 80%) obtained from crude garlic extract (CGE) was fractionated by reverse-phase ultrafast liquid chromatography with UV (RP-UFLC-UV) using a Shim-pack PREP-ODS column. All fractions obtained were tested using a microbial growth inhibition test against the S. agalactiae strain (ATCC 12386). Five clinical isolates were used to confirm the action of the fractions with antimicrobial activity, and the bacterial growth curve was determined. Identification of the antimicrobial compounds was carried out through liquid chromatography coupled with mass spectrometry (LC/MS) and nuclear magnetic resonance (NMR). The active compounds found to exhibit antimicrobial activity were Ƴ-glutamyl-S-allyl-cysteine (fraction 18), Ƴ-glutamyl-phenylalanine (fraction 20), and the two stereoisomers (E and Z) of ajoene (fraction 42). The MICs of these fractions were 5.41 mg/ml, 4.60 mg/ml, and 0.16 mg/ml, respectively, and they inhibited the growth of the clinical isolates tested. Antimicrobial compounds from garlic may be a promising source in the search for new drugs against S. agalactiae. IMPORTANCE Invasive disease due to group B streptococcal (GBS) infection results in a wide spectrum of clinical disease in neonates. Maternal colonization by GBS is the primary risk factor for disease. The strategy recommended by the Centers for Disease Control to reduce neonatal GBS infection is the culture-based screening of all pregnant women at 35 to 37 weeks of gestation and intrapartum antibiotic prophylaxis (IAP). However, indiscriminate use of antibiotics favors the selection and spread of resistant bacteria. The global scenario of antibacterial resistance has been of great concern for public health, and natural products can be a source of new substances to help us grapple with this problem.

Overexpression of glioma-associated oncogene (Gli), a transcription factor at the final step of Hedgehog (Hh) pathway, is involved in pancreatic cancer development. Therefore, inhibition of Gli can be a therapeutic strategy to treat pancreatic cancer. The objective of this study was to determine effects of Z-ajoene from garlic, on Gli-mediated transcription and proliferation of pancreatic cancer cells. We found that Z-ajoene could inhibit Gli transcriptional activity in Sonic Hedgehog (Shh) stimulated C3H10T1/2 mesenchymal stem cells. Z-Ajoene suppressed Gli transcriptional activity and Gli-target protein expressions in PANC-1 human pancreatic cancer cells. Z-Ajoene also reduced expression of FoxM1, one of Gli-target proteins, and subsequently down-regulated expressions of cell cycle-related proteins. Moreover, Z-ajoene reduced cell proliferation and increased G2/M phase of PANC-1 cells. These results suggest that Z-ajoene can repress pancreatic cancer cell proliferation by inhibiting Gli signaling. Thus, Z-ajoene might be a lead compound for the development of anti-pancreatic cancer agent.

Abstract Background Garlic has been used for centuries for its flavour and health promoting properties that include protection against cancer. The vinyl disulfide-sulfoxide ajoene is one of the phytochemicals found in crushed cloves, hypothesised to act by S-thiolating reactive cysteines in target proteins. Methods Using our fluorescently labelled ajoene analogue called dansyl-ajoene, ajoene’s protein targets in MDA-MB-231 breast cancer cells were tagged and separated by 2D electrophoresis. A predominant band was identified by MALDI-TOF MS/MS to be vimentin. Target validation experiments were performed using pure recombinant vimentin protein. Computational modelling of vimentin bound to ajoene was performed using Schrödinger and pK a calculations by Epik software. Cytotoxicity of ajoene in MDA-MB-231 and HeLa cells was measured by the MTT assay. The vimentin filament network was visualised in ajoene-treated and non-treated cells by immunofluorescence and vimentin protein expression was determined by immunoblot. The invasion and migration activity was measured by wound healing and transwell assays using wildtype cells and cells in which the vimentin protein had been transiently knocked down by siRNA or overexpressed. Results The dominant protein tagged by dansyl-ajoene was identified to be the 57 kDa protein vimentin. The vimentin target was validated to reveal that ajoene and dansyl-ajoene covalently bind to recombinant vimentin via a disulfide linkage at Cys-328. Computational modelling showed Cys-328 to be exposed at the termini of the vimentin tetramer. Treatment of MDA-MB-231 or HeLa cells with a non-cytotoxic concentration of ajoene caused the vimentin filament network to condense; and to increase vimentin protein expression. Ajoene inhibited the invasion and migration of both cancer cell lines which was found to be dependent on the presence of vimentin. Vimentin overexpression caused cells to become more migratory, an effect that was completely rescued by ajoene. Conclusions The garlic-derived phytochemical ajoene targets and covalently modifies vimentin in cancer cells by S-thiolating Cys-328. This interaction results in the disruption of the vimentin filament network and contributes to the anti-metastatic activity of ajoene in cancer cells.

Ajoene is a compound found in garlic extracts exhibiting a large range of biological activity. Novel ajoene analogues have been prepared in the search of compounds with superior bioactivity. Modifications include the alteration of the sulfoxide, the central alkene and the terminal allyl groups. [ABSTRACT FROM AUTHOR]

Throughout history, many plants and their products have been widely used as medicines for the prevention and treatment of different diseases in many cultures. Garlic (Allium sativum), is commonly used as a spice and traditionally used for its medicinal value since ancient times. Recent studies support the effects of garlic and its extracts in a wide range of applications. Due to the presence of sulfur containing compounds, high trace mineral content and enzymes, garlic has been reported to have implications in disease management and play a role as anti-diabetic, anti-microbial, anti-obesity, anti-oxidant and anti-tumor, dyslipidaemia effect, neuroprotective, cardio-preventive and photo-protection effects. It contains various active compound such as allicin, ajoene, diallyl disulfide and S-allyl-cysteine that modulates various biological cascades and prevent the pathogenesis. This review illustrates the role of garlic and their active ingredients in the health management based on in vivo and in vitro studies. [ABSTRACT FROM AUTHOR]

An experiment of five-kilo pots was carried out during the 2018-2019 autumn growth season in 2018 - 2019 at one of the seedbeds of Al-Hadara district in Al-Diwaniyah city. The aim of the experiment is to evaluate the effect of nano (boron and copper), inoculation of Anabaena sp. algae and magnetization of irrigation water on the production of some active materials (allicin and ajoene) in garlic Allium sativum L. The experiment was designed with Randomized Complete Block Design (RCBD) with a factorial organization that included three factors (different concentrations to nano boron and copper, Anabaena sp. legalization and magnetized water). Results showed a significant effect for all factors in this study especially the interaction of three factors; addition of 4g.l-1 of nano boron and use 1000 gauss of magnetized water for inoculated plants. It is reached (2722.48, 1516.29 microgram/milliliter) allicin, ajoene, respectively. The highest average of allicin and ajoene content showed by using different concentrations of nano boron and copper as well as magnetized water either 1000 or 500 gauss for inoculated plants or not, however, inoculated were more effective as in Tables 2, 3. [ABSTRACT FROM AUTHOR]

A short total synthesis of ajoene, (E,Z)‐4,5,9‐trithiadodeca‐1,6,11‐triene 9‐oxide, has been achieved over six steps. In addition, a continuous flow synthesis under mild reaction conditions to (E,Z)‐4,5,9‐trithiadodeca‐1,7,11‐triene is described starting from simple and easily accessible starting materials. Over four steps including propargylation, radical addition of thioacetate, deprotection, and disulfide formation/ allylation, the target product can be obtained at a rate of 0.26 g h−1 in an overall yield of 12 %. [ABSTRACT FROM AUTHOR]

• Z-Ajoene modulates Hedgehog/Gli pathway by reducing Gli transcriptional activity. • Z-Ajoene inhibits expressions of Gli- and FoxM1-target proteins in PANC-1 cells. • Z-Ajoene inhibits growth of PANC-1 cells via cell cycle arrest at G2/M phase. Overexpression of glioma-associated oncogene (Gli), a transcription factor at the final step of Hedgehog (Hh) pathway, is involved in pancreatic cancer development. Therefore, inhibition of Gli can be a therapeutic strategy to treat pancreatic cancer. The objective of this study was to determine effects of Z-ajoene from garlic, on Gli-mediated transcription and proliferation of pancreatic cancer cells. We found that Z-ajoene could inhibit Gli transcriptional activity in Sonic Hedgehog (Shh) stimulated C3H10T1/2 mesenchymal stem cells. Z-Ajoene suppressed Gli transcriptional activity and Gli-target protein expressions in PANC-1 human pancreatic cancer cells. Z-Ajoene also reduced expression of FoxM1, one of Gli-target proteins, and subsequently down-regulated expressions of cell cycle-related proteins. Moreover, Z-ajoene reduced cell proliferation and increased G2/M phase of PANC-1 cells. These results suggest that Z-ajoene can repress pancreatic cancer cell proliferation by inhibiting Gli signaling. Thus, Z-ajoene might be a lead compound for the development of anti-pancreatic cancer agent. [ABSTRACT FROM AUTHOR]

Background: Garlic has been used for centuries for its flavour and health promoting properties that include protection against cancer. The vinyl disulfide-sulfoxide ajoene is one of the phytochemicals found in crushed cloves, hypothesised to act by S-thiolating reactive cysteines in target proteins.Methods: Using our fluorescently labelled ajoene analogue called dansyl-ajoene, ajoene's protein targets in MDA-MB-231 breast cancer cells were tagged and separated by 2D electrophoresis. A predominant band was identified by MALDI-TOF MS/MS to be vimentin. Target validation experiments were performed using pure recombinant vimentin protein. Computational modelling of vimentin bound to ajoene was performed using Schrödinger and pKa calculations by Epik software. Cytotoxicity of ajoene in MDA-MB-231 and HeLa cells was measured by the MTT assay. The vimentin filament network was visualised in ajoene-treated and non-treated cells by immunofluorescence and vimentin protein expression was determined by immunoblot. The invasion and migration activity was measured by wound healing and transwell assays using wildtype cells and cells in which the vimentin protein had been transiently knocked down by siRNA or overexpressed.Results: The dominant protein tagged by dansyl-ajoene was identified to be the 57 kDa protein vimentin. The vimentin target was validated to reveal that ajoene and dansyl-ajoene covalently bind to recombinant vimentin via a disulfide linkage at Cys-328. Computational modelling showed Cys-328 to be exposed at the termini of the vimentin tetramer. Treatment of MDA-MB-231 or HeLa cells with a non-cytotoxic concentration of ajoene caused the vimentin filament network to condense; and to increase vimentin protein expression. Ajoene inhibited the invasion and migration of both cancer cell lines which was found to be dependent on the presence of vimentin. Vimentin overexpression caused cells to become more migratory, an effect that was completely rescued by ajoene.Conclusions: The garlic-derived phytochemical ajoene targets and covalently modifies vimentin in cancer cells by S-thiolating Cys-328. This interaction results in the disruption of the vimentin filament network and contributes to the anti-metastatic activity of ajoene in cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: Wir beschreiben eine kurze Totalsynthese von Ajoen, einem wichtigen biologisch aktiven Bestandteil von Knoblauch. Die Instabilität von Allicin, dem einzigen bekannten alternativen Ausgangsmaterial, hat zur Entwicklung eines zuverlässigen Protokolls für die Synthese von Ajoen aus einfachen Bausteinen geführt, welches sich auch für größere Mengen eignet. [ABSTRACT FROM AUTHOR]

Abstract: We describe a short total synthesis of ajoene, a major biologically active constituent of garlic. The instability of allicin as the only other known alternative starting material has led to the development of a reliable procedure for the synthesis of ajoene from simple building blocks that is also suitable for upscale operations. [ABSTRACT FROM AUTHOR]

The two major forms of cholinesterase enzymes found in the mammalian brain are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). BuChE usually found mainly in glial cells and neuron in normal physiological condition, whereas AChE found near nerve synapse and axons, both are involved in the breakdown of acetylcholine (ACh) in the brain. The dual inhibition of these enzymes is considered as a promising strategy for the treatment of a neurological disorder such as Alzheimer's disease, senile dementia, ataxia, and myasthenia gravis. The objective is to study the dual anticholinesterase activity of ajoene using in silico and in vitro methods. The anticholinesterase activity of ajoene was evaluated using Ellman's assay, and molecular docking was performed on Schrödinger suite software. The present study demonstrated ajoene ([E, Z]-4, 5, 9-trithiadodeca-1, 6, 11-triene-9-oxide) inhibited both AChE and BuChE in a concentration-dependent manner. The IC50value of ajoene was 2.34 mM for AChE and 2.09 mM for BuChE. Kinetic studies showed mixed noncompetitive inhibition of AChE and uncompetitive inhibition of BuChE. Molecular docking studies revealed that ajoene interacts hydrophobically with catalytic residues of AChE while in case of BuChE the interaction is through noncatalytic binding site residues. Ajoene exhibits dual inhibitory activity against both AChE and BuChE enzymes. Abbreviations Used: AChE: Acetylcholinesterease; BuChE: Butyrylcholinesterase; AD: Alzheimer's disease; Ach: Acetylcholine; ChAT: Choline acetyltransferase; ATChI: Acetylthiocholine iodide; BuChI: Butyrylcholine iodide; DTNB: 5,5-Dithiobis-2-nitrobenzoic acid; PDB: Protein data bank; RMSD: Root mean square deviation; OPLS: Optimized potentials for liquid simulations; ADME: Absorption, distribution, metabolism, excretion; DADS: Diallyl disulfide; QPlogPo/w: Predicted octanol/water partition coefficient; donorHB: Number of hydrogen bond donors; accptHB: Number of hydrogen bond acceptors; MW: Molecular weight of the compounds. [ABSTRACT FROM AUTHOR]

Ajoene, a garlic-derived sulfur-containing compound, has broad-spectrum antimicrobial activity. To assess the potential of ajoene for treating tuberculosis (TB), we determined whether it induces the stress response of the endoplasmic reticulum (ER), which plays an important role in TB. We showed that ajoene stimulation induced the production of ER stress sensor molecules and reactive oxygen species (ROS) levels. Ajoene-induced ROS production was dependent on c-Jun N-terminal kinase (JNK) activation. Interestingly, the inhibition of JNK activity and suppression of ROS production reduced ajoene-induced CHOP production in macrophages. Because ER stress activates autophagy, the activation of which suppresses the growth of mycobacteria, we investigated the ajoene-induced production of autophagy-related factors, including LC3-II, P62 and Beclin-1. As expected, ajoene treatment increased the levels of these factors in RAW 264.7 cells. Remarkably, the total amount of Mycobacterium tuberculosis (Mtb) H37Rv was significantly reduced in ajoene-treated RAW 264.7 cells. The treatment of macrophages with ajoene resulted in the activation of JNK, induction of ROS synthesis and accumulation of ROS, possibly leading to the activation of ER stress and autophagy. These results reveal the mechanism of the antimycobacterial effects of ajoene against Mtb H37Rv. Our findings might facilitate the development of novel therapies for patients with TB. [ABSTRACT FROM AUTHOR]

We describe the synthesis, reactivity, and antithrombotic and anti-angiogenesis activity of difluoroallicin (S-(2-fluoroallyl) 2-fluoroprop-2-ene-1-sulfinothioate) and S-2-fluoro-2-propenyl-Lcysteine, both easily prepared from commercially available 3-chloro-2-fluoroprop-1-ene, as well as the synthesis of 1,2-bis(2-fluoroallyl)disulfane, 5-fluoro-3-(1-fluorovinyl)-3,4-dihydro-1,2-dithiin, trifluoroajoene ((E,Z)-1-(2-fluoro-3-((2-fluoroallyl)sulfinyl)prop-1-en-1-yl)-2-(2-fluoroallyl)disulfane), and a bis(2-fluoroallyl)polysulfane mixture. All tested organosulfur compounds demonstrated effective inhibition of either FGF or VEG-mediated angiogenesis (anti-angiogenesis activity) in the chick chorioallantoic membrane (CAM) or the mouse Matrigel® models. No embryo mortality was observed. Difluoroallicin demonstrated greater inhibition (p < 0.01) versus organosulfur compounds tested. Difluoroallicin demonstrated dose-dependent inhibition of angiogenesis in the mouse Matrigel® model, with maximal inhibition at 0.01 mg/implant. Allicin and difluoroallicin showed an effective antiplatelet effect in suppressing platelet aggregation compared to other organosulfur compounds tested. In platelet/fibrin clotting (anti-coagulant activity), difluoroallicin showed concentration-dependent inhibition of clot strength compared to allicin and the other organosulfur compounds tested. [ABSTRACT FROM AUTHOR]

Plant organosulfur compounds represent one of the main groups of phytochemicals that evidence an ample spectrum of biological activities. There are two major sources of sulfur-containing compounds in plant foods; Allium vegetables, such as garlic, onion, and leek; and cruciferous vegetables, such as broccoli, cabbage, and cauliflower. Among them, garlic is the most studied species, mainly due to the multiple health-enhancing effects attributed to its consumption. Most of these properties have been attributed to organosulfur compounds. Thus, knowledge on the analytical determinations available for the main bioactive sulfur compounds in Allium is of interest. In the present review, an extensive bibliographic survey was performed to compile information regarding the different methodologies that can be used for the determination of alk(en)yl cysteine sulfoxides (ACSOs), S-allyl cysteine (SAC), thiosulfinates (mainly allicin), diallyl, mono- di-, and tri-sulfides, vinyldithiins and (E)- and (Z)-ajoene, as influenced by plant matrices and other factors. The gathered information was analyzed and presented in a systemic and comparative way, describing advantages and disadvantages of the methodologies, considering both extractive and separative techniques, the type of matrices, columns and analytical performance data. In addition, new trends and future prospects for the analysis of sulfur compounds in plants were critically discussed. [ABSTRACT FROM AUTHOR]

Garlic is a food and medicinal plant that has been used in folk medicine since ancient times for its beneficial health effects, which include protection against cancer. Crushed garlic cloves contain an array of small sulfur-rich compounds such as ajoene. Ajoene is able to interfere with biological processes and is cytotoxic to cancer cells in the low micromolar range. BisPMB is a synthetic ajoene analogue that has been shown in our laboratory to have superior cytotoxicity to ajoene. In the current study we have performed a DNA microarray analysis of bisPMB-treated WHCO1 oesophageal cancer cells to identify pathways and processes that are affected by bisPMB. The most significantly enriched biological pathways as assessed by gene ontology, KEGG and ingenuity pathway analysis were those involving protein processing in the endoplasmic reticulum (ER) and the unfolded protein response. In support of these pathways, bisPMB was found to inhibit global protein synthesis and lead to increased levels of ubiquitinated proteins. BisPMB also induced alternate splicing of the transcription factor XBP-1; increased the expression of the ER stress sensor GRP78 and induced expression of the ER stress marker CHOP/GADD153. CHOP expression was found to be central to the cytotoxicity of bisPMB as its silencing with siRNA rendered the cells resistant to bisPMB. The MAPK proteins, JNK and ERK1/2 were activated following bisPMB treatment. However JNK activation was not critical in the cytotoxicity of bisPMB, and ERK1/2 activation was found to play a pro-survival role. Overall the ajoene analogue bisPMB appears to induce cytotoxicity in WHCO1 cells by activating the unfolded protein response through CHOP/GADD153. [ABSTRACT FROM AUTHOR]

Allicin and its derivatives are physiologically active molecules with many potential health benefits. It is not clear if they have a direct effect on DNA or protein. In order to elucidate the allicin and its derivatives’ effect on DNA base pairs, we investigated various complexes of base pair and its bridge with an allicin and its derivatives. The investigated allicin derivatives were (E)-Ajoene, (Z)-Ajoene, Amz121, and Bmz73 radicals. The DFT calculation results revealed that the investigated molecules would favor binding to bridge of the base pairs instead of directly affecting the base pairs. The Bmz73 radical could break DNA by change bonding in it because the Bmz73 radical significantly affected the P-O bond of the bridge of base pair. [ABSTRACT FROM AUTHOR]

Since its discovery 22 years ago, the bacterial cell-to-cell communication system, termed quorum sensing (QS), has shown potential as antipathogenic target. Previous studies reported that ajoene from garlic inhibits QS in opportunistic human pathogen Pseudomonas aeruginosa. In this study, screening of an in-house compound library revealed two sulfur-containing compounds which possess structural resemblance with ajoene and inhibit QS in bioreporter assay. Following a quantitative structure-activity relationship (SAR) study, 25 disulfide bond-containing analogues were synthesized and tested for QS inhibition activities. SAR study indicated that the allyl group could be replaced with other substituents, with the most active being benzothiazole derivative (IC50 = 0.56 μM). The compounds were able to reduce QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin) and successfully inhibit P. aeruginosa infection in murine model of implant-associated infection. Altogether, the QS inhibition activity of the synthesized compounds is encouraging for further exploration of novel analogues in antimicrobial drug development. [ABSTRACT FROM AUTHOR]

Leishmaniasis is caused by an obligate intracellular protozoa belonging to Leishmania genus. The current drugs for treatment of leishmaniasis possess many disadvantages; therefore, researchers are continuously looking for the more effective and safer drugs. The aim of this study is to review the effectiveness, toxicities, and possible mechanisms of pharmaceutical actions of different garlic extracts and organosulfur compounds isolated from garlic against Leishmania spp. in a variety of in vitro, in vivo and clinical trials reports. All relevant databases were searched using the terms “Allium sativum,” “Garlic,” “Allicin,” “Ajoene,” “Leishmania,” “in vitro,” “in vivo,” and “clinical trial,” alone or in combination from 5 English databases (Web of Science, PubMed, Science Direct, Scopus, Google Scholar) and 3 Persian databases (Scientific Information Database, Iran Medex, and Magiran) from 1990 to 2014. In summary, garlic with immunomodulatory effects and apoptosis induction contributes to the treatment of leishmaniasis. [ABSTRACT FROM AUTHOR]

Oxidative stress exacerbates drug dependence induced by administration of opiate analgesics such as morphine-induced tolerance and physical dependence associated with the reduction in hepatic glutathione (GSH) level. Ajoene obtained from garlic ( Allium sativum L.) has been reported for anti-tumorigenic, anti-oxidative and neuroprotective properties, however, little is known about its effect on morphine-induced dependence. Therefore, this study aimed at the effect of ajoene on physical and/or psychological dependence and liver GSH content in morphine-treated mice. Conditioned place preference (CPP) test and measurement of morphine withdrawal syndrome were performed in C57BL6 mice for behavioral experiments. Thereafter, mice were sacrificed for measurement of serum and liver GSH levels. Ajoene restored CPP and naloxone-precipitated jumping behavior in mice exposed to morphine. Moreover, the reduced level of liver GSH content in morphine treated mice was back to normal after ajoene administration. Taken together, ajoene improved behavioral patterns in mice exposed to morphine suggesting its potential therapeutic benefit against morphine-induced dependence. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) caused by P-glycoprotein (P-gp) overexpression impedes successful cancer chemotherapy. In this study, we investigated the anticancer effects of SPA3015, a synthetic ajoene analog, in P-gp-overexpressing MDR cancer cells (KBV20C and MES-SA/DX5). Treatment with SPA3015 caused a dramatic decrease in the cell viabilities of both KBV20C and MES-SA/DX5 cells. This decrease was accompanied by apoptotic cell death without affecting the expression level or drug efflux function of P-gp. SPA3015 selectively suppressed NF-κB reporter gene activity, which led to decreased expression of NF-κB target genes such as CIAP1, CIAP2, XIAP, and Bcl-XL. Surprisingly, nuclear localization and DNA binding affinity of the p65 subunit were not affected by SPA3015, suggesting that SPA3015 inhibits the transcriptional activity of NF-κB at the nucleus. Indeed, SPA3015 treatment led to an increase in the physical interaction of p65 with PPARγ, which resulted in the inhibition of NF-κB activity. Our findings support the hypothesis that SPA3015 inhibits NF-κB transcriptional activity by facilitating the physical interaction of the p65 subunit and PPARγ, which leads to apoptotic cell death in MDR cancer cells. [ABSTRACT FROM AUTHOR]

The study investigated thein vitro,ex vivoandin vivoefficacy of ajoene and ciprofloxacin (CIP) alone and in combination againstPseudomonas aeruginosabiofilms and biofilm-associated murine acute pyelonephritis. The ajoene–CIP combination exhibited significant greater (p< 0.05) antimotility and biofilm inhibitory effects than those obtained when they were applied individually. The combined action of the agents resulted in a significant increase in serum sensitivity and phagocytic uptake and killing ofP. aeruginosa(p< 0.001) compared to the untreated control. Mice groups treated with an ajoene (25 mg kg−1) and CIP (30 mg kg−1or 15 mg kg−1) combination showed a significantly (p< 0.001) reduced bacterial load in the kidney and bladder as compared to that of infected controls and mice treated with solo agents on the fifth day post-infection. The decreased levels of biomarkers and photomicrographs of the kidney tissue of the treated mice showed a reduced severity of damage. Hence, the study highlights the antivirulent and therapeutic efficacy of the ajoene-CIP combination at the minimal dosage of CIP. [ABSTRACT FROM PUBLISHER]

The formation of corrosive sulfur as a result of the addition of dibenzyl disulfide (DBDS) to transformer oils has been investigated. Corrosive sulfur in a transformer affects all aspects of its insulation and conductive components by deposition of Cu2S. Previous studies have suggested that the formation of Cu2S was initiated by a DBDS-Cu complex. This work shows an alternate pathway via thiolate formation for the deposition of corrosive sulfur on copper conductors. The open circuit potential results showed no reduction of DBDS onto copper surfaces, but the degradation products of DBDS, which include dibenzyl sulfide and benzyl mercaptan, were both found to adsorb on copper surfaces, forming a copper thiolate. The formation of copper thiolates was also demonstrated by a heterogeneous reaction of CuO and benzyl mercaptan. Thermal degradation of the thiolate eventually produced copper sulfide Cu7.2S4 as identified by X-ray diffraction analysis. [ABSTRACT FROM AUTHOR]

Spironucleus vortens is a protozoan parasite associated with significant mortalities in the freshwater angelfish, Pterophyllum scalare . Control of this parasite is especially problematic due to restrictions on the use of the drug of choice, metronidazole (MTZ), on fish farms. Use of garlic ( Allium sativum ) is undergoing a renaissance following experimental validations of its antimicrobial efficiency. Ajoene ((E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide), is a stable transformation product of allicin, the primary biologically active component of garlic. In the current study, an ajoene oil crude extract had a minimum inhibitory concentration (MIC) of 40 μg/ml against S . vortens . GC–MS and NMR spectroscopy revealed this ajoene extract contained a mixture of the (E) and (Z)-ajoene isomers along with diallyl disulphide (DADS) and diallyl trisulphide (DATS). The only component of the ajoene crude oil found to substantially inhibit S. vortens growth by optical density monitoring (Bioscreen C Reader) was (Z)-ajoene (MIC 16 μg/ml). Ajoene oil acted in synergy with MTZ in vitro , reducing the individual MIC of this drug (4 μg/ml) by 16-fold, and that of ajoene oil by 200-fold with a fractional inhibitory concentration (FIC) index of 0.263. This synergistic interaction was confirmed in vivo . S. vortens -infected Pterophyllum scalare angelfish dosed orally with 0.5% (v/w) MTZ combined with 0.05% (v/w) ajoene displayed a significant reduction in faecal trophozoite count, whilst those fed on 0.5% MTZ flakes (half the recommended oral dose) alone did not. This study demonstrates for the first time the synergistic interaction between the synthetic drug MTZ and natural ajoene oil both in vitro and in vivo . Future work should evaluate the potential synergy of ajoene and MTZ against MTZ-resistant bacteria and protists. [ABSTRACT FROM AUTHOR]

Ajoene, a garlic-derived organosulfur compound, exerts anti-tumorigenic effect against various cancers. However, little is known about the biological effect of ajoene on lung adenocarcinoma, an aggressive malignancy with dismal prognosis. We investigated the biological effect of ajoene on lung adenocarcinoma and the underlying pathway. Lung adenocarcinoma cells A549, NCI-H1373, and NCI-H1395, along with the noncancerous lung bronchus cells BEAS-2B, were used. MTT test showed that ajoene (25 μM) reduces viability of lung adenocarcinoma cells but not the noncancerous BEAS-2B cells. Bromodeoxyuridine incorporation assay revealed that ajoene inhibits proliferation of lung adenocarcinoma cells. Treatment of lung adenocarcinoma cells with ajoene enhances apoptosis and ROS generation in a time- and dose-dependent fashion. Abrogation of caspase activation by zVAD-fmk completely prevents the ajoene-induced apoptosis; whereas block of ROS generation by N-acetylcysteine partly abolishes the ajoene-induced apoptosis. ROS-mediated induction of apoptosis contributes partially to the anti-tumorigenic property of ajoene observed, a phenomenon also confirmed by xenograft tumor study. Mitogen activated protein kinases (MAPKs), pivots of ROS-mediated signaling pathway, are activated upon ajoene treatment; Jun-N-terminal kinase (JNK)/p38 activations are required for signaling pathway underlying the ajoene-induced apoptosis. Our results suggest that ROS-mediated activation of JNK/p38 contributes partially to the pro-apoptotic action of ajoene on cells of lung adenocarcinoma. Ajoene may be a promising chemotherapeutic agent for lung adenocarcinoma. [ABSTRACT FROM AUTHOR]