Exploring the therapeutic potential of quercetin: A focus on its sirtuin-mediated benefits.

As the global population ages, preventing lifestyle- and aging-related diseases is increasing, necessitating the search for safe and affordable therapeutic interventions. Among nutraceuticals, quercetin, a flavonoid ubiquitously present in various plants, has garnered considerable interest. This review aimed to collate and analyze existing literature on the therapeutic potentials of quercetin, especially its interactions with SIRTs and its clinical applicability based on its bioavailability and safety. This narrative review was based on a literature survey spanning from 2015 to 2023 using PUBMED. The keywords and MeSH terms used were: "quercetin" AND "bioavailability" OR "metabolism" OR "metabolites" as well as "quercetin" AND "SIRTuin" OR "SIRT*" AND "cellular effects" OR "pathway" OR "signaling" OR "neuroprotective" OR "cardioprotective" OR "nephroprotective" OR "antiatherosclerosis" OR "diabetes" OR "antidiabetic" OR "dyslipidemia" AND "mice" OR "rats". Quercetin demonstrates multiple therapeutic activities, including neuroprotective, cardioprotective, and anti-atherosclerotic effects. Its antioxidant, anti-inflammatory, antiviral, and immunomodulatory properties are well-established. At a molecular level, it majorly interacts with SIRTs, particularly SIRT1 and SIRT6, and modulates numerous signaling pathways, contributing to its therapeutic effects. These pathways play roles in reducing oxidative stress, inflammation, autophagy regulation, mitochondrial biogenesis, glucose utilization, fatty acid oxidation, and genome stability. However, clinical trials on quercetin's effectiveness in humans are scarce. Quercetin exhibits a wide range of SIRT-mediated therapeutic effects. Despite the compelling preclinical data, more standardized clinical trials are needed to fully understand its therapeutic potential. Future research should focus on addressing its bioavailability and safety concerns.

Exploring the Multifaceted Potential of Sildenafil in Medicine.

Phosphodiesterase type 5 (PDE5) is pivotal in cellular signalling, regulating cyclic guanosine monophosphate (cGMP) levels crucial for smooth muscle relaxation and vasodilation. By targeting cGMP for degradation, PDE5 inhibits sustained vasodilation. PDE5 operates in diverse anatomical regions, with its upregulation linked to various pathologies, including cancer and neurodegenerative diseases. Sildenafil, a selective PDE5 inhibitor, is prescribed for erectile dysfunction and pulmonary arterial hypertension. However, considering the extensive roles of PDE5, sildenafil might be useful in other pathologies. This review aims to comprehensively explore sildenafil's therapeutic potential across medicine, addressing a gap in the current literature. Recognising sildenafil's broader potential may unveil new treatment avenues, optimising existing approaches and broadening its clinical application.

Cetirizine and Levetiracetam as Inhibitors of Monoacylglycerol Lipase: Investigating Their Repurposing Potential as Novel Osteoarthritic Pain Therapies.

Osteoarthritis is characterized by progressive articular cartilage degradation, subchondral bone changes, and synovial inflammation, and affects various joints, causing pain and disability. Current osteoarthritis therapies, primarily focused on pain management, face limitations due to limited effectiveness and high risks of adverse effects. Safer and more effective treatments are urgently needed. Considering that the endocannabinoid 2-arachidonoyl glycerol is involved in pain processing, increasing its concentration through monoacylglycerol lipase (MAGL) inhibition reduces pain in various animal models. Furthermore, drug repurposing approaches leverage established drug safety profiles, presenting a cost-effective route to accelerate clinical application. To this end, cetirizine and levetiracetam were examined for their MAGL inhibitory effects. In vitro studies revealed that cetirizine and levetiracetam inhibited MAGL with IC50 values of 9.3931 µM and 3.0095 µM, respectively. In vivo experiments demonstrated that cetirizine, and to a lesser extent levetiracetam, reduced mechanical and thermal nociception in complete Freund adjuvant (CFA)-induced osteoarthritis in rats. Cetirizine exhibited a notable anti-inflammatory effect, reducing CFA-induced inflammation, as well as the inflammatory infiltrate and granuloma formation in the affected paw. These findings suggest that cetirizine may serve as a promising starting point for the development of novel compounds for osteoarthritis treatment, addressing both pain and inflammation.

Boletus edulis Extract-A New Modulator of Dysbiotic Microbiota.

The regular administration of antibiotics is a public concern due to the prejudices of large population groups and the high frequency with which antimicrobial products are prescribed. The current study aimed to evaluate the in vitro effect of a new extract from Boletus edulis (BEE) on the human microbiota. One of the disadvantages of this extensive use is the disruption of the human microbiota, leading to potential negative health consequences. The in vitro evaluation of BEE consisted in determining its cytotoxicity, influence on the concentration of four types of cytokines (IL-6, IL-10, IL-1ß, TNFα), and capacity to modulate the human microbiota after administering antibiotics. The latter was assessed by microbiome analysis and the evaluation of short-chain fatty acid synthesis (SCFAs). Simultaneously, the content of total polyphenols, the antioxidant capacity, and the compositional analysis of the extract (individual polyphenols composition) were determined. The results showed that BEE modulates the microbial pattern and reduces inflammatory progression. The data demonstrated antioxidant properties correlated with the increase in synthesizing some biomarkers, such as SCFAs, which mitigated antibiotic-induced dysbiosis without using probiotic products.

Recent Progress in Gels for Neuropathic Pain.

Neuropathic pain is a complex and debilitating condition that affects millions of people worldwide. While several treatment options are available, they often have limited efficacy and are associated with adverse effects. In recent years, gels have emerged as a promising option for the treatment of neuropathic pain. Inclusion of various nanocarriers, such as cubosomes and niosomes, into gels results in pharmaceutical forms with higher drug stability and increased drug penetration into tissues compared to products currently marketed for the treatment of neuropathic pain. Furthermore, these compounds usually provide sustained drug release and are biocompatible and biodegradable, which makes them a safe option for drug delivery. The purpose of this narrative review was to provide a comprehensive analysis of the current state of the field and identify potential directions for future research in the development of effective and safe gels for the treatment of neuropathic pain, ultimately improving the quality of life for patients suffering from neuropathic pain.

Sirtuins, resveratrol and the intertwining cellular pathways connecting them.

Sirtuins are a family of NAD+-dependent deacylases with numerous physiological and pathological implications, which lately became an attractive therapeutic target. Sirtuin-activating compounds (STACs) could be useful in disease prevention and treatment. Despite its bioavailability issues, resveratrol exerts a myriad of beneficial effects, known as the "resveratrol paradox". Modulation of sirtuins' expression and activity may, in fact, underlie many of resveratrol revered actions; however, the cellular pathways affected by modulating the activity of each sirtuin isoform, in different physio-pathological conditions, are not fully known. The purpose of this review was to summarize recent reports concerning the effects of resveratrol on the activity of sirtuins in different experimental settings, focusing on in vitro and in vivo preclinical studies. Most reports concern SIRT1, however recent studies dive into the effects initiated via other isoforms. Numerous cellular signaling pathways were reported to be modulated by resveratrol in a sirtuin-dependent manner (increased phosphorylation of MAPKs, AKT, AMPK, RhoA, BDNF, decreased activation of NLRP3 inflammasome, NF-κB, STAT3, upregulation of SIRT1/SREBP1c pathway, reduced ß-amyloid via SIRT1-NF-κB-BACE1 signaling and counteracting mitochondrial damage by deacetylating PGC-1α). Thus, resveratrol may be the ideal candidate in the search for STACs as a tool for preventing and treating inflammatory and neurodegenerative diseases.

Natural Active Ingredients and TRPV1 Modulation: Focus on Key Chemical Moieties Involved in Ligand-Target Interaction.

Diseases such as cancer, neurological pathologies and chronic pain represent currently unmet needs. The existing pharmacotherapeutic options available for treating these conditions are limited by lack of efficiency and/or side effects. Transient receptor potential vanilloid 1 ion channel emerged as an attractive therapeutic target for developing new analgesic, anti-cancer and antiepileptic agents. Furthermore, various natural ingredients were shown to have affinity for this receptor. The aim of this narrative review was to summarize the diverse natural scaffolds of TRPV1 modulators based on their agonistic/antagonistic properties and to analyze the structure-activity relationships between the ligands and molecular targets based on the results of the existing molecular docking, mutagenesis and in vitro studies. We present here an exhaustive collection of TRPV1 modulators grouped by relevant chemical features: vanilloids, guaiacols, phenols, alkylbenzenes, monoterpenes, sesquiterpenoids, alkaloids, etc. The information herein is useful for understanding the key structural elements mediating the interaction with TRPV1 and how their structural variation impacts the interaction between the ligand and receptor. We hope this data will contribute to the design of novel effective and safe TRPV1 modulators, to help overcome the lack of effective therapeutic agents against pathologies with high morbidity and mortality.

In Vitro and In Vivo Antihyperglycemic Effects of New Metabiotics from Boletus edulis.

The increasing incidence of diabetes has prompted the need for new treatment strategies, including natural products that reduce glycemia values. This work examined the in vitro and in vivo antihyperglycemic effects of new metabiotics derived from Boletus edulis extracts. The metabiotics were obtained from 100% B. edulis, and two other products, CARDIO and GLYCEMIC, from Anoom Laboratories SRL, which contain other microbial species related to B. edulis. Our in vitro investigations (simulations of the microbiota of patients with type 2 diabetes (T2D)) demonstrated that B. edulis extracts modulate the microbiota, normalizing its pattern. The effects were further tested in vivo, employing a mouse model of T2D. The tested extracts decreased glycemia values compared to the control and modulated the microbiota. The metabiotics had positive effects on T2D in vitro and in vivo, suggesting their potential to alleviate diabetes-associated microbiota dysbiosis.

In Silico Drug Repurposing Framework Predicts Repaglinide, Agomelatine and Protokylol as TRPV1 Modulators with Analgesic Activity.

Pain is one of the most common symptoms experienced by patients. The use of current analgesics is limited by low efficacy and important side effects. Transient receptor potential vanilloid-1 (TRPV1) is a non-selective cation channel, activated by capsaicin, heat, low pH or pro-inflammatory agents. Since TRPV1 is a potential target for the development of novel analgesics due to its distribution and function, we aimed to develop an in silico drug repositioning framework to predict potential TRPV1 ligands among approved drugs as candidates for treating various types of pain. Structures of known TRPV1 agonists and antagonists were retrieved from ChEMBL databases and three datasets were established: agonists, antagonists and inactive molecules (pIC50 or pEC50 < 5 M). Structures of candidates for repurposing were retrieved from the DrugBank database. The curated active/inactive datasets were used to build and validate ligand-based predictive models using Bemis−Murcko structural scaffolds, plain ring systems, flexophore similarities and molecular descriptors. Further, molecular docking studies were performed on both active and inactive conformations of the TRPV1 channel to predict the binding affinities of repurposing candidates. Variables obtained from calculated scaffold-based activity scores, molecular descriptors criteria and molecular docking were used to build a multi-class neural network as an integrated machine learning algorithm to predict TRPV1 antagonists and agonists. The proposed predictive model had a higher accuracy for classifying TRPV1 agonists than antagonists, the ROC AUC values being 0.980 for predicting agonists, 0.972 for antagonists and 0.952 for inactive molecules. After screening the approved drugs with the validated algorithm, repaglinide (antidiabetic) and agomelatine (antidepressant) emerged as potential TRPV1 antagonists, and protokylol (bronchodilator) as an agonist. Further studies are required to confirm the predicted activity on TRPV1 and to assess the candidates' efficacy in alleviating pain.

Discovery of New Microbial Collagenase Inhibitors.

Bacterial virulence factors are mediating bacterial pathogenesis and infectivity. Collagenases are virulence factors secreted by several bacterial stains, such as Clostridium, Bacillus, Vibrio and Pseudomonas. These enzymes are among the most efficient degraders of collagen, playing a crucial role in host colonization. Thus, they are an important target for developing new anti-infective agents because of their pivotal roles in the infection process. A primary screening using a fluorescence resonance energy-transfer assay was used to experimentally evaluate the inhibitory activity of 77 compounds on collagenase A. Based on their inhibitory activity and chemical diversity, a small number of compounds was selected to determine the corresponding half maximal inhibitory con-centration (IC50). Additionally, we used molecular docking to get a better understanding of the enzyme-compound interaction. Several natural compounds (capsaicin, 4',5-dihydroxyflavone, curcumin, dihydrorobinetin, palmatine chloride, biochanin A, 2'-hydroxychalcone, and juglone) were identified as promising candidates for further development into useful anti-infective agents against infections caused by multi-drug-resistant bacterial pathogens which include collagenase A in their enzymatic set.

Regulation of Gene Expression through Food-Curcumin as a Sirtuin Activity Modulator.

The sirtuin family comprises NAD+-dependent protein lysine deacylases, mammalian sirtuins being either nuclear (SIRT1, SIRT2, SIRT6, and SIRT7), mitochondrial (SIRT3, SIRT4, and SIRT5) or cytosolic enzymes (SIRT2 and SIRT5). They are able to catalyze direct metabolic reactions, thus regulating several physiological functions, such as energy metabolism, stress response, inflammation, cell survival, DNA repair, tissue regeneration, neuronal signaling, and even circadian rhythms. Based on these data, recent research was focused on finding molecules that could regulate sirtuins' expression and/or activity, natural compounds being among the most promising in the field. Curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) can induce, through SIRT, modulation of cancer cell senescence, improve endothelial cells protection against atherosclerotic factors, enhance muscle regeneration in atrophy models, and act as a pro-longevity factor counteracting the neurotoxicity of amyloid-beta. Although a plethora of protective effects was reported (antioxidant, anti-inflammatory, anticancer, etc.), its therapeutical use is limited due to its bioavailability issues. However, all the reported effects may be explained via the bioactivation theory, which postulates that curcumin's observed actions are modulated via its metabolites and/or degradation products. The present article is focused on bringing together the literature data correlating the ability of curcumin and its metabolites to modulate SIRT activity and its consequent beneficial effects.

Interleukins and redox impairment in type 2 diabetes mellitus: mini-review and pilot study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) represents a leading cause of morbidity and premature mortality, low-grade inflammation being acknowledged as a key contributor to its development and progression. A tailored therapeutic approach, based on sensitive and specific biomarkers, could allow a more accurate analysis of disease susceptibility/prognostic and of the response to treatment. OBJECTIVES: This mini-review and pilot study had two main goals: (1) reviewing the most recent literature encompassing the use of interleukins as inflammatory markers influenced by the redox imbalances in T2DM and (2) assessing parameters that conjunctly evaluate the redox impairment and inflammatory burden of T2DM patients, taking into consideration smoking status, as such group-specific biomarkers are scarcely reported in literature. METHODS: Firstly, PubMed database was surveyed to select and review the relevant studies employing interleukins as T2DM biomarkers and to assess if studies using combined inflammatory-redox indices were reported. Then, routine biochemical parameters were assessed in a pilot study -T2DM patients with 3 subgroups: non-smokers, smokers and ex-smokers, were compared to a control group of non-diabetic, apparently healthy non-smokers. Protein (AOPPs, AGEs), lipid/HDL (Amplex Red-based method) oxidative damage and inflammatory status (CRP, IL-1ß, IL-6, IL-10) biomarkers were assessed. Cytokine ratios and 2 oxidative-inflammatory status indices were developed (IH1 and IH2) and evaluated. RESULTS: We observed significant differences in terms of serum redox and inflammatory status (AOPPs, AGEs, CRP, CRP/HDL, CRP/IL-6, IL-10/IL-6, IH1) between T2DM patients compared to control and, moreover, between the subgroups formed considering smoking status (CRP, CRP/HDL, IH1). Glycemic control strongly influenced inflammatory status biomarkers: glycemia was positively correlated with the inflammatory parameters (CRP/IL-10) and inversely with the anti-inflammatory ones (IL-10, IL-10/IL-1ß ratio). CONCLUSIONS: Several of the assessed parameters may possess prognostic value for diabetics, especially when comparing subgroups with a different smoking history and could prove useful in clinical practice for assessing disease progress and therapeutic efficacy.

Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases.

Neurological and neurodegenerative diseases are debilitating conditions, and frequently lack an effective treatment. Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of 2-AG (2-arachidonoylglycerol), a neuroprotective endocannabinoid intimately linked to the generation of pro- and anti-inflammatory molecules. Consequently, synthesizing selective MAGL inhibitors has become a focus point in drug design and development. The purpose of this review was to summarize the diverse synthetic scaffolds of MAGL inhibitors concerning their potency, mechanisms of action and potential therapeutic applications, focusing on the results of studies published in the past five years. The main irreversible inhibitors identified were derivatives of hexafluoroisopropyl alcohol carbamates, glycol carbamates, azetidone triazole ureas and benzisothiazolinone, whereas the most promising reversible inhibitors were derivatives of salicylketoxime, piperidine, pyrrolidone and azetidinyl amides. We reviewed the results of in-depth chemical, mechanistic and computational studies on MAGL inhibitors, in addition to the results of in vitro findings concerning selectivity and potency of inhibitors, using the half maximal inhibitory concentration (IC50) as an indicator of their effect on MAGL. Further, for highlighting the potential usefulness of highly selective and effective inhibitors, we examined the preclinical in vivo reports regarding the promising therapeutic applications of MAGL pharmacological inhibition.

Effects of Venlafaxine, Risperidone and Febuxostat on Cuprizone-Induced Demyelination, Behavioral Deficits and Oxidative Stress.

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands.

Targeting Bacterial Sortases in Search of Anti-Virulence Therapies with Low Risk of Resistance Development.

Increasingly ineffective antibiotics and rapid spread of multi- and pan-resistant bacteria represent a global health threat; hence, the need of developing new antimicrobial medicines. A first step in this direction is identifying new molecular targets, such as virulence factors. Sortase A represents a virulence factor essential for the pathogenesis of Gram-positive pathogens, some of which have a high risk for human health. We present here an exhaustive collection of sortases inhibitors grouped by relevant chemical features: vinyl sulfones, 3-aryl acrylic acids and derivatives, flavonoids, naphtoquinones, anthraquinones, indoles, pyrrolomycins, isoquinoline derivatives, aryl ß-aminoethyl ketones, pyrazolethiones, pyridazinones, benzisothiazolinones, 2-phenyl-benzoxazole and 2-phenyl-benzofuran derivatives, thiadiazoles, triazolothiadiazoles, 2-(2-phenylhydrazinylidene)alkanoic acids, and 1,2,4-thiadiazolidine-3,5-dione. This review focuses on highlighting their structure-activity relationships, using the half maximal inhibitory concentration (IC50), when available, as an indicator of each compound effect on a specific sortase. The information herein is useful for acquiring knowledge on diverse natural and synthetic sortases inhibitors scaffolds and for understanding the way their structural variations impact IC50. It will hopefully be the inspiration for designing novel effective and safe sortase inhibitors in order to create new anti-infective compounds and to help overcoming the current worldwide antibiotic shortage.

Vitamin E beyond Its Antioxidant Label.

Vitamin E, comprising tocopherols and tocotrienols, is mainly known as an antioxidant. The aim of this review is to summarize the molecular mechanisms and signaling pathways linked to inflammation and malignancy modulated by its vitamers. Preclinical reports highlighted a myriad of cellular effects like modulating the synthesis of pro-inflammatory molecules and oxidative stress response, inhibiting the NF-κB pathway, regulating cell cycle, and apoptosis. Furthermore, animal-based models have shown that these molecules affect the activity of various enzymes and signaling pathways, such as MAPK, PI3K/Akt/mTOR, JAK/STAT, and NF-κB, acting as the underlying mechanisms of their reported anti-inflammatory, neuroprotective, and anti-cancer effects. In clinical settings, not all of these were proven, with reports varying considerably. Nonetheless, vitamin E was shown to improve redox and inflammatory status in healthy, diabetic, and metabolic syndrome subjects. The anti-cancer effects were inconsistent, with both pro- and anti-malignant being reported. Regarding its neuroprotective properties, several studies have shown protective effects suggesting vitamin E as a potential prevention and therapeutic (as adjuvant) tool. However, source and dosage greatly influence the observed effects, with bioavailability seemingly a key factor in obtaining the preferred outcome. We conclude that this group of molecules presents exciting potential for the prevention and treatment of diseases with an inflammatory, redox, or malignant component.

Identifying FAAH Inhibitors as New Therapeutic Options for the Treatment of Chronic Pain through Drug Repurposing.

Chronic pain determines a substantial burden on individuals, employers, healthcare systems, and society. Most of the affected patients report dissatisfaction with currently available treatments. There are only a few and poor therapeutic options-some therapeutic agents are an outgrowth of drugs targeting acute pain, while others have several serious side effects. One of the primary degradative enzymes for endocannabinoids, fatty acid amide hydrolase (FAAH) attracted attention as a significant molecular target for developing new therapies for neuropsychiatric and neurological diseases, including chronic pain. Using chemical graph mining, quantitative structure-activity relationship (QSAR) modeling, and molecular docking techniques we developed a multi-step screening protocol to identify repurposable drugs as FAAH inhibitors. After screening the DrugBank database using our protocol, 273 structures were selected, with five already approved drugs, montelukast, repaglinide, revefenacin, raloxifene, and buclizine emerging as the most promising repurposable agents for treating chronic pain. Molecular docking studies indicated that the selected compounds interact with the enzyme mostly non-covalently (except for revefenacin) through shape complementarity to the large substrate-binding pocket in the active site. A molecular dynamics simulation was employed for montelukast and revealed stable interactions with the enzyme. The biological activity of the selected compounds should be further confirmed by employing in vitro and in vivo studies.

Candidates for Repurposing as Anti-Virulence Agents Based on the Structural Profile Analysis of Microbial Collagenase Inhibitors.

The pharmacological inhibition of the bacterial collagenases (BC) enzymes is considered a promising strategy to block the virulence of the bacteria without targeting the selection mechanism leading to drug resistance. The chemical structures of the Clostridium perfringens collagenase A (ColA) inhibitors were analyzed using Bemis-Murcko skeletons, Murcko frameworks, the type of plain rings, and docking studies. The inhibitors were classified based on their structural architecture and various scoring methods were implemented to predict the probability of new compounds to inhibit ColA and other BC. The analyses indicated that all compounds contain at least one aromatic ring, which is often a nitrobenzene fragment. 2-Nitrobenzene based compounds are, on average, more potent BC inhibitors compared to those derived from 4-nitrobenzene. The molecular descriptors MDEO-11, AATS0s, ASP-0, and MAXDN were determined as filters to identify new BC inhibitors and highlighted the necessity for a compound to contain at least three primary oxygen atoms. The DrugBank database was virtually screened using the developed methods. A total of 100 compounds were identified as potential BC inhibitors, of which, 10 are human approved drugs. Benzthiazide, entacapone, and lodoxamide were chosen as the best candidates for in vitro testing based on their pharmaco-toxicological profile.

Discovery of natural naphthoquinones as sortase A inhibitors and potential anti-infective solutions against Staphylococcus aureus.

Three natural naphthoquinones were screened to find new anti-virulence agents as inhibitors against sortase A from Staphylococcus aureus (SaSrtA) by quantifying the increase in fluorescence intensity upon substrate cleavage at various concentrations. The 5-hydroxy-1,4-naphthalenedione derivatives, juglone and plumbagin, demonstrated a potent inhibitory effect, with IC50 values of 1.78 µM, respectively, 16.71 µM. The related 2-hydroxy-1,4-naphthalenedione derivative, lawsone, demonstrated the selectivity of the chemical scaffold having no significant effect on SaSrtA. The experimental assay was reinforced by molecular docking experiments, antimicrobial, and toxicological studies. Molecular docking studies and the electrophilic character analysis suggest bonding to the enzyme active cysteine residue by a Michael addition reaction. None of the compounds had a significant effect on the concentration of total thiol proteins in the Daphnia magna toxicological assay after 24 hr exposure. Juglone and plumbagin moderately inhibited biofilm formation with no significant effect on bacterial growth of S. aureus, Enterococcus faecalis, and Staphylococcus epidermidis, indicating a selective anti-virulence profile.

Predictive power of the Triticum root elongation test for the assessment of novel anti­proliferative therapies.

The use of alternative techniques to reduce the number of animals used in anticancer research is an issue of current interest. The aim of this study was to validate the use of a simple and efficient alternative tool for the assessment of the potential of novel anti­proliferative agents. A set of 20 compounds with various mechanisms were tested in the Triticum aestivum root elongation assay, using aminophylline as negative control. Hierarchical cluster analyses were performed using the furthest neighbor method based on Euclidean distance measure, and the compounds were statistically analyzed in reference to their anti­proliferative pattern registered in the NCI60 human tumor cell line anticancer drug screen. A correlation between the Triticum test results and the NCI60 anti­proliferative profile was made for a number of human cells that we defined as the Triticum cell panel. Linear equations were computed that can be used to transform the inhibitory effect measured in any future Triticum assay in order to predict the effect on particular human cells. Of the tested anti­proliferative agents, methotrexate, colchicine, cantharidin, cisplatin and verapamil produced a growth inhibition over 50%. On the whole, the findings of this study suggest that the Triticum test can be used to detect several types of anti­proliferative mechanisms, particularly those targeting tubulin, rendering it a useful tool with which to identify novel mitotic spindle inhibitors.