An insight into the last 5-year patents on Porphyromonas gingivalis and Streptococcus mutans, the pivotal pathogens in the oral cavity.

INTRODUCTION: The oral cavity harbors an extensive array of over 700 microorganisms, forming the most complex biome of the entire human body, with bacterial species being the most abundant. Oral diseases, e.g. periodontitis and caries, are strictly associated with bacterial dysbiosis. Porphyromonas gingivalis and Streptococcus mutans stand out among bacteria colonizing the oral cavity. AREAS COVERED: After a brief overview of the bacterial populations in the oral cavity and their roles in regulating (flora) oral cavity or causing diseases like periodontal and cariogenic pathogens, we focused our attention on P. gingivalis and S. mutans, searching for the last-5-year patents dealing with the proposal of new strategies to fight their infections. Following the PRISMA protocol, we filtered the results and analyzed over 100 applied/granted patents, to provide an in-depth insight into this R&D scenario. EXPERT OPINION: Several antibacterial proposals have been patented in this period, from both chemical - peptides and small molecules - and biological - probiotics and antibodies - sources, along with natural extracts, polymers, and drug delivery systems. Most of the inventors are from China and Korea and their studies also investigated anti-inflammatory and antioxidant effects, being beneficial to oral health through a prophylactic, protective, or curative effect.

New Hybrid Compounds Incorporating Natural Products as Multifunctional Agents against Alzheimer's Disease.

A series of new hybrid derivatives 1a-c, 2a-c, 3a-c, 4a-c, 5a-c, inspired by nature, were synthesized and studied as multifunctional agents for the treatment of Alzheimer's disease (AD). These compounds were designed to merge together the trifluoromethyl benzyloxyaminic bioactive moiety, previously identified, with different acids available in nature. The ability of the synthesized compounds to chelate biometals, such as Cu2+, Zn2+ and Fe2+, was studied by UV-Vis spectrometer, and through a preliminary screening their antioxidant activity was evaluated by DPPH. Then, selected compounds were tested by in vitro ABTS free radical method and ex vivo rat brain TBARS assay. Compounds 2a-c, combining the strongest antioxidant and biometal chelators activities, were studied for their ability to contrast Aß1-40 fibrillization process. Finally, starting from the promising profile obtained for compound 2a, we evaluated if it could be able to induce a positive cross-interaction between transthyretin (TTR) and Aß in presence and in absence of Cu2+.

A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment.

Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a potent and highly selective ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, CDKN2A expression and cell growth arrest. We observed that, in CDKN2A proficient cells, NR6 treatment induced IL6 expression, but abolished CXCL8 expression and IL-8 release, preventing both neutrophil recruitment and generation of neutrophil extracellular traps (NETs). Furthermore, we demonstrate that in response to ALDH1A3 inhibition, CDKN2A loss skewed cell fate from senescence to apoptosis. Dissecting the role of ALDH1A3 isoform in MPM cells and tumour microenvironment can open new fronts in the treatment of this cancer.

Antineoplastic Activity of Pazopanib in Anaplastic Thyroid Cancer in Primary Culture.

Anaplastic thyroid cancer (ATC) is a rare and rapidly fatal human cancer. Its usual treatment includes the combination of surgery, external hyperfractionated radiation therapy, and chemotherapy. These treatments permit achieving about 6-10 months of median survival. For this reason, it is challenging to predict the ATC patient clinical therapy responsiveness. Pazopanib is a multitarget tyrosine kinase inhibitor of VEGF receptors, PDGF, and c-Kit. Until now, the effect of pazopanib in primary human ATC cells (pATC) has not been reported in the literature. The aim of our study was to evaluate in vitro the antineoplastic effect of pazopanib in pATC. Surgical thyroidal tissues were collected from five patients with ATC, from thyroid biopsy at the moment of first surgical operation. An inhibition of proliferation, migration, and invasion, and an increase in apoptosis were demonstrated upon treating pATC cells with pazopanib (p < 0.05). Moreover, pazopanib was able to significantly decrease the VEGF expression in pATC cells (p < 0.05). To conclude, in this study, we demonstrate the antineoplastic activity of the antiangiogenic inhibitor, pazopanib, in human pATC in vitro.

Complexing the Marine Sesquiterpene Euplotin C by Means of Cyclodextrin-Based Nanosponges: A Preliminary Investigation.

Euplotin C is a sesquiterpene of marine origin endowed with significant anti-microbial and anti-tumor properties. Despite the promising functional profile, its progress as a novel drug candidate has failed so far, due to its scarce solubility and poor stability in aqueous media, such as biological fluids. Therefore, overcoming these limits is an intriguing challenge for the scientific community. In this work, we synthesized ß-cyclodextrin-based nanosponges and investigated their use as colloidal carriers for stably complex euplotin C. Results obtained proved the ability of the carrier to include the natural compound, showing remarkable values of both loading efficiency and capacity. Moreover, it also allowed us to preserve the chemical structure of the loaded compound, which was recovered unaltered once extracted from the complex. Therefore, the use of ß-cyclodextrin-based nanosponges represents a viable option to vehiculate euplotin C, thus opening up its possible use as pharmacologically active compound.

Improving the Bioaccessibility and Bioavailability of Carotenoids by Means of Nanostructured Delivery Systems: A Comprehensive Review.

Carotenoids are bioactive compounds provided by the diet playing a key role in maintaining human health. Therefore, they should be ingested daily in an adequate amount. However, even a varied and well-balanced diet does not guarantee an adequate intake, as both the bioaccessibility and bioavailability of the compounds significantly affect their absorption. This review summarizes the main results achieved in improving the bioaccessibility and bioavailability of carotenoids by means of nanostructured delivery systems, discussing in detail the available lipid-based and biopolymeric nanocarriers at present, with a focus on their formulation and functional efficiency. Although the toxicity profile of these innovative delivery systems is not fully understood, especially for long-term intake, these systems are an effective and valuable approach to increase the availability of compounds of nutritional interest.

The Use of the Coenzyme Q10 as a Food Supplement in the Management of Fibromyalgia: A Critical Review.

The coenzyme Q10 is a naturally occurring benzoquinone derivative widely prescribed as a food supplement for different physical conditions and pathologies. This review aims to sum up the key structural and functional characteristics of Q10, taking stock of its use in people affected by fibromyalgia. A thorough survey has been conducted, using Pubmed, Scifinder, and ClinicalTrials.gov as the reference research applications and registry database, respectively. Original articles, reviews, and editorials published within the last 15 years, as well as open clinical investigations in the field, if any, were analyzed to point out the lights and shadows of this kind of supplementation as they emerge from the literature.

Nature-Inspired O-Benzyl Oxime-Based Derivatives as New Dual-Acting Agents Targeting Aldose Reductase and Oxidative Stress.

Aldose reductase (ALR2) is the enzyme in charge of developing cellular toxicity caused by diabetic hyperglycemia, which in turn leads to the generation of reactive oxygen species triggering oxidative stress. Therefore, inhibiting ALR2 while pursuing a concomitant anti-oxidant activity through dual-acting agents is now recognized as the gold standard treatment for preventing or at least delaying the progression of diabetic complications. Herein we describe a novel series of (E)-benzaldehyde O-benzyl oximes 6a-e, 7a-e, 8a-e, and 9-11 as ALR2 inhibitors endowed with anti-oxidant properties. Inspired by the natural products, the synthesized derivatives are characterized by a different polyhydroxy substitution pattern on their benzaldehyde fragment, which proved crucial for both the enzyme inhibitory activity and the anti-oxidant capacity. Derivatives (E)-2,3,4-trihydroxybenzaldehyde O-(3-methoxybenzyl) oxime (7b) and (E)-2,3,4-trihydroxybenzaldehyde O-(4-methoxybenzyl) oxime (8b) turned out to be the most effective dual-acting products, proving to combine the best ALR2 inhibitory properties with significant anti-oxidant efficacy.

Lenvatinib: an investigational agent for the treatment of differentiated thyroid cancer.

INTRODUCTION: Differentiated thyroid cancer (DTC; >90% of all TCs) derives from follicular cells. Surgery is the main therapeutic strategy, and radioiodine (RAI) is administered after thyroidectomy. When DTC progresses, it does not respond to RAI and thyroid-stimulating hormone (TSH)-suppressive thyroid hormone treatment, and other therapies (i.e. surgery, external beam radiation therapy and chemotherapy) do not lead to a better survival. Thanks to the understanding of the molecular pathways involved in TC progression, important advances have been done. Lenvatinib is a multitargeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT signaling networks implicated in tumor angiogenesis, approved in locally recurrent or metastatic, progressive, RAI-refractory DTC. Unmet needs regarding the patient clinical therapy responsiveness in aggressive RAI-refractory DTC still remain. AREAS COVERED: We provide an overview from the literature of in vitro, in vivo and real-life studies regarding lenvatinib as an investigational agent for the treatment of aggressive TC. EXPERT OPINION: According to the SELECT trial, the treatment should be initiated with a dosage of 24 mg/day, subsequently decreasing it in relation to the side effects. The decision making process in patients with aggressive RAI-refractory DTC should be personalized and the potential toxicity should be properly managed.

Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis.

Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.

Preclinical Development of FA5, a Novel AMP-Activated Protein Kinase (AMPK) Activator as an Innovative Drug for the Management of Bowel Inflammation.

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.

Identification of novel SIRT1 activators endowed with cardioprotective profile.

Drugs targeting epigenetic mechanisms are attracting the attention of scientists since it was observed that the modulation of this post-translational apparatus, could help to identify innovative therapeutic strategies. Among the epigenetic druggable targets, the positive modulation of SIRT1 has also been related to significant cardioprotective effects. Unfortunately, actual SIRT1 activators (natural products and synthetic molecules) suffer from several drawbacks, particularly poor pharmacokinetic profiles. Accordingly, in this article we present the development of an integrated screening platform aimed at identifying novel SIRT1 activators with favorable drug-like features as cardioprotective agents. Encompassing several competencies (in silico, medicinal chemistry, and pharmacology), we describe a multidisciplinary approach for rapidly identifying SIRT1 activators and their preliminary pharmacological characterization. In the first step, we virtually screened an in-house chemical library comprising synthetic molecules inspired by nature, against SIRT1 enzyme. To this end, we combined molecular docking-based approach with the estimation of relative ligand binding energy, using the crystal structure of SIRT1 enzyme in complex with resveratrol. Eleven computational hits were identified, synthesized and tested against the isolated enzyme for validating the in silico strategy. Among the tested molecules, five of them behave as SIRT1 enzyme activators. Due to the superior response in activating the enzyme and its favorable calculated physico-chemical properties, compound 8 was further characterized in ex vivo studies on isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R) period. The pharmacological profile of compound 8, suggests that this molecule represents a prototypic SIRT1 activator with satisfactory drug-like profile, paving the way for developing novel epigenetic cardioprotective agents.

A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro.

Aldehyde dehydrogenase 1A3 (ALDH1A3) belongs to an enzymatic superfamily composed by 19 different isoforms, with a scavenger role, involved in the oxidation of a plethora of aldehydes to the respective carboxylic acids, through a NAD+-dependent reaction. Previous clinical studies highlighted the high expression of ALDH1A3 in cancer stem cells (CSCs) correlated to a higher risk of cancer relapses, chemoresistance and a poor clinical outcome. We report on the structural, biochemical, and cellular characterization of NR6, a new selective ALDH1A3 inhibitor derived from an already published ALDH non-selective inhibitor with cytotoxic activity on glioblastoma and colorectal cancer cells. Crystal structure, through X-Ray analysis, showed that NR6 binds a non-conserved tyrosine residue of ALDH1A3 which drives the selectivity towards this isoform, as supported by computational binding simulations. Moreover, NR6 shows anti-metastatic activity in wound healing and invasion assays and induces the downregulation of cancer stem cell markers. Overall, our work confirms the role of ALDH1A3 as an important target in glioblastoma and colorectal cells and propose NR6 as a promising molecule for future preclinical studies.

Aurones: A Golden Resource for Active Compounds.

Deemed as poorly represented in nature, aurones have been often overlooked by researchers compared to other members of the flavonoid superfamily. However, over the past two decades, they have been reassessed by the scientific community, who are increasingly appreciating their ability to modulate several biological pathways. This review summarizes the recent literature on this class of compounds, which has been analyzed from both a chemical and a functional point of view. Original articles, reviews and editorials featured in Pubmed and Scifinder over the last twenty years have been taken into account to provide the readers with a view of the chemical strategies to obtain them, their functional properties, and their potential of technological use. The resulting comprehensive picture aims at raising the awareness of these natural derivatives as effective drug candidates, fostering the development of novel synthetic analogues.

Aldehyde Dehydrogenases and Prostate Cancer: Shedding Light on Isoform Distribution to Reveal Druggable Target.

Prostate cancer represents the most common malignancy diagnosed in men, and is the second-leading cause of cancer death in this population. In spite of dedicated efforts, the current therapies are rarely curative, requiring the development of novel approaches based on innovative molecular targets. In this work, we validated aldehyde dehydrogenase 1A1 and 1A3 isoform expressions in different prostatic tissue-derived cell lines (normal, benign and malignant) and patient-derived primary prostate tumor epithelial cells, demonstrating their potential for therapeutic intervention using a small library of aldehyde dehydrogenase inhibitors. Compound 3b, 6-(4-fluorophenyl)-2-phenylimidazo [1,2-a]pyridine exhibited not only antiproliferative activity in the nanomolar range against the P4E6 cell line, derived from localized prostate cancer, and PC3 cell lines, derived from prostate cancer bone metastasis, but also inhibitory efficacy against PC3 colony-forming efficiency. Considering its concomitant reduced activity against normal prostate cells, 3b has the potential as a lead compound to treat prostate cancer by means of a still untapped molecular target.

Progress in the Field of Aldehyde Dehydrogenase Inhibitors: Novel Imidazo[1,2-a]pyridines against the 1A Family.

Members of the aldehyde dehydrogenase 1A family are commonly acknowledged as hallmarks of cancer stem cells, and their overexpression is significantly associated with poor prognosis in different types of malignancies. Accordingly, treatments targeting these enzymes may represent a successful strategy to fight cancer. In this work we describe a novel series of imidazo[1,2-a]pyridines, designed as aldehyde dehydrogenase inhibitors by means of a structure-based optimization of a previously developed lead. The novel compounds were evaluated in vitro for their activity and selectivity against the three isoforms of the ALDH1A family and investigated through crystallization and modeling studies for their ability to interact with the catalytic site of the 1A3 isoform. Compound 3f emerged as the first in class submicromolar competitive inhibitor of the target enzyme.

Oxy-imino saccharidic derivatives as a new structural class of aldose reductase inhibitors endowed with anti-oxidant activity.

Aldose reductase is a key enzyme in the development of long term diabetic complications and its inhibition represents a viable therapeutic solution for people affected by these pathologies. Therefore, the search for effective aldose reductase inhibitors is a timely and pressing challenge. Herein we describe the access to a novel class of oxyimino derivatives, obtained by reaction of a 1,5-dicarbonyl substrate with O-(arylmethyl)hydroxylamines. The synthesised compounds proved to be active against the target enzyme. The best performing inhibitor, compound (Z)-8, proved also to reduce both cell death and the apoptotic process when tested in an in vitro model of diabetic retinopathy made of photoreceptor-like 661w cell line exposed to high-glucose medium, counteracting oxidative stress triggered by hyperglycaemic conditions.

Imidazo[1,2-a]pyridine Derivatives as Aldehyde Dehydrogenase Inhibitors: Novel Chemotypes to Target Glioblastoma Stem Cells.

Glioblastoma multiforme (GBM) is the deadliest form of brain tumor. It is known for its ability to escape the therapeutic options available to date thanks to the presence of a subset of cells endowed with stem-like properties and ability to resist to cytotoxic treatments. As the cytosolic enzyme aldehyde dehydrogenase 1A3 turns out to be overexpressed in these kinds of cells, playing a key role for their vitality, treatments targeting this enzyme may represent a successful strategy to fight GBM. In this work, we describe a novel class of imidazo[1,2-a]pyridine derivatives as aldehyde dehydrogenase 1A3 inhibitors, reporting the evidence of their significance as novel drug candidates for the treatment of GBM. Besides showing an interesting functional profile, in terms of activity against the target enzyme and selectivity toward highly homologous isoenzymes, representative examples of the series also showed a nanomolar to picomolar efficacy against patient-derived GBM stem-like cells, thus proving the concept that targeting aldehyde dehydrogenase might represent a novel and promising way to combat GBM by striking its ability to divide immortally.

Identification of ALDH1A3 as a Viable Therapeutic Target in Breast Cancer Metastasis-Initiating Cells.

The development of efficacious therapies targeting metastatic spread of breast cancer to the brain represents an unmet clinical need. Accordingly, an improved understanding of the molecular underpinnings of central nervous system spread and progression of breast cancer brain metastases (BCBM) is required. In this study, the clinical burden of disease in BCBM was investigated, as well as the role of aldehyde dehydrogenase 1A3 (ALDH1A3) in the metastatic cascade leading to BCBM development. Initial analysis of clinical survival trends for breast cancer and BCBM determined improvement of breast cancer survival rates; however, this has failed to positively affect the prognostic milestones of triple-negative breast cancer (TNBC) brain metastases (BM). ALDH1A3 and a representative epithelial-mesenchymal transition (EMT) gene signature (mesenchymal markers, CD44 or Vimentin) were compared in tumors derived from BM, lung metastases (LM), or bone metastases (BoM) of patients as well as mice after injection of TNBC cells. Selective elevation of the EMT signature and ALDH1A3 were observed in BM, unlike LM and BoM, especially in the tumor edge. Furthermore, ALDH1A3 was determined to play a role in BCBM establishment via regulation of circulating tumor cell adhesion and migration phases in the BCBM cascade. Validation through genetic and pharmacologic inhibition of ALDH1A3 via lentiviral shRNA knockdown and a novel small-molecule inhibitor demonstrated selective inhibition of BCBM formation with prolonged survival of tumor-bearing mice. Given the survival benefits via targeting ALDH1A3, it may prove an effective therapeutic strategy for BCBM prevention and/or treatment.

Novel treatments for anaplastic thyroid carcinoma.

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and it is less than 2% of thyroid carcinomas (TCs). The standard treatment of ATC includes surgical debulking, accelerated hyperfractionated external beam radiation therapy (EBRT), and chemotherapy, in particular with cisplatin or doxorubicin, achieving about 10 months of median survival. Since ATC is a rare and aggressive tumor, it is still challenging to predict the patient clinical therapy responsiveness. Several genetic mutations have been described in ATC, involved in different molecular pathways linked to tumor progression, and novel therapies acting on these molecular pathways have been investigated, to improve the quality of life in these patients. Here we review the new targeted therapy of ATC. We report interesting results obtained with molecules targeting different pathways: angiogenesis (vandetanib, combretastatin, sorafenib, lenvatinib, sunitinib, CLM94, CLM3, etc.); EGFR (gefitinib, docetaxel); BRAF (dabrafenib/trametinib, vemurafenib); PPARγ agonists (rosiglitazone, pioglitazone, efatutazone); PD-1 and PD-L1 (pembrolizumab); TERT. To escape resistance to monotherapies, the evaluation of combination strategies with radiotherapy, chemotherapy, or targeted drugs is ongoing. The results of clinical trials with dabrafenib and trametinib led to the approval from FDA of this combination for patients with BRAF V600E mutated ATC with locally advanced, unresectable, or metastatic ATC. The anti-PD-L1 antibody immunotherapy, alone or combined with a BRAF inhibitor, has been shown also promising in the treatment of ATC. Furthermore, to increase the therapeutic success and not to use ineffective or even harmful treatments, a real tailored therapy should be pursued, and this can be achieved thanks to the new available genomic analysis methods and to the possibility to test in vitro novel treatments directly in primary cells from each ATC patient. Exploring new treatment strategies is mandatory to improve the survival of these patients, guaranteeing a good quality of life.