Exploiting new strategies in combating head and neck carcinoma: A comprehensive review on phytochemical approaches passing through PI3K/Akt/mTOR signaling pathway.

Recently, malignant neoplasms have growingly caused human morbidity and mortality. Head and neck cancer (HNC) constitutes a substantial group of malignancies occurring in various anatomical regions of the head and neck, including lips, mouth, throat, larynx, nose, sinuses, oropharynx, hypopharynx, nasopharynx, and salivary glands. The present study addresses the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway as a possible therapeutic target in cancer therapy. Finding new multitargeting agents capable of modulating PI3K/Akt/mTOR and cross-linked mediators could be viewed as an effective strategy in combating HNC. Recent studies have introduced phytochemicals as multitargeting agents and rich sources for finding and developing new therapeutic agents. Phytochemicals have exhibited immense anticancer effects, including targeting different stages of HNC through the modulation of several signaling pathways. Moreover, phenolic/polyphenolic compounds, alkaloids, terpenes/terpenoids, and other secondary metabolites have demonstrated promising anticancer activities because of their diverse pharmacological and biological properties like antiproliferative, antineoplastic, antioxidant, and anti-inflammatory activities. The current review is mainly focused on new therapeutic strategies for HNC passing through the PI3K/Akt/mTOR pathway as new strategies in combating HNC.

New perspective on DNA response pathway (DDR) in glioblastoma, focus on classic biomarkers and emerging roles of ncRNAs.

BACKGROUND: Glioblastoma (GBM) is the most frequent type of primary brain cancer, having a median survival of only 15 months. The current standard of care includes a combination of surgery, radiotherapy (RT) and chemotherapy with temozolomide, but with limited results. Moreover, multiple studies have shown that tumour relapse and resistance to classic therapeutic approaches are common events that occur in the majority of patients, and eventually leading to death. New approaches to better understand the intricated tumour biology involved in GBM are needed in order to develop personalised treatment approaches. Advances in cancer biology have widen our understanding over the GBM genome and allowing a better classification of these tumours based on their molecular profile. METHODS: A new targeted therapeutic approach that is currently investigated in multiple clinical trials in GBM is represented by molecules that target various defects in the DNA damage repair (DDR) pathway, a mechanism activated by endogenous and exogenous factors that induce alteration of DNA, and is involved for the development of chemotherapy and RT resistance. This intricate pathway is regulated by p53, two important kinases ATR and ATM and non-coding RNAs including microRNAs, long-non-coding RNAs and circular RNAs that regulate the expression of all the proteins involved in the pathway. RESULTS: Currently, the most studied DDR inhibitors are represented by PARP inhibitors (PARPi) with important results in ovarian and breast cancer. PARPi are a class of tumour agnostic drugs that showed their efficacy also in other localisations such as colon and prostate tumours that have a molecular signature associated with genomic instability. These inhibitors induce the accumulation of intracellular DNA damage, cell cycle arrest, mitotic catastrophe and apoptosis. CONCLUSIONS: This study aims to provide an integrated image of the DDR pathway in glioblastoma under physiological and treatment pressure with a focus of the regulatory roles of ncRNAs. The DDR inhibitors are emerging as an important new therapeutic approach for tumours with genomic instability and alterations in DDR pathways. The first clinical trials with PARPi in GBM are currently ongoing and will be presented in the article. Moreover, we consider that by incorporating the regulatory network in the DDR pathway in GBM we can fill the missing gaps that limited previous attempts to effectively target it in brain tumours. An overview of the importance of ncRNAs in GBM and DDR physiology and how they are interconnected is presented.

Plant based food bioactives: A boon or bane for neurological disorders.

Neurological disorders are the foremost occurring diseases across the globe resulting in progressive dysfunction, loss of neuronal structure ultimately cell death. Therefore, attention has been drawn toward the natural resources for the search of neuroprotective agents. Plant-based food bioactives have emerged as potential neuroprotective agents for the treatment of neurodegenerative disorders. This comprehensive review primarily focuses on various plant food bioactive, mechanisms, therapeutic targets, in vitro and in vivo studies in the treatment of neurological disorders to explore whether they are boon or bane for neurological disorders. In addition, the clinical perspective of plant food bioactives in neurological disorders are also highlighted. Scientific evidences point toward the enormous therapeutic efficacy of plant food bioactives in the prevention or treatment of neurological disorders. Nevertheless, identification of food bioactive components accountable for the neuroprotective effects, mechanism, clinical trials, and consolidation of information flow are warranted. Plant food bioactives primarily act by mediating through various pathways including oxidative stress, neuroinflammation, apoptosis, excitotoxicity, specific proteins, mitochondrial dysfunction, and reversing neurodegeneration and can be used for the prevention and therapy of neurodegenerative disorders. In conclusion, the plant based food bioactives are boon for neurological disorders.

Scalable (Enantioselective) Syntheses of Novel 3-Methylated Analogs of Pazinaclone, (S)-PD172938 and Related Biologically Relevant Isoindolinones.

Herein, we report the application of an efficient and practical K2CO3 promoted cascade reaction of 2-acetylbenzonitrile in the synthesis of novel 3-methylated analogs of Pazinaclone and PD172938, belonging to isoindolinones heterocyclic class bearing a tetrasubstituted stereocenter. Organocatalytic asymmetric synthesis of the key intermediate and its transformation into highly enantioenriched 3-methylated analog of (S)-PD172938 was also developed. These achievements can be of particular interest also for medicinal chemistry, since the methyl group is a very useful structural modification in the rational design of new and more effective bioactive compounds.

Curcumin-cisplatin chemotherapy: A novel strategy in promoting chemotherapy efficacy and reducing side effects.

The efficacy of chemotherapy in cancer therapy is limited due to resistance, treatment selectivity, and severe adverse effects. Immunotherapy, chemotherapy, targeted therapy, radiation, and surgery are the most common therapeutic strategies for treatment, with chemotherapy being the most successful. Nonetheless, these treatments exhibit poor effectiveness due to toxicity and resistance. Therefore, combination therapies of natural products may be used as an effective and novel strategy to overcome such barriers. Cisplatin is a platinum-based chemotherapy agent, and when administered alone, it can lead to severe adverse effects and resistance mechanism resulting in therapeutic failure. Curcumin is a polyphenolic compound extracted from turmeric (Curcuma longa) exhibiting anticancer potential with minimal adverse effects. The combination therapy of curcumin and cisplatin is a novel strategy to mitigate/attenuate cisplatin-related adverse effects and improve the barrier of resistance reducing unwanted effects. However, there are uncertainties on the efficacy of curcumin, and more in depth and high-quality studies are needed. This review aims to explain the adverse effects related to individual cisplatin delivery, the positive outcome of individual curcumin delivery, and the combination therapy of curcumin and cisplatin from nano platform as a novel strategy for cancer therapy.

Targeting NF-κB signaling pathway in cancer by dietary polyphenols.

Being a transcription factor, NF-κB regulates gene expressions involving cell survival and proliferation, drug resistance, metastasis, and angiogenesis. The activation of NF-κB plays a central role in the development of inflammation and cancer. Thus, the down-regulation of NF-κB may be an exciting target in prevention and treatment of cancer. NF-κB could act as a tumor activator or tumor suppressant decided by the site of action (organ). Polyphenols are widely distributed in plant species, consumption of which have been documented to negatively regulate the NF-κB signaling pathway. They depress the phosphorylation of kinases, inhibit NF-κB translocate into the nucleus as well as interfere interactions between NF-κB and DNA. Through inhibition of NF-κB, polyphenols downregulate inflammatory cascade, induce apoptosis and decrease cell proliferation and metastasis. This review highlights the anticancer effects of polyphenols on the basis of NF-κB signaling pathway regulation.

Anti-Inflammatory Drugs as Anticancer Agents.

Inflammation is strictly associated with cancer and plays a key role in tumor development and progression. Several epidemiological studies have demonstrated that inflammation can predispose to tumors, therefore targeting inflammation and the molecules involved in the inflammatory process could represent a good strategy for cancer prevention and therapy. In the past, several clinical studies have demonstrated that many anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAIDs), are able to interfere with the tumor microenvironment by reducing cell migration and increasing apoptosis and chemo-sensitivity. This review focuses on the link between inflammation and cancer by describing the anti-inflammatory agents used in cancer therapy, and their mechanisms of action, emphasizing the use of novel anti-inflammatory agents with significant anticancer activity.

Evaluation of the status quo of polyphenols analysis: Part I-phytochemistry, bioactivity, interactions, and industrial uses.

Phytochemicals, especially polyphenols, are gaining more attention from both the scientific community and food, pharmaceutical, and cosmetics industries due to their implications in human health. In this line, lately new applications have emerged, and of great importance is the selection of accurate and reliable analytical methods for better evaluation of the quality of the end-products, which depends on diverse process variables as well as on the matrices and on the physicochemical properties of different polyphenols. The first of a two-part review on polyphenols will address the phytochemistry and biological activities of different classes of polyphenols including flavonoids, lignans and flavanolignans, stilbenoids, tannins, curcuminoids, and coumarins. Moreover, the possible interactions of polyphenols and current and potential industrial applications of polyphenols are discussed.

MicroRNA targeting by quercetin in cancer treatment and chemoprotection.

A growing number of evidences from clinical and preclinical studies have shown that dysregulation of microRNA (miRNA) function contributes to the progression of cancer and thus miRNA can be an effective target in therapy. Dietary phytochemicals, such as quercetin, are natural products that have potential anti-cancer properties due to their proven antioxidant, anti-inflammatory, and anti-proliferative effects. Available experimental studies indicate that quercetin could modulate multiple cancer-relevant miRNAs including let-7, miR-21, miR-146a and miR-155, thereby inhibiting cancer initiation and development. This paper reviews the data supporting the use of quercetin for miRNA-mediated chemopreventive and therapeutic strategies in various cancers, with the aim to comprehensively understand its health-promoting benefits and pharmacological potential. Integration of technology platforms for miRNAs biomarker and drug discovery is also presented.

Targeting STATs in neuroinflammation: The road less traveled!

JAK/STAT transduction pathway is a highly conserved pathway implicated in regulating cellular proliferation, differentiation, survival and apoptosis. Dysregulation of this pathway is involved in the onset of autoimmune, haematological, oncological, metabolic and neurological diseases. Over the last few years, the research of anti-neuroinflammatory agents has gained considerable attention. The ability to diminish the STAT-induced transcription of inflammatory genes is documented for both natural compounds (such as polyphenols) and chemical drugs. Among polyphenols, quercetin and curcumin directly inhibit STAT, while Berberis vulgaris L. and Sophora alopecuroides L extracts act indirectly. Also, the Food and Drug Administration has approved several JAK/STAT inhibitors (direct or indirect) for treating inflammatory diseases, indicating STAT can be considered as a therapeutic target for neuroinflammatory pathologies. Considering the encouraging data obtained so far, clinical trials are warranted to demonstrate the effectiveness and potential use in the clinical practice of STAT inhibitors to treat inflammation-associated neurodegenerative pathologies.

A Hydroquinone-Based Derivative Elicits Apoptosis and Autophagy via Activating a ROS-Dependent Unfolded Protein Response in Human Glioblastoma.

5-Lipoxygenase (5-LO) has been reported to be highly expressed in brain tumors and to promote glioma cell proliferation. Therefore, we investigated the anticancer activity of the novel 5-LO inhibitor derivative 3-tridecyl-4,5-dimethoxybenzene-1,2-diol hydroquinone (EA-100C red) on glioblastoma (GBM) cell growth. Cell viability was evaluated by MTT assay. The effects of the compound on apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array, Real Time qPCR, confocal microscopy analysis and the western blotting technique. Our results showed that EA-100C Red had a higher anti-proliferative effect on LN229 as compared to U87MG cells. The compound induced a significant increase of apoptosis and autophagy and up-regulated pro-apoptotic genes (Bcl3, BNIP3L, and NFKBIA) in both GBM cell lines. In this light, we studied the effects of EA-100C red on the expression of CHOP and XBP1, that are implicated in ER-stress-mediated cell death. In summary, our findings revealed that EA-100C red induced ER stress-mediated apoptosis associated to autophagy in GBM cells through CHOP and Beclin1 up-regulation and activation of caspases 3, 9, JNK and NF-kappaB pathway. On these bases, EA-100C red could represent a promising compound for anti-cancer treatment.

Discovery of novel multi-target indole-based derivatives as potent and selective inhibitors of chikungunya virus replication.

We recently identified indole derivatives (IIIe and IIIf) with anti-chikungunya virus (CHIKV) activities at lower micro molar concentrations and a selective index of inhibition higher than the lead compound Arbidol. Here we highlight new structural information for the optimization of the previously identified lead compounds that contain the indole chemical core. Based on the structural data, a series of indole derivatives was synthesized and tested for their antiviral activity against chikungunya virus in Vero cell culture by a CPE reduction assay. Systematic optimization of the lead compounds resulted in tert-butyl-5-hydroxy-1-methyl-2-(2-trifluoromethysulfynyl)methyl)-indole-3-carboxylate derivative IIc with a 10-fold improved anti-CHIKV inhibitory activity (EC50=6.5±1µM) as compared to Arbidol demonstrating a potent, selective and specific inhibition of CHIKV replication with only a moderate cell protective effect against other related alphaviruses. The reported computational insights, together with the accessible synthetic procedure, pave the road towards the design of novel synthetic derivatives with enhanced anti-viral activities.

Binding of Harmine Derivatives to DNA: A Spectroscopic Investigation.

Harmine belongs to a group of ß-carboline alkaloids endowed with antitumor properties. Harmine and its derivatives are thought to bind to DNA and interfere with topoisomerase activities. We investigated the base-dependent binding of harmine, and three of its synthetic anticancer-active derivatives to the genomic DNA from calf thymus and two synthetic 20-mer double helices, the poly(dG-dC)·poly(dG-dC) and the poly(dA-dT)·poly(dA-dT), by means of UV-Vis and circular dichroism (CD) spectroscopies. The data show that the DNA binding and stabilising properties of the investigated derivatives are base pair-dependent. These results could be used as a guide to design and develop further bioactive analogues.

Role of adiponectin in sphingosine-1-phosphate induced airway hyperresponsiveness and inflammation.

Epidemiological data suggest that obesity represent an important risk factor for asthma, but the link between excess fat and airway hyperresponsiveness (AHR) and inflammation is not fully understood. Recently, a key role in physiopathologic conditions of lungs has been given to adiponectin (Acrp30). Acrp30 is one of the most expressed adipokines produced and secreted by adipose tissue, showing an intriguing relationship with metabolism of sphingolipids. Sphingosine-1-phosphate (S1P) has been proposed as an important inflammatory mediator implicated in the pathogenesis of airway inflammation and asthma. In the present study we analyze the effects of recombinant Acrp30 administration in an experimental model of S1P-induced AHR and inflammation. The results show that S1P is able to reduce endogenous Acrp30 serum levels and that recombinant Acrp30 treatment significantly reduce S1P-induced AHR and inflammation. Moreover, we observed a reduction of Adiponectin receptors (AdipoR1, AdipoR2 and T-cadherin) expression in S1P treated mice. Treatment with recombinant Acrp30 was able to restore Acrp30 serum levels and adiponectin receptors expression. These results could indicate the ability of S1P to modulate the Acrp30 action, by modulating not only the serum levels of the protein, but also its receptors. Taken together, these data suggest that adiponectin could represent a possible biomarker in obesity-associated asthma.

Synthesis and pharmacological evaluation of functionalized isoindolinones on GABA-activated chloride currents in rat cerebellum granule cells in culture.

A focused N-substituted 3-(2-piperazin-1-yl-2-oxoethyl)-2-(pyridin-2-yl)iso-indolin-1-ones small library was synthesized for modulation of GABA-A receptor function and compared to Zopiclone for the ability to increase GABA-activated chloride currents. All compounds were tested for their effects on GABA-activated chloride currents in rat cerebellar granule cells by use of the whole-cell patch clamp technique. Electrophysiological studies on cultured cerebellar granule cells revealed 3-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-(5-nitropyridin-2-yl)iso-indolin-1-one (Id) as a partial agonist displaying 34% increase of the 10µM GABA evoked peak chloride currents, antagonized by flumazenil. Moreover, a second group of compounds, with bulky functional groups at N-4 position of piperazine, have shown inverse agonist effects. The simple synthetic procedure and the possibility of modulating the efficacy of this class of ligands through additional structural modifications pave the way for further development of new molecules as a novel class of compounds able to interfere with benzodiazepine receptors.

Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones.

New bifunctional chiral ammonium salts were investigated in an asymmetric cascade synthesis of a key building block for a variety of biologically relevant isoindolinones. With this chiral compound in hand, the development of further transformations allowed for the synthesis of diverse derivatives of high pharmaceutical value, such as the Belliotti (S)-PD172938 and arylated analogues with hypnotic sedative activity, obtained in good overall total yield (50%) and high enantiomeric purity (95% ee). The synthetic routes developed herein are particularly convenient in comparison with the current methods available in literature and are particularly promising for large scale applications.

Structure-activity relationship study of arbidol derivatives as inhibitors of chikungunya virus replication.

Chikungunya virus (CHIKV), a mosquito-borne arthrogenic Alphavirus, causes an acute febrile illness in humans, that is, accompanied by severe joint pains. In many cases, the infection leads to persistent arthralgia, which may last for weeks to several years. The re-emergence of this infection in the early 2000s was exemplified by numerous outbreaks in the eastern hemisphere. Since then, the virus is rapidly spreading. Currently, no drugs have been approved or are in development for the treatment of CHIKV, which makes this viral infection particularly interesting for academic medicinal chemistry efforts. Several molecules have already been identified that inhibit CHIKV replication in phenotypic virus-cell-based assays. One of these is arbidol, a molecule that already has been licensed for the treatment of influenza A and B virus infections. For structural optimization, a dedicated libraries of 43 indole-based derivatives were evaluated leading to more potent analogues (IIIe and IIIf) with anti-chikungunya virus (CHIKV) activities higher than those of the other derivatives, including the lead compound, and with a selective index of inhibition 13.2 and 14.6, respectively, higher than that of ARB (4.6).

Cardiac and Pulmonary Rehabilitation: Two Underutilized Approaches with Some Unexpected Benefits.

Although still underutilized [...].

Curcumin-loaded mesoporous silica nanoparticles for drug delivery: synthesis, biological assays and therapeutic potential - a review.

Curcumin-loaded mesoporous silica nanoparticles (MSNs) have shown promise as drug delivery systems to address the limited pharmacokinetic characteristics of curcumin. Functionalization with folic acid and PEGylation enhance anticancer activity, biocompatibility, stability, and permeability. Co-delivery with other drugs results in synergistically enhanced cytotoxic activity. Environment-responsive MSNs prevent undesirable drug leakage and increase selectivity towards target tissues. This review summarizes the methods of Cur-loaded MSN synthesis and functionalization and their application in various diseases, and also highlights the potential of Cur-loaded MSNs as a promising drug delivery system.

Highly potent and selective 5-lipoxygenase inhibition by new, simple heteroaryl-substituted catechols for treatment of inflammation.

5-Lipoxygenase (LO) catalyzes the first steps in the formation of pro-inflammatory leukotrienes (LT) that are pivotal lipid mediators contributing to allergic reactions and inflammatory disorders. Based on its key role in LT biosynthesis, 5-LO is an attractive drug target, demanding for effective and selective inhibitors with efficacy in vivo, which however, are still rare. Encouraged by the recent identification of the catechol 4-(3,4-dihydroxyphenyl)dibenzofuran 1 as 5-LO inhibitor, simple structural modifications were made to yield even more effective and selective catechol derivatives. Within this new series, the two most potent compounds 3,4-dihydroxy-3'-phenoxybiphenyl (6b) and 2-(3,4-dihydroxyphenyl)benzo[b]thiophene (6d) potently inhibited human 5-LO in cell-free (IC506b and 6d = 20 nM) and cell-based assays (IC506b = 70 nM, 6d = 60 nM). Inhibition of 5-LO was reversible, unaffected by exogenously added substrate arachidonic acid, and not primarily mediated via radical scavenging and antioxidant activities. Functional 5-LO mutants expressed in HEK293 cells were still prone to inhibition by 6b and 6d, and docking simulations revealed distinct binding of the catechol moiety to 5-LO at an allosteric site. Analysis of 5-LO nuclear membrane translocation and intracellular Ca2+ mobilization revealed that these 5-LO-activating events are hardly affected by the catechols. Importantly, the high inhibitory potency of 6b and 6d was confirmed in human blood and in a murine zymosan-induced peritonitis model in vivo. Our results enclose these novel catechol derivatives as highly potent, novel type inhibitors of 5-LO with high selectivity and with marked effectiveness under pathophysiological conditions.