MicroRNAs as possible biomarkers for diagnosis and prognosis of hepatitis b- and c-related-hepatocellularcarcinoma

Aim of the present review is to summarize the current knowledge about the potential relationship between mi RNAs and hepatitis B virus(HBV)-hepatitis C virus(HCV) related liver diseases. A systematic computerbased search of published articles, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis Statement, was performed to identify relevant studies on usefulness of serum/plasma/urine mi RNAs, as noninvasive biomarkers for early detection of HBV and HCV-induced hepatocellular carcinoma(HCC) development, as well as for its prognostic evaluation. The used Medical Subject Headings terms and keywords were: "HBV", "HCV", "hepatocellular carcinoma", "micro RNAs", "mi RNAs", "diagnosis", "prognosis", "therapy", "treatment". Some serum/plasma mi RNAs, including mi R-21, mi R-122, mi-125a/b, mi R-199a/b, mi R-221, mi R-222, mi R-223, mi R-224 might serve as biomarkers for early diagnosis/prognosis of HCC, but, to date, not definitive results or well-defined panels of mi RNAs have been obtained. More well-designed studies, focusing on populations of different geographical areas and involving larger series of patients, should be carried out to improve our knowledge on the potential role of mi RNAs for HCC early detection and prognosis.

Possible association between hepatitis C virus and malignancies different from hepatocellular carcinoma:A systematic review

AIM: To summarize the current knowledge about the potential relationship between hepatitis C virus(HCV) infection and the risk of several extra-liver cancers. METHODS: We performed a systematic review of the literature, according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis(PRISMA) Statement. We extracted the pertinent articles, published in MEDLINE and the Cochrane Library, using the following search terms: neoplasm/cancer/malignancy/tumor/carcinoma/adeno-carcinoma and non-Hodgkin lymphomas, kidney/renal-, cholangio-, pancreatic-, thyroid-, breast-,oral-, skin-, prostate-, lung-, colon-, stomach-, haematologic. Case series, case-series with control-group, case-control, cohort-studies as well as meta-analyses, written in English were collected. Some of the main characteristics of retrieved trials, which were designed to investigate the prevalence of HCV infection in each type of the above-mentioned human malignancies were summarised. A main table was defined and included a short description in the text for each of these tumours, whether at least five studies about a specific neoplasm, meeting inclusion criteria, were available in literature. According to these criteria, we created the following sections and the corresponding tables and we indicated the number of included or excluded articles, as well as of meta-analyses and reviews:(1) HCV and haematopoietic malignancies;(2) HCV and cholangiocarcinoma;(3) HCV and pancreatic cancer;(4) HCV and breast cancer;(5) HCV and kidney cancer;(6) HCV and skin or oral cancer; and(7) HCV and thyroid cancer. RESULTS: According to available data, a clear correlation between regions of HCV prevalence and risk of extra-liver cancers has emerged only for a very small group of types and histological subtypes of malignancies. In particular, HCV infection has been associated with:(1) a higher incidence of some B-cell Non-HodgkinLymphoma types, in countries, where an elevated prevalence of this pathogen is detectable, accounting to a percentage of about 10%;(2) an increased risk of intra-hepatic cholangiocarcinoma; and(3) a correlation between HCV prevalence and pancreatic cancer(PAC) incidence. CONCLUSION: To date no definitive conclusions may be obtained from the analysis of relationship between HCV and extra-hepatic cancers. Further studies, recruiting an adequate number of patients are requiredto confirm or deny this association.

Improvement on the Synthesis of Primary Amino Sugar Derivatives <i>via</i><i>N</i>-Benzyl Intermediates

Primary tosylates 1a-d were converted to the corresponding amino species 3a-d. Benzylamine was proved effective for the substitution of tosylates, using acetonitrile (MeCN) as the solvent of choice and citric acid to remove excess of the reagent from crude products 2a-d. Debenzylation was carried out at circa (ca.) atmospheric pressure of hydrogen gas in the presence of acetic acid (AcOH). The method was also demonstrated in a demo batch experiment for the synthesis of compound 3a on a 50 g scale of 1a.

Profiles of the Headspace Volatile Organic and Essential Oil Compounds from the Tunisian Cardaria draba (L.) Desv. and Its Leaf and Stem Epidermal Micromorphology

In this work, we investigated aroma volatiles emanated by dry roots, stems, leaves, flowers, and fruits of Cardariadraba (L.) Desv. growing wild in Tunisia and its aerial part essential oils (EOs) composition. A total of 37 volatileorganic compounds (96.7%–98.9%) were identified;4 esters, 4 alcohols, 7 hydrocarbons, 12 aldehydes, 5 ketones,1 lactone, 1 organosulfur compound, 2 organonitrogen compounds, and 1 acid. The hydrocarbons form the maingroup, representing 49.5%–84.6% of the total detected volatiles. The main constituent was 2,2,4,6,6-pentamethylheptane(44.5%–76.2%) reaching the highest relative percentages. Forty-two compounds were determined in thetwo fractions of EOs, representing 98.8% and 97.2% of the total oil composition, respectively. The principal componentswere hexadecanoic acid (34.6%), 6-methyl-5-hepten-2-one (18.3%), decanal (15.0%), 6,10,14-trimethyl-2-pentadecanone (13.2%), and n-pentacosane (13%). Micromorphological details of the leaf and stem epidermisusing light microscopy revealed polygonal cells with sinuous walls in the adaxial and abaxial leaf surfaces andnearly rectangular and long ones with linear and thick walls for the stem epidermis. The stomata complexes wereanisocytic in the leaf epidermis and mainly anisocytic and rarely paracytic in the stem epidermis. Non-glandulartrichomes were unbranched and long with an acute apex or short with a convex apex. The glandular ones wereidentified for the first time in this species. They were short-stalked with a large secretory head. The highest stomatalindex (17.02%) was recorded in the abaxial leaf surface. The identification of headspace volatiles and essentialoil compounds can be used to characterize this species, and the various epidermis micromorphologicalfeatures are very useful for biosystematics taxonomic studies within Brassicaceae.

One-neutron stripping process in the^(209)Bi(^(6)Li,^(5)Li)^(210)Bi*reaction reaction

One-neutron stripping process between^(6)Li and^(209)Bi was studied at 28,30,and 34 MeV using the in-beamγ-ray spectroscopy method.Theγ-γcoincident analysis clearly identified twoγ-rays feeding the ground and long-lived isomeric states,which were employed to determine the cross section.The one-neutron stripping cross sections were similar to the cross sections of complete fusion in the^(6)Li+^(209)Bi system,but the one-neutron stripping cross sections decreased more gradually at the sub-barrier region.A coupled-reaction-channel calculation was performed to study the detailed reaction mechanism of the one-neutron stripping process in^(6)Li.The calculations indicated that the first excited state of 5 Li is critical in the actual one-neutron transfer mechanism,and the valence proton of 209Bi can be excited to the low-lying excited state in(^(6)Li,^(5)Li)reaction,unlike in the(d,p)reaction.

role of microRNAs in the main molecular pathways of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the most common primary liver malignant neoplasia. HCC is characterized by a poor prognosis. The need to find new molecular markers for its diagnosis and prognosis has led to a progressive increase in the number of scientific studies on this topic. MicroRNAs(miRNAs) are small noncoding RNA that play a role in almost all main cellular pathways. miRNAs are involved in the regulation of expression of the major tumor-related genes in carcinogenesis, acting as oncogenes or tumor suppressor genes. The aim of this review was to identify papers published in 2017 investigating the role of miRNAs in HCC tumorigenesis. miRNAs were classified according to their role in the main molecular pathways involved in HCC tumorigenesis:(1) m TOR;(2) Wnt;(3) JAK/STAT;(4) apoptosis; and(5) MAPK. The role of miRNAs in prognosis/response prediction was taken into consideration. Bearing in mind that the analysis of miRNAs in serum and other body fluids would be crucial for clinical management, the role of circulating miRNAs in HCC patients was also investigated. The most represented mi RNA-regulated pathway in HCC is m TOR, but apoptosis, Wnt, JAK/STAT or MAPK pathways are also influenced by mi RNA expression levels. These miRNAs could thus be used in clinical practice as diagnostic, prognostic or therapeutic targets for HCC treatment.

ER exit pathways and the control of proteostasis:Crucial role of the UPR,COPII,and ER-phagy in the secretory pathway

The endoplasmic reticulum(ER)is the site of entry of all proteins that function in the secretory pathway including the extracellular environment.Because it controls the folding of newly synthesized secretory proteins,the ER is indispensable for the maintenance of proteostasis in the secretory pathway.Within the ER and,in part,in post-ER compartments,the quality control of protein folding is under the regulation of the unfolded protein response(UPR)pathways.The UPR strategy is to enhance protein folding,increase the ER degradation pathway of misfolded proteins,and allow the exit from the ER of only correctly folded proteins.The latter is controlled by the multimeric complex COPII,which also provides some of the components for ER-phagy the only route for the disposal of protein aggregates.In this overview,we wish to contribute to the introduction of new perspectives in the study of the mechanisms underlying the control of proteostasis within the secretory pathway.

NHC-gold(Ⅰ)-alkyne complexes induced hepatocellular carcinoma cell death through bioorthogonal activation by palladium complex in living system

Bioorthogonal reactions can take place in biological environments without interfering with biochemical processes.In this study,Pd(PPh_(3))_(2)Cl_(2)was used as a bioorthogonal catalyst to in situ transform the stable N-heterocyclic carbene(NHC)-gold(Ⅰ)-alkyne complex 5 to its active species which can effectively inhibit thioredoxin reductase(TrxR)and exhibit significant anticancer bioactivity in hepatocellular carcinoma(HCC).

The dimerization of ⊿~9-tetrahydrocannabinolic acid A(THCA-A)

The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and antidiabetic agents provided a rationale to investigate the dimerization of the substituted salicylate D9-tetrahydrocannabinolic acid(THCA-A, 3 a) as a strategy to solve its instability to decarboxylation and to generate analogues and/or pro-drugs of this native pre-cannabinoid. Activation of the carboxylic group with the DCC-HOBt-DMAP protocol afforded a high yield of the OBt ester 4, that was next converted into the highly crystalline di-depsidic dimer 5 upon treatment with DMAP. The mono-depsidic dimer 6 was also formed when the reaction was carried out with partially decarboxylated THCA-A samples. The structure of the depsidic dimers was established by spectroscopic methods and by aminolysis of 5 into the pre-cannabinoid amide 7. Both dimers showed excellent shelf stability and did not generate significant amounts of D9-THC upon heating. However, only the didepsidic dimer 5 activated PPAR-g, the major target of pre-cannabinoids, but strong binding to serum proteins abolished this activity, also shielding it from the action of esterases.

Further investigation on the fusion of ^(6)Li with ^(209)Bi target at near-barrier energies

The complete and incomplete fusion cross sections for ^(6)Li+^(209)Bi were measured using the in-beamγ-ray method around the Coulomb barrier.The cross sections of(deuteron captured)incomplete fusion(ICF)products were re-quantified experimentally for this reaction system.The results reveal that the ICF cross section is equivalent to that of complete fusion(CF)above the Coulomb barrier and dominant near or below the Coulomb barrier.A theoretical calculation based on the continuum discretized coupled channel(CDCC)method was performed for the aforementioned CF and ICF cross sections;the result is consistent with the experiments.The universal fusion function(UFF)was also compared with the measured CF cross section for different barrier parameters,demonstrating that the CF suppression factor is significantly influenced by the choice of potential,which can reflect both dynamic and static effects of breakup on the fusion process.

Integrin-targeting with peptide-bioconjugated semiconductor-magnetic nanocrystalline heterostructures

Binary asymmetric nanocrystals （BNCs）, composed of a photoactive TiO2 nanorod joined with a superparamagnetic γ-Fe203 spherical domain, were embedded in polyethylene glycol modified phospholipid micelle and successfully bioconjugated to a suitably designed peptide containing an RGD motif. BNCs represent a relevant multifunctional nanomaterial, owing to the coexistence of two distinct domains in one particle, characterized by high photoactivity and magnetic properties, that is particularly suited for use as a phototherapy and hyperthermia agent as well as a magnetic probe in biological imaging. We selected the RGD motif in order to target integrin expressed on activated endothelial cells and several types of cancer cells. The prepared RGD-peptide/BNC conjugates, comprehensively monitored by using complementary optical and structural techniques, demon- strated a high stability and uniform dispersibility in biological media. The cytotoxicity of the RGD-peptide/BNC conjugates was studied in vitro. The cellular uptake of RGD-peptide conjugates in the cells, assessed by means of two distinct approaches, namely confocal microscopy analysis and emission spectroscopy determination in cell lysates, displayed selectivity of the RGD-peptide-BNC conjugate for the cw]33 integrin. These RGD-peptide-BNC conjugates have a high potential for theranostic treatment of cancer.

The reaction of cinnamaldehyde and cinnam(o)yl derivatives with thiols

Spurred by the alleged relevance of the thia-Michael reaction in the bioactivity of various classes of cinnam(o)yl natural products and by the development of a quick NMR assay to study this reaction, we have carried out a systematic study of the "native" reactivity of these compounds with dodecanethiol and cysteamine as models, respectively, of simple thiols and reactive protein thiols that can benefit from iminium ion catalysis in Michael reactions. Cinnamoyl esters and amides, as well as cinnamyl ketones and oximes, did not show any reactivity with the two probe thiols, while cinnamaldehyde(1a) reacted with cysteamine to afford a mixture of a thiazoline derivative and compounds of multiple addition, and with aliphatic thiols to give a single bis-dithioacetal(6). Chalchones and their vinylogous C5-curcuminoid derivatives were the only cinnamoyl derivatives that gave a thiaMichael reaction. From a mechanistic standpoint, loss of conjugation in the adduct might underlie the lack of a native Michael reactivity. This property is restored by the presence of another conjugating group on the carbonyl, as in chalcones and C5-curcuminoids. A critical mechanistic revision of the chemical and biomedical literature on cinnamaldehyde and related compounds seems therefore required.

Synthesis of Water-soluble, Polyester-based Dendrimer Prodrugs for Exploiting Therapeutic Properties of Two Triterpenoid Acids

Dendrimers are macromolecules characterized by high controlled size, shape and architecture, presence of inner cavities able to accommodate small molecules and many peripheral functional groups to bind target entities. They are of eminent interest for biomedical applications, including gene transfection, tissue engineering, imaging, and drug delivery. The well-known pharmacological activities of ursolic and oleanolic acids are limited by their small water solubility, non-specific cell distribution, low bioavailability, poor pharmacokinetics, and their direct administration could result in the release of thrombi. To overcome such problems, in this paper we described their physical incorporation inside amino acids-modified polyester-based dendrimers which made them highly water-soluble. IR, NMR, zeta potential, mean size of particles, buffer capacity and drug release profiles of prepared materials were reported. The achieved water-soluble complexes harmonize a polycationic character and a buffer capacity which presuppose efficient cell penetration and increased residence time with a biodegradable cell respectful scaffold, thus appearing as a promising team of not toxic prodrugs for safe administration of ursolic and oleanolic acids.

Roots and rhizomes of wild Asparagus:Nutritional composition,bioactivity and nanoencapsulation of the most potent extract

The nutritional composition and bioactive properties of roots and rhizomes of Asparagus stipularis were evaluated.Antioxidant activity of extracts obtained by infusion was evaluated using free radicals scavenging and reducing power methods.Porcine liver primary cell was used to check the hepatotoxicity of infusions.Results revealed that Asparagus samples are likely a source of nutrients,such as dietary fibre and essential fatty acids.HPLC-DAD-ESI/MS characterization of infusions allowed the identification and quantitation of 7 phenolic compounds,all hydroxycinnamoyl derivatives,with caffeic acid as the most abundant.Roots infusion contained the highest amounts of these compounds.It also exhibited the highest antioxidant activity in all assays,with EC_(50) values of 0.44±0.01,0.98±0.03 and 0.64±0.01 mg/mL for DPPH,ABTS and FRAP assays,respectively,with no toxicity towards PLP2 primary cell cultures(GI_(50)>400μg/mL).PLGA nanoparticles loaded with root extract were prepared using solvent-evaporation double emulsion method.Nanoparticles size was about 260 nm and a polydispersity index around 0.1,with a zeta potential of about-36 mV,as well as a good encapsulation efficiency of approximately 83%.Their morphology was analysed by SEM and spherical polymeric nanoparticles with a smooth surface were observed.FTIR and DSC were also performed,which allowed corroborating the efficacy of the encapsulation and to confirm the production of a stable and robust system to load Asparagus extracts.The developed nanoparticles are expected to be used as delivery systems for bioactive compounds of A.stipularis and they could be used as an innovative dietary supplement.