Heart failure (HF) is a severe public health problem because of its highmorbidity and mortality and elevated costs, thus requiring betterunderstanding of its course. In its complex and multifactorial pathogenesis,sympathetic hyperactivity plays a relevant role. Considering thatsympathetic dysfunction is already present in the initial phases of chronicChagas cardiomyopathy (CCC) and frequently associated with a worseprognosis, we assumed it could be more severe in CCC than incardiomyopathies of other etiologies (non-CCC).123I-MIBG) of HF,comparing individuals with CCC to those with non-CCC, using heart transplant(HT) patients as denervated heart parameters.To assess the cardiac sympathetic dysfunction 123I-metaiodobenzylguanidine 123I-MIBG)scintigraphy, estimating the early and late heart-to-mediastinum ratio (HMR)of 123I-MIBG uptake and cardiac washout (WO%). The 5%significance level was adopted in the statistical analysis.We assessed 76 patients with functional class II-VI HF, being 25 CCC (17men), 25 non-CCC (14 men) and 26 HT (20 men), by use of cardiacThe early and late HMR values were 1.73 ± 0.24 and 1.58 ± 0.27,respectively, in CCC, and 1.62 ± 0.21 and 1.44 ± 0.16 innon-CCC (p = NS), being, however, higher in HT patients (p < 0.001). TheWO% values were 41.65 ± 21.4 (CCC), 47.37 ± 14.19% (non-CCC)and 43.29 ± 23.02 (HT), p = 0.057. The late HMR values showed apositive weak correlation with left ventricular ejection fraction (LVEF) inCCC and non-CCC .123I-MIBG) was evidenced in patientswith class II-IV HF, LVEF < 45%, independently of the HF etiology, ascompared to HT patients.Sympathetic hyperactivity  Chagasic versus non-Chagasic patientswere compared, and heart transplant (HT) patients were considered as the denervatedheart pattern .23 Cardiac 123I-metaiodobenzylguanidine(123I-MIBG) scintigraphy was used to assess the patients, because itproperly evaluates cardiac sympathetic dysfunction,12,13,24,25providing relevant parameters to understand the progression of HF.12,13,24Because cardiac autonomous dysfunction is present early in CCC and the incidence ofmalignant arrhythmias and sudden death is elevated in those patients,This is a cross-sectional study of 76 patients selected from the Heart Failure andHeart Transplant outpatient clinic of our institution from March 2014 to February2016.26 andaccepting to participate in the study. In addition, for individuals with HFsubmitted to HT (comparison group or denervated heart model),23 time from HT shorter than 12months was required. Patients with diabetes mellitus, chronic kidney disease,chronic obstructive pulmonary disease, Parkinson disease, non-sinus heart rhythm orimplantable pacemaker were excluded.The eligibility criteria for individuals with HF were: age over 18 years; leftventricular ejection fraction (LVEF) ≤ 45%; confirmed non-Chagasic orChagasic etiology  associated with left ventricular systolicdysfunction;The patients were studied prospectively, divided into three groups: CCC group - 25patients with CCC ; non-CCC group - 25patients with heart disease etiologies other than CCC ; andHT group - 26 patients previously submitted to HT within less than 12 months , with mean age of 47.3 ± 13.1 years, being 20 of themale sex. All patients provided written informed consent, which had been approved bythe Ethics Committee of the institution, according to the Declaration of Helsinki.All patients underwent clinical control during the study period.27 Planar scintigraphy of the myocardial innervation was performedby use of slow intravenous administration of 111 MBq/3 mCi 123I-MIBG(IPEN/CNEN), with anterior image acquisition of the chest after 15 minutes and 180minutes on a Hawkeye® gamma-camera , 10min/frame, 123I photopeak of 159 KeV, window of 20%, and low-energyhigh-resolution collimator (LEHR). The heart region of interest (ROI) was drawnencompassing the entire left ventricle, while that of the superior mediastinumencompassed a square ROI of 12x12 pixels. Early and late cardiac uptakes wereestimated by use of the ratio between the radioactive counts of the heart andmediastinal ROIs on early and late imaging .The cardiac washout rate (WO%) of 123I-MIBG was calculated using theformula:   /  x 100, withoutconsidering radioactive decay, and expressed as percentages28  and echocardiographic data werecollected by the same researcher. Echocardiography was performed using the PhillipsiE33® ultrasound device , LVEF beingestimated by using Simpson's formula.ntages28 . Two nuc123I-MIBG was estimated as approximately 4.8 mSv,comparable to one of the phases of myocardial perfusion studies with99mTc-isonitrile.30The effective radiation dose for the patient, resulting from the administration of111 MBq/3mCi of 123I-MIBG uptake (HMR), with 5% alphaerror and 80% power (CI = 95%) for three groups of patients.For this analysis, a sample of 76 patients was calculated to detect a 12%variation in the early or late 123I-MIBG expressed according to the distribution of frequencyor measures of central tendency and variability. This analysis was stratifiedper group . When comparing the three groups, for thecategorical variables ,Pearson chi-square test was performed; for the continuous variables , one-factor analysis of variance (ANOVA) was used; and for multiplecomparisons, the least significant difference (LSD) test was used. In addition,ANOVA was used to assess the variables (early and late HMR), based, however, onrepeated-measures analysis and LSD test for multiple comparisons.To characterize the sample, descriptive analysis of the following variables wasinitially performed: sex, age, heart rate (HR), LVEF, early HMR, late HMR andWO% of It is worth noting that the assumptions to use ANOVA were verified and accepted,that is, normally distributed residuals (Kolmogorov-Smirnov test) and constantvariances (Levene's test).31,32To analyze the correlation between the measures of early HMR, late HMR or WO% andLVEF, Pearson correlation test and its respective p value were used. In allanalyses, a 5% significance level was considered, and the statistical softwareSPSS, version 17.0 , was used.The early and late HMR values were greater than those reported for HT patients (p< 0.001) , but didThe WO% values showed no statistically significant difference between individualswith HF, and between individuals with HF and those submitted to HT (p = 0.577).A weak positive correlation was observed between late HMR values and LVEF in CCCpatients . Regarding the non-CCC patients, a positivecorrelation was observed both between LVEF and early HMR  andbetween LVEF and late HMR . However, none of the groups showeda correlation between LVEF and WO% ,5 and 6123I-MIBG scintigraphy.Patients were divided into three groups, CCC, non-CCC and HT, the latter, byrepresenting the denervated heart model, served as the abnormalitypattern.23This study investigated the presence and magnitude of cardiac dysautonomia inpatients with HF and LVEF ≤ 45% by use of 123I-MIBG uptake (early and late HMR) by the presynaptic endingsin the three groups studied, which is aligned with the literature.13,23,24,28 The low 123I-MIBGuptake indicates dysfunction of the receptors and integrity loss of the presynapticsympathetic fibers, reinforcing the theory of sympathetic hyperactivity in thepathogenesis of HF.8-10,12,24There was scintigraphic evidence of sympathetic hyperactivity, based on the findingsof low 12,24 that can provide parameters known for their accuracy andreproducibility to estimate the efficacy of clinical treatment13 and the prognosis of patients withHF.13,24,25,33However, the lack of standardization in the scintigraphic imaging acquisition andprocessing hinders the incorporation of the method into clinical practice, becausethere is no well-defined reference value.28,29 In a meta-analysis of seven studies with 96 healthyindividuals, Patel and Iskandrian have reported HMR of 2.13 ± 0.3 and WO% of20 ± 10% (ranging from 10 ± 6% to 37 ± 5%) for healthyindividuals.29Scintigraphy is the only noninvasive and safe method, sufficiently sensitive toassess the autonomic sympathetic nervous system,24 with a correlation between areduction in uptake and worse prognosis, expressed as a higher number of cardiacevents and higher mortality.13,24,25The late HMR values found for our patients with HF , with HF  were low23,29The HMR values found for HT patients (1.20 ± 0.12) were lower than those foundfor individuals with HF, with statistical significance (p<0.001), which isaligned with that reported in the literature for patients within the first post-HTyear, specially individuals with idiopathic heart disease.123I-MIBG uptake.34 Thus, supposedly, the HMR valuesof our patients are overestimated, reinforcing their sympathetic dysfunctiondegree.It is worth noting that the patients of this study were on regular use ofbeta-blockers and ACEI, which do not interfere directly in the uptake ofnoradrenaline. However, by improving the cardiac performance, and, thus, thesympathetic tone, they increment the 21 have reported a significant correlation between late HMR valuesof 1.68 ± 0.19 and severe ventricular arrhythmias, we assumed that thesympathetic dysfunction was more severe in the CCC group because of its arrhythmicfindings as compared to the non-CCC group.20,22 However, in our study, those values did not differsignificantly from those of the non-CCC group (1.44 ± 0.16), even whenstatistically adjusted to age and LVEF (p = 0.111).Considering that the late HMR values of individuals with CCC (1.58 ± 0.27) areoverestimated, and that Gadioli et al.8-10,13,24,25,33independently of etiology, which is aligned with the report by otherauthors.13This fact might be explained by the advanced HF stage of our patients, when sustainedautonomic sympathetic dysfunction represents a deleterious mechanism in thepathogenesis of HF itself,19presence of autonomic dysfunction in the early stages of Chagas disease;4,15,19 correlation between persistence ofthe myocardial inflammatory process and those patients' morbidity andmortality,35 despite theserum levels of catecholamines.On the other hand, the importance of sympathetic dysfunction in CCC has beenquestioned by different authors because of: variation in the intensity ofdenervation; absence of correlation between parasympathetic denervation andmyocardial dysfunction extent;13,28 might be altered earlier and moremarkedly than late HMR, and, thus, could be a more sensitive parameter forprognostic assessment, as described.33The estimated WO% values were elevated and abnormal in the three groups studied,being compatible with sympathetic dysfunction in patients with HF and not differentfrom those of HT (p = 0.577). The sympathetic tone, translated by WO%,22,36Thus, that weak correlation can indicate that this scintigraphic parameter is moreaccurate and earlier altered, as reported by Ogita et al., suggesting it is a betterpredictor of prognosis than LVEF.33 In addition, it is worth noting that the correlation of earlyand late HMR with LVEF in CCC patients identified in this study has not beenreported in the literature.Finally, a positive, although weak, but statistically significant correlation betweenHMR and LVEF was observed in individuals with HF. The LVEF is routinely used for theprognostic assessment of HF.28,29 The maintenance of themedication by the patients (ACEI and beta-blockers) might have led tooverestimation of the HMR values and influenced our results, although the numberof patients on medications did not differ between the CCC and non-CCC groups,and most studies in the literature have been performed considering the severityof HF.24,25,33This is a cross-sectional nonrandomized study of patients with advanced HF , thus its findings cannot be generalized to allindividuals with CCC. There are no strictly established reference values toquantify the scintigraphic parameters because different methodologies have beenused .123I-MIBG scintigraphy, regardless of the HF etiology, and itsmagnitude was equal in individuals with CCC and non-CCC as compared to HTpatients.This study evidenced the presence of cardiac sympathetic autonomic dysfunction onmyocardial


Among all the oligonucleotides, a sequence C3AC3AC3TC3G (3T4G) has been identified, which grows three different near-infrared-emitting NC species with absorption/emission maxima at ~620/700 (species I), 730/800 (species II), and 830 (Species III) nm, respectively. The nature of the spectral profiles, along with relevant parameters namely absorption maximum (r), lifetime (τ), circular dichroism spectral data are used to understand the microenvironments of the fluorescent NC species I, II, and III. DNA:Ag stiochiometric, pH and solvent dependent studies proved that i-motif scaffolds with different folding topologies are associated with the growth of these three species and a certain concentration of silver and H+ favor the growth of species III. Size exclusion chromatographic measurements provided similar indications that a folded, more compact, classic i-motif template is associated with the formation of the longer NIR (~830 nm) absorbing species. This study provides a more definitive approach to design and obtain a targeted DNA templated Ag-NC with required emission properties for biophysical and cellular applications.Fluorescent silver nanoclusters (Ag-NCs) are in prominence as novel sensing materials due to their biocompatibility, photostability, and molecule-like optical properties. The present work is carried out on an array (17 sequences) of 16 bases long cytosine rich, single stranded DNA templates 5′-C Metal nanoclusters (NCs) with sizes around 1 nm or less, have discrete electronic transitions, which give rise to light absorption and emission ,3,4,5. TCompared to organic dyes and quantum dots, DNA scaffolded Ag-NCs are more photostable and less prone to blinking on long timescales ,7,8. The+ strongly, while adenine (A) and thymine (T) have weaker influence :[Ag] stiochiometric and pH dependent studies reveal that the right combination of H


The marine environment presents a high biodiversity and a valuable source of bioactive compounds with therapeutic and biotechnological potential. Among the organisms present in marine environment, the endophytic fungi isolated from seaweed stand out. These microorganisms have aroused interest in the scientific community regarding its various activities such as antiviral, antimicrobial, antioxidant, photoprotective, cytotoxic, genotoxic, anti-inflammatory, and anticancer, besides establishing important ecological relations with its hosts. Anticancer molecules derived from marine natural sources are a promising target against different types of cancer. The disease’s high rates of morbidity and mortality affect millions of people world wild and the search for new therapeutic alternatives is needed. Thus, this review partially summarizes the methodologies for the isolation of seaweed-derived endophytic fungi, as well as describes the anticancer compounds isolated from such microorganisms, reported in the literature from 2009 to the present. In addition, it describes how some biotechnological processes can help in the discovery of bioactive compounds, especially with anticancer activity. Cancer cells can develop from any tissue in the human body, they multiply and grow uncontrolled. Some types of cancers can form tumors and spread throughout the body, forming metastases . TalkingPlants, microorganisms  and marine organisms are sources of natural products with new and unique chemical structures. In addition, many of these molecules are potential anticancer agents ,8. The r®), it is a derivative from a marine sponge, used for leukemia; trabectidine (Yondelis®), isolated from a tunicate, medicinally in use for ovarian cancer and soft tissue sarcoma; eribulin mesylate , a derivative from a sponge and, brentuximab vedotin , from a mollusk source. Marine-derived substances with antitumoral activities are continuously being isolated and tested. For example, lurbinectedin, plitidepsin and plinabulin (isolated from marine fungus) are currently in phases I, II, and III of clinical trials [In recent years, the search for new compounds from the marine environment has constantly increased due to the discovery of distinct chemical structures and their bioactivity. There are four clinical approved drugs from natural marine products that are in use for the treatment of cancer: cytarabine  ,12,13,14Leptoshaeria sp., an endophyte of the macroalgae Sargassum tortile. Terpenoids, lactones, and alkaloids isolated from marine fungi also have cytotoxic activity against leukemia, HCT-116 colon carcinoma, A549 lung cancer cells and others [Cytotoxic metabolites from endophytic fungi are well represented for the dimeric diketopirerazines, as an example we can cite the leptosins, which are inhibitors of the DNA topoisomerases (I and II) and, great candidates for anticancer drugs. They were isolated from the fungus d others ,15.Laurencia, Sargassum and Pterocladiella and their endophytes, especially, Aspergillus, Cladosporium and Penicillium. The secondary metabolites that are shown in the current paper present in vitro and/or in vivo studies tested in different cancer cells lines. We also summarize some mechanisms of action and biotechnological processes to obtain anticancer natural products. Due to the high incidence rate of cancer, resistance to many chemotherapeutic drugs and their adverse effects on the patient, as mentioned above, the relentless search for new natural products leads becomes necessary, in order to alleviate these unpleasant symptoms that occur during treatment and increase the chances of cure of the patient.The aim of this review is to report the findings about anticancer compounds isolated from seaweed derived-endophytic fungi in the last ten years (2009-2019) which have shown bioactivity against different types of cancer cell lines: NCI-H460 and NCI-H446 (human lung carcinoma), A-549 , MDA-MB-231 (human breast cancer), HCT-116 (human colon carcinoma), etc. Herein, we report the compounds from a variety species of macroalgae including Endophytic fungi are a polyphyletic group comprising mainly Ascomycetous fungi , which hPetrini  defined All plants in natural ecosystems studied to date appear to be symbiotic with fungal endophytes ,23. RegaFungal associations with land plants date back from early evolutionary times . SymbionAcremonium spp., Acremonium fuci which the conidia were only capable to germinate in the presence of Fucus serratus tissue or its aqueous tissue homogenates, and not in seawater alone. The production of these metabolites provides chemical adaptation to environmental conditions, substrate competitionand, also it helps to protect the host against pathogens attacks [Pyropia yezoensis against the infection by protistan pathogens of marine algae, highlighting the importance of this symbiosis [Macroalgae are a prolific source of natural products with industrial interest and can have the secondary metabolism influenced by associated microorganisms such as endophytic fungi and vice-versa . As it o attacks . A recenymbiosis .Ascophyllum, Ballia, Caulerpa, Ceramium, Ceratiodictyon, Cladophora, Chondrus, Dictyota, Dilsea, Egregia, Enteromorpha, Fucus, Gelidiella, Gracilaria, Grateloupia, Halimeda, Halymenia, Hypnea, Laminaria, Lobophora, Padina, Porphyra, Portieria, Saccorhiza, Sargassum, Stoechospermum, Turbinaria, and Ulva [Many macroalgal species have been studied worldwide regarding their associated fungal communities, which includes the genera and Ulva .Sargassum and Laurencia the most studied to date, followed by Enteromorpha, Ulva, Codium, Grateloupia, Leathesia, Pterocladiella, and Undaria. Associated to these genera, we can correlate 10 genera of endophytic fungi, which includes Aspergillus, Cladosporium, Paecilomyces, Chaetomium, Penicillium, Guignardia, Phoma, Talaromyces, Gibberella, Coniothyrium, being Aspergillus and Penicillium the prevalent ones , washing off macroalgae fragments in three different distilled water recipients to remove sterilizers residue; (ii) 5 seconds in ethanol 70% (v/v) followed by 5 seconds in sodium hypochlorite (2.5% v/v); and (iii) 5 seconds in ethanol 70% (v/v) followed by 10 seconds in sodium hypochlorite (2.5% v/v), after the sterilization procedure macroalgae segments are used to make imprints on agar surface (negative control 1). Macroalgae is then aseptically cut into fragments (0.5 mm to 1 cm) and placed in agar plates. The third distilled water of the washing procedure is also inoculated in agar plates, aiming to check no microorganism’s growth (negative control 2). To the selective isolation of fungi, the culture medium utilized is supplemented with chloramphenicol (200 mg·L−1) [Our research group developed a protocol for fungi endophytes isolation from tropical and polar macroalgae, from adaptations of the study of methodologies published by Erbert and co-workers , based o mg·L−1) .Fungi as well as bacteria, are versatile organisms that can be found in diverse habitats, occupying even inhospitable ecological niches, of all ecosystems around the planet. The ecological role of these organisms goes far beyond interactions between living beings, as they can adapt to virtually any environment and promote new biological interactions from chemical communications. The association between fungi and marine algae promotes the biosynthesis of metabolites with therapeutic potential by these microorganisms ,63,64. CThe chemical and biological potential of fungi of marine origin in the search for new structures with promising antitumor activities led to the identification of several relevant compounds. Over the past few years, several metabolites produced by seaweed derived-endophytic fungi or other organisms have shown potent antitumor effects, which have been evaluated by different mechanisms, such as the ability to kill cancer cells with low or no toxicity to healthy host cells, blocking key enzymes, stimulating the pathways of death, or promoting growth arrest ,66. The (1-2)  [Cytochalasans are fungal alkaloids with biological activities cytoskeletal processes, including cytotoxicity against tumor cell lines. Cytoglobosins C and D (1-2) , cytocha(3) and (−)−cereoaldomine (4) −cereolactam mine (4)  are phenrpha sp. .(5) -4-(4’-hydroxyphenoxy)pyrrolidin-2-one (5)  was isolectively .Penicillium and Aspergillus. Some of these compounds have insecticidal, cytotoxic, anthelmintic and antibacterial activities. Two prenylated indole alkaloids, dihydrocarneamide A (6) and iso-notoamide B (7) (Paecilomyces variotii EN-291. These compounds were assayed for their cytotoxic activities against human large cell lung carcinoma cell line (NCI-H460) and showed weak activity with IC50 values of 69.30 and 55.90 µmol L−1, respectively [(8) and B (9)   were isond B (9)  were alsectively .Guignardia sp. isolated from brown algae Undaria pinnatifida (Harv.) Sur. collected in Changdao sea area, China, two of the five peptides that were isolated, cyclo-(Tyr-Leu) (10), cyclo-(Phe-Pro) (11)  co-assayed as a positive reference [From the culture of the endophytic fungus ro) (11)  presenteeference .Aspergillus sp. XNM-4 derived from brown algae Leathesia nana are highlighted. Compounds asperpyrone B (12), aurasperone F (13) and especially asperpyrone A (14) ((14) possessed the greatest inhibitory effects against PANC-1, with an IC50 value of 8.25 ± 2.20 µM [As an example of polyketides with anticancer potential, natural naphthopyrones isolated from the endophytic fungus e A (14)  exhibite 2.20 µM .Cladosporium cladosporioides EN-399. All compounds were assayed for cytotoxicity activity. Cladodosporol H (15)    exhibitel C (16)  showed a 4.00 µM . Cladospactivity ,70,71,72Coniothyrium cereale isolated from the green alga Enteromorpha sp. collected from Fehmarn, Baltic Sea, seven new phenalenone derivatives as well as known compounds were isolated and assayed for cytotoxicity activity against human urinary bladder carcinoma cells 5637 (HTB-9) and HLE. The isolated compounds, coniosclerodin (17), conioscleroderolide (18) and coniolactone (19)   showed pectively .(20)  cell line with IC50 value of 32.00 µg mL−1 [Penicitide A (20)  was isol µg mL−1 .3 and G, besides 11 known compounds were purified from endophytic fungal strain Phoma sp. NTOU4195 isolated from the marine red alga Pterocladiella capillacea and evaluated for their antiangiogenic activity. Angiogenesis is defined as the formation of blood vessels from an existing vascular network towards a tumor, is crucial for the progression of the disease in tumor types. Thus, the antitumor activity of compounds isolated from Phoma sp. was assessed by the ability to prevent or not the capillary-like tube formation, which is one of the most important steps in angiogenesis. Compound phomaketide A (21) (50 of 8.10 µM. The others compound phomaketide C (22), D (23), E (24) and pseurotin G (25)   exhibiten G (25)  showed wectively .(26)  when 3 µg of the pure compound was applied to the filter disk, while compounds emodin (27) and variculanol (28) (A new metabolite named isorhodoptilometrin-1-methy ether (26)  along winol (28)  showed wTalaromycesis landicus EN-501, an endophytic fungus obtained from the inner tissue of the marine red alga Laurencia okamurai. These compounds were assayed for cytotoxicity against sensitive and cisplatin-resistant human ovarian cancer cell lines A2780 and A2780 CisR, respectively. However, none of the compounds were active (IC50 < 10 µM) [Five new polyhydroxylated hydroanthraquinone derivatives were isolated and identified from the culture extract of < 10 µM) .Aspergillus ochraceus Jcma1F17, which was isolated from a marine alga Coelarthrum sp. resulted in the isolation of a new nitrobenzoyl sesquiterpenoid, 6β, 9α-dihydroxy-14-p-nitrobenzoylcinnamolide (29), and a known analogue, insulicolide A (30)  . The com 6.35 µM . There asediment , and frosediment ,41,72 ansediment .A. ochraceus Jcma1F17, together with three known nitrobenzoyl sesquiterpenoids and a derivative sesquiterpenoid. All compounds were evaluated for their cytotoxicity against three renal carcinoma cell lines, ACHN, OS-RC-2, and 786-O cells. Compounds 14-O-acetylinsulicolide A (31), 6β,9α-dihydroxy-14-p-nitrobenzoylcinnamolide (29) and insulicolide A (30)   displaye-O cells . TherefoAspergillus wentii EN-48, an endophytic fungus isolated from an unidentified marine brown alga species of the genus Sargassum. All compounds were assayed for their cytotoxic activities against HeLa, HepG2, MCF-7, MDA-MB-231, NCI-H460, SMMC-7721 and SW1990 tumor cell lines, with fluorouracil and adriamycin as positive controls. None of these compounds had significant activity (IC50 ≤ 10 µM). Wentilactone B (32)  were obtained of the culture extract of e B (32)  was the ell line .32. Zhang et al. [(32) could efficiently induce SMMC-7721 cells apoptosis, but not normal hepatic cells and inhibit the metastasis of this cell line. In addition, further studies have shown that wentilactone B (32) can significantly induce cell cycle arrest at G2 phase and mitochondrial-related apoptoses, accompanying the accumulation of reactive oxygen species (ROS). Therefore, this agent may be a potentially useful compound for developing anticancer agents for hepatocellular carcinoma [Other researchers have explored the promising antitumor activity of compound g et al.  demonstrarcinoma .(33), isolated from endophytic fungus A. wentii EN-48 [33 triggered G2/M phase arrest and mitochondrial-related apoptosis in human lung carcinoma cells (NCI-H460 and NCI-H446), accompanying the ROS accumulation. In vivo studies, wentilactone A (33) ((34)  illustrated a marked inhibition of tumor growth, and little toxicity compared to cisplatin therapy, which proves its potential antitumor activity [Further studies carried out with wentilactone A ii EN-48 , demonste A (33)  suppress3) ((34)  isolatedβ, 11α-dihydroxyergosta-8,24(28)-dien-7-one (35) and 3β-hydroxyergosta-8,24(28)-dien-7-one, and a rare 7-norsteroid with an un usual pentalactone B-ring system, the 7-Nor-esgosterolide (36)   were chaectively .Guignardia sp. isolated from brown algae Undaria pinnatifida (Harv.) Sur. collected in Changdao sea area, China, ergosterol peroxide, 6,22-diene-5,8-epidioxyergosta-3-ol (37) (37 exhibited activity with IC50 of 20.00 μg mL−1 [From the culture of the endophytic fungus -ol (37)  and ergo μg mL−1 .(38) and B (39), two new polyoxygenated steroids, together with seven known steroids were obtained from the culture extract of Penicillium chrysogenum QEN-24S, an endophytic fungus isolated from unidentified marine red algal species of the genus Laurencia. The cytotoxicity against seven tumor cells was determined and compound 38 displayed selective activity against the tumor cells line HeLa, SW1990 and NCI-H460 with the IC50 of 15.00, 31.00 and 40.00 μg mL−1, respectively, while the other compounds displayed weak or no appreciable activity. The hydroxyl group at C-6 in B-ring seems essential for their cytotoxicity, which is likelythe reason for that penicisteroid A (38) ((39) (Penicisteroids A d A (38)  showed c8) ((39)  showed nAspergillus tennesseensis, a marine algal-derived endophytic fungus isolated from the fresh tissue of an unidentified marine alga, were isolated two new compounds with a prenylated diphenyl ether structure, diorcinol L and (R)-diorcinol B, along seven known compounds. All compounds were evaluated for cytotoxicity against six tumor cells lines  in vitro. Compound 3-(2-(1-hydroxy-1-methyl-ethyl)-6-methyl-2,3-dihydrobenzofuran-4-yloxy)-5-methylphenol (40)  [From the culture of the fungus nol (40)  selectivμg mL−1) .(41)  and detoxified by glutathione S-transferases (GST), quinine reductase (QR) and epoxide hydrolase (mEH). The researchers demonstrated in their studies that chromanone A is a promising inhibitor of CYP1A activity up to 60% of the stimulated-CYP1A in Hepa1c1c7 cells, and it significantly induced GST but not total thiols at low concentrations. In addition, chromanone A had influence on QR activity, while it resulted in a significant dose-dependent echancement mEH activity in Hepa1c1c7 cells. Therefore, chromanone A may act as an active tumoranti-initiating via modulation of carcinogen metabolizing enzymes and protection from DNA damage [A new chromone derivatives, 2-(hydroxymethyl)-8-methoxy-3-methyl-4H-chromen-4-one (chromanone A) (41) , was obtA damage .As previously reported endophytic fungi of marine origin have a promising therapeutic and biotechnological potential. Bioprospecting and the development of these products require sustainable processes that substantially increase the biomass of such microorganisms. Thus, marine biotechnology can contribute significantly to the production of these bioactive metabolites at various levels of the process, including obtaining, production, processing and development. However, biotechnological protocols applied to obtain bioactive metabolites of marine fungi are still quite deficient .Taxus brevifolia by the terrestrial endophytic fungus Taxomyces andrenae [The methods and technologies applied in marine fungal biotechnology derive largely from terrestrial fungi processes and rarely reflect the specific demands of fungi of marine origin . The mosandrenae ,76. The andrenae ,78.Aspergillus, Penicillium and Emericellopsis. Another example of using the dereplication technique can be observed in the work of El-Elimat et al. [In general, for the discovery of a new product with therapeutic, alimentary, cosmetic or biotechnological potential, a species of endophytic fungus is selected, its metabolites are extracted, it is carried out the screening for several activities (bioactivity-guided), process of isolation and the natural product is obtained in its pure form. This strategy of discovery is slow, tedious, intensely laborious and sometimes inefficient . Dereplit et al. , who anat et al. ,84,85,86Microascus brevicaulis revealed how the biotechnological fermentation process should be controlled in order to increase the production of anticancer compounds, scopularides A and B [Biotechnology can help to accelerate the discovery of natural products of endophytic fungi of marine origin . Silber  A and B .Aspergillus wentii EM-48, a fungus isolated from brown seaweed in order to increase the production of asperid A. Factors such as salinity, initial pH, temperature, culture time and addition of plant growth regulators were evaluated in the study cited. Zhou et al. [Halorosellinia sp. in bioreactor fermentation. Medium, culture pH, agitation speed, impeller type, inoculum level and dissolved oxygen were considered and systematically optimized, and an integrated nutrition and bioprocess strategy was established. The resulting 1403C production reached 2.07 g·L−1, which was 143.5% higher than the original production. Another study showed that the distribution of anticancer 1403C in the fermentation broth of the fungus Halorosellinia sp. was closely related to pH variations. The 1403C levels in the supernatant decreased while in mycelium increased with increasing pH. Thus, pH regulation was proposed and applied in order to accumulate the compound in the mycelium prior to broth extraction [One of the major challenges for those working with natural products, regardless of source is obtaining sufficient amounts of the metabolite of interest for drug development. Biotechnological approaches such as the production using full fermentative process can assist in obtaining these products. That is, large-scale cultivation (bioreactors) using different approaches to optimize culture media and induce increased production of target molecules are an alternative to this problem . Howeveru et al.  increasetraction .Penicillium chysogenum showed some consequences, like as, a decreasing in penicillin productions (1250 and 1500 rpm) and elevation in cell growth (100–900 rpm), besides restriction of oxygen in 700 rpm, however, this does not mean that it diminishes the production of other substances for the fungus P. chysogenum [In addition to the physical-chemical parameters that must be controlled, the morphology also influences the biosynthesis of the target product in filamentous fungi of marine origin. Filamentous fungi have the ability to grow in different morphological appearances, ranging from dispersed filaments to highly dense networks of mycelia (pellets). Therefore, depending on the morphology presented by the fungus under study, effects such as oxygenation and nutrient levels may alter the biosynthesis of these microorganisms. For example, it was observed that in higher speeds for the fungus ysogenum . These arac-camphor using whole cells of marine-derived fungus Botryosphaeria sp. isolated from marine alga Bostrychia radicans obtaining mainly (49%) 6-endo-hydroxycamphor and other products. These products are important for use in pharmaceutical formulations and these chemical modifications usually cannot be done by conventional organic synthesis.When the use of bioreactors cannot be carried out in an economically feasible manner and there is a structural chemical complexity limiting the synthesis of the product of interest, semi-synthetic processes offer an alternative pathway in the development of natural products derived from marine fungi . In the Halosarpheia sp. [Aspergillus terreus, emodin from A. nidulans, new cladochrome congener from Cladosporium cladosporides and nygerone A from A. niger [Glarea lozoyensis, led to the isolation of pneumocandin derivatives, such as caspofungin from the pneumocandin B0 pathway. The new substances obtained show more pharmacological properties which are important for drug discovery [Acremonium chrysogenum strains in the production of cephalosporin C [In addition to the biotechnological applications already described (bioreactors and semi-synthesis) for the production of bioactive compounds from marine fungi, there isalso the use of heterologous systems and genetic and metabolic engineering . For exaheia sp. . A revieA. niger . Anotheriscovery . In relasporin C .After the production process of the metabolites, for example in bioreactors, the next step in the development of a product of therapeutic interest by biotechnological procedures is “downstream processing” (DSP). This process comprises the steps of separating, disrupting, capturing and concentrating the cells, as well as extracting, purifying, refining, and obtaining the final product. Few authors report these DSP processes in fungal biotechnology, a classic example is the enzymatic treatment as part of the purification of cephalosporin ,108. TheAll procedures cited here to advancethe performance in the discovery, production, and procurement of a natural product from marine endophytic fungi need to be improved taking into account the ideal developmental conditions and particular characteristics of these microorganisms. Therefore, further studies related to fungal biotechnology should be carried out in order to obtain more information and improve the procedures for obtaining a quality final product.Marine fungi can grow on a wide variety of substrates such as wood, sediment, sand, mangroves, corals, shellfish, and marine invertebrates, on the surface and interior of algae. Among the fungi that live associated with macroalgae, endophytic fungi have a diversity of species and stand out as an extraordinary source of new bioactive compounds, as well as compounds known from other sources. Microorganisms have advantages such as the short growth cycle, easy preservation and control of cultivation conditions, besides perform strain through mutation breeding, genetic engineering, and other means. Therefore, it can significantly increase productivity and achieve industrial production. Consequently, studying seaweed-derived endophytic fungi to produce secondary metabolites has a very broad prospect on medical research and development.The incidence rate of cancer has been growing, due to the influence of the living environment and living habits and the increasing aging of the population. High costs, serious side-effects, and multidrug-resistance tumors accelerate the complexity and difficulty of cancer treatment. Thus, the increasing demand for anticancer drugs in the international market, the search for novel and effective molecules from endophytic fungi has become urgent. This review summarizes a total of 41  compound


Cellular mRNAs in plants and animals have a 5′-cap structure that is accepted as the recognition point to initiate translation by ribosomes. Consequently, it was long assumed that the translation initiation apparatus was built solely for a cap-dependent (CD) mechanism. Exceptions that emerged invoke structural damage (proteolytic cleavage) to eukaryotic initiation factor 4 (eIF4) factors that disable cap recognition. The residual eIF4 complex is thought to be crippled, but capable of cap-independent (CI) translation to recruit viral or death-associated mRNAs begrudgingly when cells are in great distress. However, situations where CI translation coexists with CD translation are now known. In such cases, CI translation is still a minor mechanism in the major background of CD synthesis. In this review, I propose that germ cells do not fit this mold. Using observations from various animal models of oogenesis and spermatogenesis, I suggest that CI translation is a robust partner to CD translation to carry out the translational control that is so prevalent in germ cell development. Evidence suggests that CI translation provides surveillance of germ cell homeostasis, while CD translation governs the regulated protein synthesis that ushers these meiotic cells through the remarkable steps in sperm/oocyte differentiation. Translation initiation independent of the mRNA cap recognition is a mechanism now broadly accepted in mammalian cells . HoweverQuite a number of cellular mRNAs, which are m7G-capped for stability, translate in a largely cap-independent fashion when the conditions present themselves . Such mRL: eIF4GI and eIF4GII), and one short form (4GS: p97/DAP5/NAT1); the latter lacks the binding site for eIF4E . Is. IsXenopnslation ,49,76,77 CI mRNA . In the  CI mRNA . Globin  mRNA [L B. This pibosomes . Cleavaggression . Conversgression ,83. ImpoL (cap-associating) and N-terminally truncated 4GL (non-cap-associating) can catalyze CI translation, and that the latter mimics 4GS [L and 4GS forms are found in all multicellular eukaryotes [It was recognized early that both 4Gmics 4GS . Naturalkaryotes ,84,85,86karyotes . Substankaryotes ,75,88,89karyotes . The unikaryotes ,93,94,95karyotes .C. elegans, the pathways for apoptosis [In the nematode worm poptosis , germ cepoptosis  and mRNApoptosis ,69 are epoptosis ,98,99. Ppoptosis .C. elegans encodes just one eIF4G gene, ifg-1, from which to make 4GL and 4GS. We discovered that worms transcribe two major mRNAs from the ifg-1 gene that independently encode a p170 isoform (4GL) that contains the N-terminal domain that binds each of five worm eIF4Es (IFEs 1-5), and a p130 (4GS) that lacks the eIF4E-binding domain [L by RNAi against p170 mRNA induces CI conditions and dramatically expands germ cell apoptosis with little effect on somatic growth [L-depleted conditions in vivo, while that of most other mRNAs was reduced [Not unexpectedly, mRNA translational control is a contributor to apoptosis which ensures homeostatic balance of the germ cell population. The activities of numerous RBPs are essential to stave off germ cell apoptosis. Some are involved in mRNA repression, like CPEB and PUF-8, or resident in mRNA storehouses, like P granule proteins PGL-1 and PGL-3 ,102,103.g domain . Selectic growth . Apoptot reduced .S and 4GL by RNAi stunts somatic growth and arrests larval development, precisely mimicking the arrest observed in an ifg-1 null mutant strain [per se, induces germ cell apoptosis. In situ metabolic labeling showed equivalent total protein synthesis activity in control and 4GL-depleted gonads that was uniform across surviving and apoptosing sibling germ cells (unpublished data). This observation, too, may suggest that neither the CD nor CI mechanism limits overall protein synthesis, but each works instead with subsets of mRNAs. Moreover, mutations in the worm Apaf-1 (ced-4) or caspase (ced-3) genes fully blocked the CI-induced germ cell apoptosis [L (p170) in vitro and in vivo [C. elegans germ cells share cytoplasm through syncytial connections, it remains to be determined how CI translation is locally maintained in only those cells destined to die (black circles). However, this must also be the case for other translational control events that act locally at mitotic and meiotic transitions in early germ cell development [By contrast, inhibition of all translation initiation would be expected to prevent both growth and development. Indeed, depletion of both 4Gt strain . The dispoptosis . Therefo in vivo  in identosis [L p0 in vitr in vivo ,19. The elopment .The balance between survival and apoptosis is also linked to the MAPK pathway ,107, whiGiven what is known about CI translational control, the underlying mechanism appears to be available, but not prominent, in somatic cells. We suggest that CI translation activity is more pronounced in germ cells. Maintaining a CD:CI balance that is closer to some critical threshold allows germ cells to use the “cell death”-like tendencies in two ways. The first is to govern homeostatic selection within the germ cell population to survive overt physiological apoptosis. The second is perhaps less obvious. There is significant use of apoptotic-like activities in spermatogenesis and oogenesis that are required, not for cell death, but for their normal maturation to gametes. The exercise of “apoptotic-like” destructive activities are critical for maturation of the surviving germ cells that differentiate. Spermatogenesis takes particularly broad advantage of these intracellular “culling” activities without killing the host cell.Drosophila spermatogenesis [Non-lethal use of death-promoting proteins is vital for reproductive strategies in many species. As anecdotal examples, apoptosis-unrelated roles for endonuclease G, Bcl-X and its family members, and numerous caspase-associated proteins are part of adaptive responses that take place during the dramatic differentiation of gametes . Expressogenesis . Apaf-1 ogenesis ,115,116.ogenesis , so it mogenesis . Interesogenesis . Snail hC. elegans, three in Xenopus, three in plants, three in zebrafish, and eight in Drosophila [Both eIF4E and eIF4G, which cooperate in CD translation, have been implicated in various cell fate decisions and even oncogenesis ,122,123.osophila ,137,138.Drosophila spermatocytes depleted of eIF4G2 show growth defects and accumulate the CDK inhibitor protein, RUX, likely as a growth checkpoint before meiotic division [Drosophila eIF4E regulates the translation of oskar mRNA, which is necessary for embryonic posterior patterning [Xenopus eIF4E1b was identified in an mRNP complex responsible for the suppression of meiotic maturation in early stage oocytes [The employment of genetics with biochemistry has helped to identify unique roles for eIF4E and eIF4G isoforms in reproduction. Both fly and mouse spermatocytes express sperm-specific eIF4Gs that have specialized roles ,124,139.division . Germ cedivision ,135,138.tterning ,140. Xen oocytes . This eI oocytes , furtherC. elegans development. Worms express five non-redundant isoforms from independent genes . At least three forms function in the germ line, and one exclusively in somatic cells [mex-1, oma-1, glp-1, gld-1, pos-1, pal-1, vab-1, rab-7, etc.), many of which encode proteins used for meiotic maturation or embryo differentiation [msh-4, msh-5) for meiotic chromosome segregation. Perhaps not surprisingly, eIF4E-1 and -2 localize differently in growing oocytes. eIF4E-1 joins large mRNPs (P granules) by binding to PGL-1, whereas eIF4E-2 is diffuse in oocyte cytoplasm [The utility of multiple eIF4E isoforms is most evident in ic cells . Studiesic cells ,142,143.ic cells ,144,145.ic cells . Withoutntiation ,144. Losntiation . As mighytoplasm ,131. eIFytoplasm ,143,146.ytoplasm ,114. We ytoplasm ).The recent epidemic of Zika virus infections that cause fetal microcephaly brings to light a potential crossroad for CI translation in germ cells, susceptibility to RNA viruses, and downstream embryonic development. The pathology observed in Zika-induced birth defects is attributed to neural tube malformation late in embryogenesis, but there is evidence that the virus may infect/accompany sperm or eggs . Zika isL-mRNA-RBP vs. eIF4GS-mRNA-RBP). But all such complexes will contribute in a combinatorial manner to mRNA recruitment potential for translation. Future studies to untangle these complexities in vivo will be facilitated by recent tools  together with versatile genetic animal models. We seem poised for molecular dissection of CD and CI translation to identify functional complexes (RNA and protein) and their roles in differentiation. This initiative bears some resemblance to emerging interest in CI vs. CD translation mechanisms in oncogenesis and cancer progression [There was previously little reason to consider roles for CD and CI initiation mechanisms in germ cells, which already possess a large repertoire of mRNA translational control events. And it is worth noting that the relevance of CI translation in vivo is still questioned . But recgression ,156,157.


Myxococcus xanthus, a bacterial model system widely used to study developmental biology and social evolution. In particular, we focus upon the isolation of myxophages from natural sources and describe the morphology and life cycle parameters, as well as the molecular genetics and genomics of the major groups of myxophages. Finally, we propose several interesting research directions which focus on the interplay between myxobacterial host sociality and bacteria–phage interactions.Bacteriophages have been used as molecular tools in fundamental biology investigations for decades. Beyond this, however, they play a crucial role in the eco-evolutionary dynamics of bacterial communities through their demographic impact and the source of genetic information they represent. The increasing interest in describing ecological and evolutionary aspects of bacteria–phage interactions has led to major insights into their fundamental characteristics, including arms race dynamics and acquired bacterial immunity. Here, we review knowledge on the phages of the myxobacteria with a major focus on phages infecting  As we b sources  to the mn nature . This enlus spp. , or the lus spp. .Myxococcus xanthus which “has become the Escherichia coli of Developmental Biology” [M. xanthus has also emerged as a model for the study of the fundamental parameters governing the evolution of multicellularity and cooperation in bacteria [M. xanthus isolates from nature [In this review, we will broadly summarize what is known about the bacteriophages of the myxobacteria, which are important model organisms for understanding the evolution of multicellularity and cooperation. Myxobacteria are a monophyletic clade within the delta-proteobacteria, and are highly diversified ,11 and gBiology” . Recentlbacteria ,24,25,26m nature ,28,29, am nature ,31,32 anm nature .In contrast to their bacterial hosts, very little is known about the myxophages. As is true for most bacterial systems, phages of the myxobacteria have been mainly used as molecular tools for strain construction to study host biology . For insIn our review, we first highlight the difficulties encountered in isolating and consistently naming myxophages, and propose a general naming scheme for both existing and novel myxophages. We then describe the main groups of myxophages, phage remnants, and prophages with regard to morphology, biology, and molecular genetics and genomics. Finally, we conclude this review by outlining several interesting research questions related to the interplay between myxobacterial host sociality and bacteria–phage interactions.M. xanthus myxophage (virulent phage “MX-1”) from cow dung, but failed to yield bacteriophages from soil, sewage, or water using classical isolation techniques [M. xanthus DZ1 [2+-ions were reported to increase resulting phage titers [l3 and Mx8l1) were discovered on plates of mutagen-treated cell cultures containing Mx4l6 [To study the genetic bases of phenotypic traits in myxobacteria, including their characteristic multicellular behaviors , severalchniques . It was thus DZ1 , while mthus DZ1 ; using Sthus DZ1 ). To chethus DZ1 ). In sumthus DZ1 ,41, (2) thus DZ1 , and/or thus DZ1 . As typie titers , and mite titers . Finallyng Mx4l6 . The autng Mx4l6 . Many ofng Mx4l6 . Such sang Mx4l6 , suggestng Mx4l6  such as M. xanthus) followed by a single digit which corresponds to the distinct serological type of the phage. The first phage ever to be described for a distinct serotype group  was then to be adopted as the general name of that group. For each subsequently isolated and characterized phage belonging to a previously characterized group, additional digits should be added, e.g., Mx4-like phages Mx41 and Mx43 were described in [Myxococcus strain from which they were isolated  or k for Karlsruhe (D), capped off by a set of running digits. Phage Mx1l3, for example, is the third phage of serotype group Mx1 isolated in Leeds M. xanthus are assigned Mx, and those of M. virescens should be named Mv. In some cases, ambiguity will arise due to identical initials. In such cases more letters should be used, e.g., Cfu and Cfe for Cystobacter fuscus and Cystobacter ferrugineus, respectively. If multiple host species are known, the myxophage name may refer to the original source host (if applicable), or arbitrarily to either of the host species if directly derived from environmental samples (such as soil).A phage found to infect a certain myxobacterial species is assigned letters composed of this initial host’s genus and species, respectively; e.g., phages found to infect (2)The letters are immediately followed by a distinct serotype category expressed as a running number. This will both help to account for existing phage names and also allow for an unlimited number of novel categories. As before, the first phage describing a novel serotype group is called the prototype-phage and is adopted as representative of that novel serogroup.(3)For non-prototype phages, the name is finally capped off by a running number separated by a dash from the main group in order of first description, e.g., novel phage isolates that are serologically classified as “Mx1-like” are labeled Mx1-1, Mx1-2, etc.In our opinion, the original nomenclature from 1976  is strail3, etc.).With this new naming convention, we also consider to appropriately rename already isolated myxophages, as summarized in Mx alpha; the sixth subsection highlights previously misclassified myxophages; and the seventh part lists phage remnants and bacteriocins encoded in the genomes of myxobacteria. Finally, we would like to highlight that we published an editable database for sharing and exchanging relevant information and resources within the bacteriophage community [In the following, we summarize knowledge about the main groups of myxophages  [Myxococcus. Phage Mx1 infects M. xanthus FBtan, M. virescens V2, and M. fulvus M upon which it forms clear plaques [M. fulvus MF [l3 is also capable of stably transducing different markers, including rifampicin resistance [The Mx1-like group  contains xanthus , as wellthus [l3  and a sethus [l3 . MorpholA1-group  with isoA1-group . Phage MA1-group . It has  of ~100 . The ads of ~100  and is i pH 7.6) . Host ce pH 7.6) . Mx1 is  pH 7.6) . All Mx1 plaques ,41,43, bulvus MF . It was sistance .l (Leeds) and k (Karlsruhe) [Myoviridae of the A1-group [M. xanthus mutants [hrm-1; originally derived and contributed by Wolfner (unpublished) and described in [ts27; reducing killing of transductants), a generalized transducing strain, Mx4 ts27htf-1hrm-1 [M. xanthus DZ1 and a burst size of 75 [Based on isolation success, the Mx4-like group  is the lrlsruhe) . Based oA1-group . Mx4-likA1-group ,45. ImpoA1-group . The hos mutants ,45, and ze of 75 . Mx4-likze of 75 .Podoviridae of subtype C1 [Salmonella phage P22 [M. xanthus strains sampled from soil [l1 was discovered on plates of mutagenized Mx4l6 [M. xanthus. Mx8 proved to be the most pivotal general transducing agent in the molecular genetic toolkit for myxobacterial research . Importrized in ; and lisM. xanthus strain sampled from soil [Salmonella phage P22 [Podoviridae of subtype C1 [attB sites (attB1 and attB2) in the M. xanthus host genome using a single phage-encoded gene, int [The Mx9-like group  is the srom soil . Mx9 is rom soil , but is hage P22 . It is abtype C1 , with a btype C1 , and intene, int .Mx alpha, has been detected in M. xanthus strain YS [Mx alpha has been found to be the causative agent of transmitting Tn5 transposon tags between different M. xanthus strains [Mx alpha prophage unit approximately covers about ~80 kilobase pairs (kbp) in the M. xanthus host genome, and that it is widespread among many different isolates, sometimes in multiple copies [Mx alpha phage heads are too small to carry the entire prophage’s genetic information of ~80 kb, it is assumed that entire units are transduced by multiple infections [Mx alpha copies in both M. xanthus FB and YS in a confined genomic region of ~300 kbp. However, several laboratory strains which together with YS are all derived from the same parent, FB [M. xanthus, only harbors a single unit, lacking around 222 kbp of that region [Mx alpha diagnostic marker [Mx alpha prophages (located between 2.1–2.25 megabase pairs (Mbp) of the M. xanthus DK1622 reference genome; [M. xanthus [Mx alpha to antagonistic social behavior among closely related Myxococcus laboratory strains [MXAN_1899 was singled out as a particularly interesting candidate gene based on short sequence homology to the CdiA C-terminal toxin domain [sitA3, has been shown to represent a toxin-immunity system involved in traA-dependent killing behavior among Myxococcus strains [Mx alpha unit, its parent, DK101, contains two additional Mx alpha units carrying sitA1 and sitA2 toxin-immunity systems, respectively [An endogenous myxophage, train YS ,57, a sitrain YS . Coincid strains . Such ge strains . Physicae copies . Since trent, FB , lack att region ,59. Anotc marker , which h genome; ) is amon xanthus . Crucial xanthus . This fi strains . Among tn domain . Recentl strains . Moreoveectively .Flavobacterium columnarae, the causative agent of columnaris disease in freshwater fish [Chondrococcus columnaris based on morphological criteria (summarized in [Chondrococcus columnaris are in fact not myxophages (even though they are labeled as such), i.e., “Myxophage” [At least two additional phages were initially described as bacteriophages of myxobacteria in the literature ,63. Theyter fish . Importarized in ), it is rized in . We therxophage”  and “MyxMyxococcus species that were phenotypically similar to myxophage Mx1 [M. virescens V2 were either completely lysed (in the case of Pseudomonas fluorescens 4b) or showed signs of cloudy plaque formation . The auand heat . Preparaand heat . Unlike and heat , xanthacand heat . Structuomycin C .Myxoccocus hosts . The lower estimate translates to a genome size of 163 kbp, when using T-even coliphage T2 as a measure [6 Daltons [6 Da, and given that Mx4 and Mx8 have comparable GC contents of ~68% [All known myxophages are linear double-stranded DNA viruses . While t xanthus ), virule xanthus ,68, and  xanthus ,69. The  xanthus ,47,51,68 measure . The gen Daltons ,47. It i Daltons ). This t of ~68% ,47, it f of ~68% ).attP in the phage genome [attB1 and attB2, situated in the host chromosome [attP is situated within the coding sequence of the integrase gene int  superinfection immunity, imm [uoi [mox [Beside the integrase gene ity, imm ,74; (2) imm [uoi ; and (3)uoi [mox , were prM. xanthus strains have been derived, of which Mx4 and Mx8 are the most widely used molecular tools [Since the late 1960s, more than 35 myxophages have been isolated, characterized, and classified into four main serological groups. Among these, several generalized transducing phages of ar tools . MoreoveM. xanthus is a model bacterium for the study of developmental biology and social evolution because most stages of its life cycle rely on cooperation  decrease phage sensitivity in M. xanthus [M. xanthus encode multiple CRISPR-Cas-systems [M. xanthus, two such CRISPR-Cas systems are involved in multicellular development [M. xanthus. Indeed, Mx1 phages have been shown to decrease germination success as they infect cells at the onset of spore formation. Here, the phage DNA is trapped in the spores and a fraction of infected spores releases phage progeny [M. xanthus genome for several cycles of host sporulation and germination despite the modification of gene expression between the different phases of the bacterial developmental cycle [peration . The isole cells ,76 and “le cells . While mle cells ,78, the ry group . While i xanthus . Importa-systems . These l-systems . In M. xelopment ,82,83, w progeny . Whetheral cycle . More ge


Breast cancer is the most frequent cause of cancer-related deaths among women worldwide. It is classified into four major molecular subtypes. Triple-negative breast cancers (TNBCs), a subgroup of breast cancer, are defined by the absence of estrogen and progesterone receptors and the lack of HER-2 expression; this subgroup accounts for ~15% of all breast cancers and exhibits the most aggressive metastatic behavior. Currently, very limited targeted therapies exist for the treatment of patients with TNBCs. On the other hand, it is important to highlight that knowledge of the molecular biology of breast cancer has recently changed the decision-making process regarding the course of cancer therapies. Thus, a number of new techniques, such as gene profiling and sequencing, proteomics, and microRNA analysis have been used to explore human breast carcinogenesis and metastasis including TNBC, which consequently could lead to new therapies. Nevertheless, based on evidence thus far, genomics profiles (gene and miRNA) can differ from one geographic location to another as well as in different ethnic groups. This review provides a comprehensive and updated information on the genomics profile alterations associated with TNBC pathogenesis associated with different ethnic backgrounds. Breast cancer is the most frequently diagnosed cancer in women worldwide . In 2012BRCA (BRCA1 and BRCA2) mutations [BRCA1/2 are autosomal dominant and tumor suppressor genes present on chromosomes 17 and 13, respectively, and are mutated in approximately 30–40% of familial BC cases [Various environmental factors contribute to a woman′s risk of developing breast cancer. Increasing age, menarche, high hormonal levels, null-parity, tobacco use, and obesity ,6,7,8,9 utations ,12,13. BBC cases .BRCA1/2, while others act through different pathways including TP53, PTEN, CHEK2, ATM and PALB2 [On the other hand, oncogenes and tumor suppressor genes are involved in the tumorigenesis of sporadic BC . While mnd PALB2 . MutatioHER-2/neu gene amplification [Various prognostic and predictive factors are studied in BC, including estrogen/progesterone receptors (ER/PR) status and fication ,22. Sterfication , howeverTP53 mutations. Genome-wide expression arrays of tumors demonstrated the tumor biology; range in patterns reflected the biological diversity [Gene expression profiling in BC started in the mid-1990s, this technique allowed classification of BC into subtypes via hierarchical clustering of several gene expression profiles of human breast tumors ,25,26. Biversity . Based oiversity . Furtheriversity . Howeveriversity .In this review, we will focus on the role of microarray molecular profiling (genes and microRNAs) as a prognostic, diagnostic as well as a therapeutic tool for the most aggressive BC phenotype in different ethnic groups, which is triple negative BC.Triple negative breast cancer (TNBC) is a subgroup of BC, representing 12–17% of all BCs . TNBCs hTNBCs have a higher prevalence in a distinct group or population ; for exaTP53, TOP-2A, Ki67, Cox-2 and heat shock protein 90 [Sub-classification of TNBCs have been attempted based on several biomarkers including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), c-kit and basal cytokeratins , otein 90 . Neverthotein 90 ,46,47, wotein 90 ,48. TNBCotein 90 .Systemic treatment for breast cancer includes the use of cytotoxic, hormonal, and immunotherapeutic agents. To date, cytotoxic chemotherapy is the only approved treatment option for TNBC ,50,51. SGenerally, breast cancer cells metastasize to the bone, liver, lung and brain . HoweverKnowledge of molecular biology in breast cancer has recently introduced new-targeted therapies using cDNA microarray, proteomics, next-generation sequencing (NGS) and miRNA technologies. Among the novel treatment agents for breast cancer are poly (ADP-ribose) polymerase (PARP) inhibitors, angiogenesis inhibitors, EGFR-targeted agents, and src kinase inhibitors . Other fThe following sections will present a comprehensive review about gene expression profiling performed on TNBC to identify potential biomarkers related to cancer progression and metastasis in TNBC patients.Microarray technologies have transformed research, allowing high-throughput whole-genome expression profiling and helped cancer scientists including oncologist to provide insight in a single assay about several diseases as well as create a molecular profile of tumor progression ,25.Although on a morphological level TNBC and basal-like breast cancer (BLBC) are comparatively similar in relation to large tumor size, high histologic grade, and substantial metastatic potential ,61, geneMolecular heterogeneity of TNBC has been recently well characterized at gene expression profiling level. An earlier investigation identified six molecular subtypes of TNBC including basal-like 1, basal-like 2, immunomodulatory, mesenchymal-like, mesenchymal stem-like, and luminal androgen receptor (LAR) subtype . NeverthATR, BRCA, Myc, NRAS), basal-like 2 subtype is characterized by high levels of EGFR, MET, EPHA2 and TP53 genes [Both basal-like subtypes  are affected by molecular alterations in cell-cycle, DNA machinery, cell proliferation, glycolysis and gluconeogenesis. These TNBC subtypes were found to be sensitive to cisplatin and PARP inhibitors. However, while, the basal-like 1 subtype displays elevated levels of Ki-67 as well as genes involved in cell division and DNA-damage . On the other hand, the mesenchymal stem-like subtype expresses genes involved in angiogenesis, growth factor pathways along with those regulating cellular proliferation and differentiation  [claudins-3,4,7; a characteristic similar to the claudin-low subtype [Gene expression profile of the other two subtypes  resemble the chemo-resistant metaplastic breast cancer. The mesenchymal subtype shows elevated levels of genes involved in EMT, cell motility, cellular proliferation and differentiation ( VEGFR2) . Moreove subtype . Further subtype .AR, FOXA1, KRT18, XBP1) [The last known subtype, luminal androgen receptor (LAR), is found to overlap with the molecular apocrine group (“molecular apocrine breast cancer”/MABC) and is enriched in genes regulating hormone signaling, in particular androgen signaling and synthesis  . This su8, XBP1) . However8, XBP1) .Research showed that the basal-like 2 subtype has worst survival, whereas, LAR has the best survival rates. Although, molecular subtypes of TNBC are associated with differences in survival and can potentially contribute in treatment selection, the association of patient race or ethnicity with subtypes of TNBC and clinical outcome still lie nascent. A recent study showed that more than half (53%) of Hispanic women had a significantly higher proportion of basal-like 2 subtype, whereas Asians had a lower proportion (19%) and a higher proportion of LAR (38%) compared to the average proportion across all groups . On the TP53 (80%), PIK3CA (9%), MLL3 (5%), AFF2 (4%), RB1 (4%), and PTEN (1%) [TP53 was the most frequently mutated gene. Moreover, clonal frequency analysis identified somatic mutations in TP53, PIK3CA and PTEN dominant in the majority of TNBCs [TP53 gene as the most commonly mutated gene (65–80%) in TNBC [TP53 resulted in enhanced metastasis and worse overall survival [TP53 can be a predictor of chemo-resistance in breast cancer [BRCA1/2; more than half of the hereditary TNBC cases (80%) carry mutation in BRCA1, while germ-line mutation in BRCA1 occurs in 15% of TNBC cases [BRCA1/2 function are sensitive to platinum derivatives as well as PARP inhibitors [The Cancer Genome Atlas Research Network (TCGA) used genomic DNA copy number arrays, exome sequencing, mRNA arrays and miRNA sequencing in 76 TNBC patients and identified several mutated genes, the most common being TEN (1%) . Whole gof TNBCs . Several in TNBC ,74; thes in TNBC . Researct cancer ,78 inclut cancer . The othTP53 %, PIK3CABC cases . Patienthibitors . Severalhibitors .PTEN gene, a negative regulator of the PI3K pathway [PTEN activates the mTOR pathway resulting in a high cellular proliferation leading to a more aggressive cancer phenotype and progression [PTEN occurred at high frequency in TNBC and was associated with poor prognosis [Recently, a tissue microarray study on African-American women displayed a significant link between TNBC and loss of  pathway . They algression . The sturognosis ; thus itrognosis .p53, BRCA1, Aurora A, Aurora B and polo-like kinase signaling networks in comparison with European women [BRCA1 mutations is relatively low in comparison with women of European descent [BRCA1 mutations. Similarly, less than 20% of African-American women had germline mutations in comparison with Caucasian non-Ashkenazi-Jewish women with TNBC who had at least 50% rate of germline BRCA1 mutations [Moreover, African-American women with breast cancer showed increased expression of an women ,86. Addi descent . Further descent ,88 and t descent  had highutations , thus, iutations ,90.INPP4B, a negative regulator of the PI3K pathway, was found to be lost in TNBC. Loss of INPP4B was linked with advanced tumor grade, larger tumor size, a loss of hormone receptors and aggressive tumors. Alterations in PIK3CA enhance the PI3K pathway and are present in around 10% of TNBC cases [INPP4B is a distinctive marker for human basal-like carcinoma and can be a potential candidate for treatment using PI3K pathway inhibitors [Furthermore, phosphatase BC cases . This dahibitors . Neverthhibitors . A phasehibitors . In addihibitors . Researchibitors . Moreovehibitors .IL32, PTX3, GATA3, TMEM158, ETS1 and MYBL1) in TNBC, which differentiated a subset of TNBC-25 (25 TNBC samples) from other TNBCs, as well as TNBC from normal-like, luminal A, luminal B and HER2 patient samples [PRKX/PRKY, UGT8, HMGA1, LPIN1, HAPLN3, FAM171A1, BCL141A, FOXC1 and ANKRD11) and 1 down-regulated gene (ANX9) involved in metabolism was discovered using microarray gene expression profiling, however, further research needs to be conducted in different populations and geographical areas [Another study identified six differentially expressed genes  involved in the onset of TNBC that could be developed as potential therapeutic targets [ADNP, AP2B1, TOMM70A and ZNF326 in nude mice, of which further research on ZNF326, showed that it regulated tumor cell growth through effects on RNA splicing, epithelial-mesenchymal transition, and cancer stem-cell self-renewal. This study identified novel tumor suppressors in TNBC that can be used as potential targets for therapeutic approach [Gene expression analysis along with pathway enrichment analysis identified pathways and genes  as well as genes involved in mitosis (ASPM and CENPK), which can be developed as molecular targets [ASPM, CENPK, MELK, NEK2, PBK genes play a role in tumorigenesis and cell cycle regulation; since they induce programmed cell death, therefore, they can be targeted as novel treatment in TNBCs [In a Japanese study conducted by Komatsu et al., DNA microarray identified 104 genes that were significantly over-expressed in TNBC and included cancer specific kinases  were identified using gene microarray to characterize TNBC [Anterior Gradient (AGR)-2 and -3 are involved in cellular migration, transformation, metastasis and apoptosis. While overexpression of AGR2 indicates bad prognosis, overexpression of AGR3 can be used as a serum-based biomarker for detecting cancer at early stages [COL4A2, BMF, DUSP1, FOXA1 and MLPH were identified as potential candidate gene targets in TNBCs [FCGR1A, RSAD2, CHRDL1 and the lncRNA species for HIF1A-AS2 and AK124454. They further demonstrated that HIF1A-AS2 and AK124454 enhanced cellular growth and invasion in TNBC cells and contributed to a paclitaxel resistance [EOMES, RASGRP1 and SOD2 were associated with better overall survival, while, loss of FA2H and GSPT1 were linked with better overall survival in TNBC [Furthermore, in China, potential biomarkers (ize TNBC . Anterioy stages . In anotin TNBCs . Anothersistance . Another in TNBC .PROM1 and KLK6) and seven downregulated  genes that could serve as plausible biomarkers [KRT18 is used to determine poor response to chemotherapy [Furthermore, based on a microarray study, other little-known genes in TNBC were identified; two upregulated  involved in cellular proliferation; CCNB1 displayed overexpression and was significantly associated with poor prognosis in TNBC [Bioinformatics analysis in TNBC showed the presence of genes , measures mRNA of 70 gene expressions as an assay with prognostic value in breast cancer patients. It has been validated for patients with stages I/II and negative or either one or three positive lymph nodes. This gene signature stratifies patients into low-and high-risk groups and identifies patients who can avoid adjuvant chemotherapy [® has been approved by the Food and Drug Administration (FDA) and has been recommended by several guidelines such as St. Gallen′s International Oncology Guidelines for the treatment of early stage breast cancer.On the other hand, the initial commercial gene expression signature of BC is MammaPrintotherapy ,124. Altotherapy . MammaPr® test  measures 21 gene-expressions (15 tested genes associated with breast cancer plus 6 reference genes). Oncotype DX® test analyzes genes associated with the ER status, proliferating genes, Her2-related genes as well as genes related to cancer invasion. This test provides information whether chemotherapy treatment will be beneficial [® test may also be utilized for ductal carcinoma in situ (DCIS), the most common form of non-invasive breast carcinoma. This test did not require the FDA approval but has been recommended by various authority bodies and guidelines [The Oncotype DXneficial , measureneficial . The Oncidelines .®, Stanford, CA, USA) is a 50-gene signature, with an algorithm for the intrinsic molecular classification of breast cancer. It was introduced to improve immunohistochemical and microarray classification. The PAM50 groups breast cancer patients into luminal A, luminal B, HER2 and basal-like [The Prediction Analysis of Microarray (PAM) algorithm to a 50-gene set , is another genomic test utilized for patients with newly diagnosed, early-stage (node negative), ER-positive and HER2-negative breast cancer. It includes 12 genes: Eight cancer related genes, three RNA reference genes and one DNA reference gene . EndoPreBreast Cancer Index  is based on the expression of five proliferation-related genes (molecular grade index (MGI)). It gives the 2-gene ratio HOXB13:IL17BR (H:I) in a linear model. The BCI was developed for the decision-making of adjuvant hormonal therapy in postmenopausal women with early stage, ER-positive BC .As indicated, the TNBC subtype is highly heterogeneous and its classification is routinely based on immunohistochemical biomarkers and limited gene signatures  ,57. AlthIn conclusion, it is evident that gene profiling of BC including TNBC in a specific population of different genetic background can play an important role in developing new biomarkers and gene targets for the management of different types of BC and especially TNBC . In addiIn parallel, it is important to highlight that microRNA profiling can also be essential in the development and management of BC and especially TBNC  which isMicroRNAs (miRNAs) belong to the class of small non-coding RNA, measuring around 25nt in length. miRNAs have distinct functions at the post-transcriptional level ,135. SinmiR-30 expression is associated with ER and PR expression while miR-213 and miR-203 expression are linked with tumor stage. In BC, loss of 29 miRNAs was identified when compared with normal breast tissues . ExperimA recent study on four ethnic groups identified differential expression of 9 miRNAs. In Nigerian patients, significantly higher levels of miR-140-5p, miR-194 and miR-423-5p were seen in BC compared with other ethnic groups . On the Various miRNAs were linked with EMT and the development of stem-cell properties. These miRNAs included upregulated expression of miR-10b, miR-21, miR-29, miR-9, miR-221/222, miR-373 as well as downregulated expression of miR-145, miR-199a-5p, miR-200 family, miR-203, miR-205 in TNBC ,144. In The miR-200 family including miR-200b, suppress cancer cell growth as well as EMT by targeting ZEB1/2, SIP1, BMI1 proteins and inhibiting PKCα ,149,150.Microarray analysis also revealed deregulation (loss) of miR-205 in cells that undergo EMT in TNBC in response to TGF-β ,156. MicPTEN, TIMP1, TIMP3, PDCD4 [Circulating miR-21 distinguished patients with loco-regional disease from those with metastases . miR-21 3, PDCD4  which in3, PDCD4 . In addi3, PDCD4 ,161.MAFB, CASR, PPP2R5C, SMAD5, LZTS1, MID1, MTCH2, ACVR1B, BMPR2, TGFBR1, IBSP, BGLAP, RUNX2 and, SP7 [Using qPCR, miR-190a, miR-136-5p, miR-126-5p, miR-135b-5p and miR-182-5p were linked with the pathogenesis of TNBC. MiR-190a plays a tumor-suppressor role preventing metastasis, growth and cell invasion by suppressing VEGF-mediated tumor angiogenesis . On the and, SP7 . MiR-34aand, SP7 ,165; losand, SP7  and miR-and, SP7  in TNBC A panel of several miRNAs were also significantly altered in TNBC, indicating their role as useful prognostic and therapeutic factors in TNBC ,169,170.ROR1; miR-30a is linked with higher histological grade and lymph node metastasis [MiRNA profiling by next-generation sequencing (NGS) in TNBCs revealed different expression patterns of miRNAs, of which three miRNAs  can be used to categorize cancers based on their proliferation, invasion and metastasis. Six miRNAs  were significantly related to decreased overall survival while 5 additional miRNAs  were associated with decreased relapse-free survival . Anothertastasis . Moreovetastasis . Deep setastasis . Genome-tastasis .eEF2K expression followed by the onset and progression of TNBC [SETBP1; indicating a tumor suppressive role of miR-211-5p in TNBC; [Lack of miR-603 resulted in high  of TNBC . Another of TNBC . Tissue  of TNBC . Using min TNBC; . While, in TNBC;  and miR-in TNBC;  were idein TNBC; .HOXD10 gene along with E-cadherin and Tiam1 [MYC amplification, higher tumor grade, as well as significant metastatic potential leading to poor outcome [SFPR1 leading to chemo-resistance and metastasis [Studies have also shown presence of upregulated miRNAs in TNBC. The miR-10 family (miR-10a and miR-10b) is involved in both the progression and metastasis of breast cancer . MiR-10bnd Tiam1 ,197,198.nd Tiam1  and stimnd Tiam1 . In TNBC outcome ,200. Mortastasis . MiR-221tastasis , miR-761tastasis  and miR-tastasis ,203,204 tastasis ,205. AmoPTEN expression in BC [miR-21 is the principal miRNA linked with migration and invasion of breast cancer cells and hence plays a critical role in tumor progression and metastasis ,207. A ron in BC , which ion in BC . Overexpon in BC . A recenon in BC .In summary, a large group of miRNAs has been reported to be implicated in TNBC initiation, progression and/or metastasis. These miRNAs can be differentiated based on their functional characterization in TNBC as tumor suppressors and oncogenes. They may also play both diagnostic and predictive roles. Therefore, we believe that miRNA represent as an important target in the management of BC including TNBCs, however, it is important to highlight that genetic backgrounds of different populations have to be carefully examined in order to identify specific miRNAs associated with populations of various ethnicities .Despite the array of miRNAs that have been suggested as plausible biomarkers, their use in clinical practice still remains nascent. One of the major reasons being the challenge in miRNA expression profiling; miRNAs are tiny molecules in which family members display a high degree of homology, and absolute miRNA concentrations in body fluids are relatively low . There aVarious miRNAs are validated in preclinical tests and are now under further clinical investigation. In 2013, The first miRNA replacement therapy with MRX34—a liposome-formulated miR-34 mimic was carried out. This study underwent human clinical trials for patients with advanced or metastatic liver cancer by intravenous injection . MoreoveIn BC, gene-expression-based-assays and the classification of patients have a robust clinical impact and help in individualized therapy and personalized cancer management . TherefoDifferential gene expression using microarray profiling on a subset of BC including TN from different geographical regions in comparison to a set of normal/benign breast tumors should be performed to further understand the underlying mechanisms of TNBCs.Numerous challenges hinder treatment of BC, particularly in TN subtype resulting in a high cancer mortality. Genetic markers of women from different ancestries that predispose them to TNBC have not been entirely elucidated. Therefore, biomarkers for TNBC prognosis of specific ethnicities are urgently needed since they can be used as predictive biomarkers as well as tools for targeted therapy in these populations. In short, discovering combined gene and miRNA signatures of TNBC in different populations and ethnicities could help identify new and specific gene targets for this subgroup of cancers and can be regarded as a fertile ground to accomplish a personalized medicine approach, which is the main objective of modern cancer treatment.