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Microorganisms have had a long and surprising history. They were “invisible” until invention of microscope in the 17th century. Until that date, although they were extensively (but inconsciously) employed in food preservation, beer and wine fermentation, cheese, vinegar, yogurt and bread making, as well as being the causative agents of infectious diseases, they were considered as “not-existing”. The work of Pasteur in the middle of the 19th century revealed several biological activities performed by microorganisms including fermentations and pathogenicity. Due to the urgent issue to treat infectious diseases (the main cause of death at those times) the “positive potential” of the microbial world has been neglected for about one century. Once the fight against the “evil” strains was fulfilled also thanks to the antibiotics, industry began to appreciate bacteria’s beneficial characteristics and exploit selected strains as starters for both food fermentations and aroma, enzyme and texturing agent production. However, it was only at the end of the 20th century that the probiotic potential of some bacteria such as lactic acid bacteria and bifidobacteria was fully recognized. Very recently, apart from the probiotic activity of in toto bacteria, attention has begun to be directed to the chemical mediators of the probiotic effect. Thanks also to the improvement of techniques such as transcriptomics, proteomics and metabolomics, several bioactive compounds are continuously being discovered. Bioactive molecules produced by bacteria, yeasts and virus-infected cells proved to be important for improving or impairing human health. The most important result of last years’ research concerns the discovery that a very complex network of signals allows communication between organisms (from intra-species interactions to inter-kingdom signaling). Based on these findings a completely new approach has arisen: the system biology standpoind. Actually, the different organisms colonizing a certain environmental niche are not merely interacting with each other as individuals but should be considered as a whole complex ecosystem continuously exchanging information at the molecular level. In this context, this topic issue explores both antagonistic compounds (i.e. antibiotics) and “multiple function” cooperative molecules improving the physiological status of both stimulators and targets of this network. From the applicative viewpoint, these molecules could be hopefully exploited to develop new pharmaceuticals and/or nutraceuticals for improving human health.

gut-brain axis --- antitumor activity --- immune-system modulation --- antibiotics --- human-microbes cross talk --- food-encrypted peptides --- Metagenomics --- Metabolomics --- Gut Microbiota

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Marine proteins and peptides have great potential application in developing pharmaceuticals, nutraceuticals, and cosmeceuticals. Proteins and peptides from marine sources are considered to be safe and inexpensive. Protein- and peptide-based drugs have been increasing in recent days to cure various diseases by serving multiple roles, such as antioxidants, anticancer drugs, antimicrobials, and anticoagulants. There are different marine sources (macroalgae, fish, shellfish, and bivalves), which possibly contain specific protein and peptides.

isolation process --- fish collagen --- fish gelatin --- antioxidant proteins and peptides --- anticancer proteins and peptides --- anticoagulant proteins and peptides --- antifreeze proteins and peptides --- antimicrobial protein and peptides --- antitumor proteins and peptides --- cardio protective proteins and peptides --- macro algae protein --- digestive enzymes --- antihypertensive proteins

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Carbonic anhydrases (CAs; EC 4.2.1.1) are metalloenzymes present in all kingdoms of life, as they equilibrate the reaction between three simple but essential chemical species: CO2, bicarbonate, and protons. Discovered more than 80 years ago, in 1933, these enzymes have been extensively investigated due to the biomedical application of their inhibitors, but also because they are an extraordinary example of convergent evolution, with seven genetically distinct CA families that evolved independently in Bacteria, Archaea, and Eukarya. CAs are also among the most efficient enzymes known in nature, due to the fact that the uncatalyzed hydration of CO2 is a very slow process and the physiological demands for its conversion to ionic, soluble species is very high. Inhibition of the CAs has pharmacological applications in many fields, such as antiglaucoma, anticonvulsant, antiobesity, and anticancer agents/diagnostic tools, but is also emerging for designing anti-infectives, i.e., antifungal, antibacterial, and antiprotozoan agents with a novel mechanism of action. Mitochondrial CAs are implicated in de novo lipogenesis, and thus selective inhibitors of such enzymes may be useful for the development of new antiobesity drugs. As tumor metabolism is diverse compared to that of normal cells, ultimately, relevant contributions on the role of the tumor-associated isoforms CA IX and XII in these phenomena have been published and the two isoforms have been validated as novel antitumor/antimetastatic drug targets, with antibodies and small-molecule inhibitors in various stages of clinical development. CAs also play a crucial role in other metabolic processes connected with urea biosynthesis, gluconeogenesis, and so on, since many carboxylation reactions catalyzed by acetyl-coenzyme A carboxylase or pyruvate carboxylase use bicarbonate, not CO2, as a substrate. In organisms other than mammals, e.g., plants, algae, and cyanobacteria, CAs are involved in photosynthesis, whereas in many parasites (fungi, protozoa), they are involved in the de novo synthesis of important metabolites (lipids, nucleic acids, etc.). The metabolic effects related to interference with CA activity, however, have been scarcely investigated. The present Special Issue of Metabolites aims to fill this gap by presenting the latest developments in the field of CAs and their role in metabolism.

tumor --- metabolism --- carbonic anhydrase --- isoforms IX and XII --- inhibitor --- sulfonamide --- antibody --- bacterial carbonic anhydrases --- inhibitors --- antibiotic --- CO2 capture --- engineered bacteria --- acidity --- hypoxia --- pH --- carbonic anhydrases --- V-ATPases --- proton pump inhibitors --- carbonic anhydrase inhibitors --- carbonic anhydrase IX --- cancer --- hypoxia --- radiation --- resistance --- tumors --- pH --- carbonic anhydrases --- metalloenzymes --- carbonic anhydrase IX --- carbonic anhydrase XII --- cancer therapeutics --- metabolism --- tumor microenvironment --- drug discovery --- hypoxia --- carbonic anhydrase IX --- cancer metabolism --- transporter --- integrin --- MMP14 --- migration --- invasion --- metastasis --- carbonic anhydrases --- CA gene family --- Chlamydomonas reinhardtii --- model alga --- metabolic role --- photosynthesis --- carbonic anhydrase --- hypoxic tumor --- metabolism --- carboxylation --- bicarbonate --- pH regulation --- antitumor agent --- sulfonamide --- bacterial enzymes --- carbonic anhydrase --- enzyme inhibition --- metalloenzymes --- amino acid --- glaucoma --- tumors --- carbonic anhydrase --- human isoform --- sulfonamide --- benzamide --- pathogens --- Entamoeba histolytica --- carbonic anhydrase --- metalloenzymes --- protozoan --- amine --- amino acid --- activator

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Many macro and micro species, from terrestrial and aquatic environments, produce structurally unique compounds and, in many countries, still are the primary sources of medicines. In fact, secondary metabolites are an important source of chemotherapeutic agents but are also lead compounds for synthetic modification and the optimization of biological activity. Therefore, the exploitation of secondary metabolites, or their inspired synthetic compounds, offers excellent opportunities for the pharmaceutical industry. This Medicines Special Issue focuses on the great potential of secondary metabolites for therapeutic application. The Special Issue contains 16 articles reporting relevant experimental results, and an overview of bioactive secondary metabolites, their biological effects, and new methodologies that improve and accelerate the process of obtained lead compounds with regard to new drug development. We would like to thank all 83 authors, from all over the world, for their valuable contributions to this Special Issue.

Juniperus --- secondary metabolites --- diterpenes --- flavonoids --- lignans --- cytotoxic --- antitumor --- antibacterial --- amentoflavone --- deoxypodophyllotoxin --- frankincense --- Boswellia --- cembranoids --- cneorubenoids --- boswellic acids --- molecular docking --- Scabiosa --- flavonoids --- iridoids --- pentacyclic triterpenoids --- antioxidant --- anti-inflammatory --- antibacterial --- anticancer --- Cordyceps militaris --- xanthine oxidase --- antioxidant --- antibacterial --- cordycepin --- GC-MS --- Artemisia species --- Artemisia vachanica --- artemisinin --- HPLC-PAD --- Tajikistan --- Malus x domestica --- Tuscany --- ancient varieties --- nutraceutics --- antioxidants --- polyphenols --- sugars --- pectin --- defensins --- secondary metabolites --- plant defense --- antimicrobial and anticancer activity --- medicine --- innate immunity --- cannabis --- cannabinoids --- therapeutics --- toxicology --- analytical determination --- legalization --- natural products --- biosynthetic gene clusters --- secondary metabolites --- antiSMASH --- Mitragyna speciosa --- kratom --- secondary metabolites --- therapeutic uses --- toxicology --- analysis --- Maytenus chiapensis --- Celastraceae --- quinonemethide triterpenoids --- pristimerin --- tingenone --- HPLC-PDA --- Ocimum sanctum --- Lamiaceae --- (-)-rabdosiin --- cytotoxic activity --- triterpenoids --- phenolic derivatives --- nanoemulsion --- essential oils --- vector control --- infectious diseases --- TCM --- phytochemistry --- LC-MS/MS --- antioxidant activity --- ABTS --- DPPH --- FRAP --- ascorbic acid --- EGCG --- total phenolics --- antimicrobial activity --- sargaquinoic acid --- sarganaphthoquinoic acid --- antiplasmodial --- malaria --- PPAR-? --- sargahydroquinoic acid --- sarganaphthoquinoic acid --- sargachromenoic acid --- inflammation --- bowel diseases --- secondary metabolites --- biological activities --- medicinal applications --- plants --- seaweeds

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Tissue fibrosis may occur for unknown causes or be the consequence of many pathological conditions including chronic inflammatory or infectious diseases, autoimmune disorders, graft rejection, or malignancy. On the other hand, malignant tumors have been identified in fibrotic tissues decades ago, and now accumulating evidence suggests that fibrotic lesions enhance the risk of cancer in several organs such as liver, lungs, and breast. Disruption of an organ parenchymal cells and of its normal structural scaffold during tissue fibrogenesis appears to induce loss of cell polarity, promoting uncontrolled cell proliferation that may eventually lead to cancer development. Many cellular and molecular abnormalities including aberrant expression of microRNAs, genetic and epigenetic alterations, evasion or delayed apoptosis, unregulated intracellular signal pathways, and dysregulation or defective intercellular communications have been proposed to explain this link between fibrogenesis and carcinogenesis. However, the precise mechanisms of this fibrosis-to-cancer transition remain unclear. This book presents a collection of reviews and original articles summarizing recent advances in understanding the molecular mechanisms of cancer development in fibrotic organs.

lung cancer --- renal injury --- fibrosis --- crizotinib --- anaplastic lymphoma kinase --- cystic formation --- pulmonary fibrosis --- butylidenephthalide --- SOX2 --- type I collagen --- bleomycin --- YAP --- TAZ --- Hippo pathway --- fibrosis --- cancer --- mechanotransduction --- TGF-? --- Wnt --- uterine fibroid --- leiomyoma --- tumor --- tumor necrosis factor ? --- cytokine --- growth factor --- inflammation --- clinical symptoms --- pathophysiology --- therapy --- hepatocellular carcinoma --- cirrhosis --- regeneration --- inflammation --- cytokines --- genetic instability --- reactive oxygen species --- idiopathic pulmonary fibrosis (IPF) --- lung cancer (LC) --- non-small cell lung cancer (NSCLC) --- acute lung injury --- protein S --- apoptosis --- signal pathway --- Erk1/2 --- lipopolysaccharide --- uterine fibroid --- leiomyoma --- smooth muscle tumor of uncertain malignant potential --- leiomyosarcoma --- myometrium --- immunohistochemistry --- marker --- pathology --- tumor --- diagnosis --- cancer-associated fibroblasts --- tumor microenvironment --- nanoparticles --- breast cancer --- antitumor efficacy --- cirrhosis --- HBV --- HCV --- hepatocellular carcinoma --- idiopathic pulmonary fibrosis --- lung cancer --- pathogenesis --- common pathways --- hepatocellular carcinoma (HCC) --- fibrosis --- cancer-associated fibroblasts (CAFs) --- hepatic stellate cells (HSCs) --- tumor microenvironment --- hepatocellular carcinoma --- non-alcoholic steatohepatitis --- fibrosis --- hepatic stellate cells --- extracellular matrix --- carcinogenesis --- angiogenesis --- cancer-associated fibroblasts --- extracellular matrix --- fibrosis --- heterogeneity --- interstitial fluid pressure --- metabolic reprogramming --- transforming growth factor-? --- tumor stiffness --- GPR40 --- GPR120 --- DHA --- omega-3 fatty acid --- SREBP-1 --- hepatocytes --- EMT --- lncRNA --- metastasis --- miRNA --- SMAD --- TGF-? --- targeted therapy --- tumor microenvironment --- n/a