1 620 268 BIOCHEMISTRY AND MOLECULAR BIOLOGY OF GELATINASE B OR MATRIX METALLOPROTEINASE-9 (MMP-9): THE NEXT DECADE. RESEARCH ON MATRIX METALLOPROTEINASES (MMPS) AND IN PARTICULAR ON GELATINASE B, ALIAS MMP-9, HAS GROWN EXPONENTIALLY IN THE DECADE 2003-2012. STRUCTURAL DETAILS ABOUT FLEXIBILITY OF MMP-9 MONOMERS, TOGETHER WITH GLYCOSYLATION, OLIGOMERIZATION, HETEROGENEITY AND INSTABILITY OF THE WILDTYPE ENZYME EXPLAIN WHY CRYSTALLOGRAPHY EXPERIMENTS HAVE NOT YET BEEN SUCCESSFUL FOR THE INTACT ENZYME. MMP-9 MAY BE VIEWED AS A MULTIDOMAIN ENZYME IN WHICH THE HEMOPEXIN, THE O-GLYCOSYLATED AND THE CATALYTIC DOMAINS YIELD SUPPORT FOR ATTACHMENT, ARTICULATION AND CATALYSIS, RESPECTIVELY. THE STEPWISE PROTEOLYTIC ACTIVATION OF THE INACTIVE ZYMOGEN INTO A CATALYTICALLY ACTIVE FORM BECOMES GRADUALLY BETTER UNDERSTOOD. PRIMING OF ACTIVATION BY MMP-3 MAY BE EXECUTED BY MEPRINS THAT DESTABILIZE THE INTERACTION OF THE AMINOTERMINUS WITH THE THIRD FIBRONECTIN REPEAT. ALTERNATIVELY, AUTOCATALYTIC ACTIVATION MAY OCCUR IN THE PRESENCE OF MOLECULES THAT TIGHTLY BIND TO THE CATALYTIC SITE AND THAT PUSH THE CYSTEIN RESIDUE IN THE PRODOMAIN AWAY FROM THE CATALYTIC ZINC ION. THANKS TO THE DEVELOPMENT OF DEGRADOMICS TECHNOLOGIES, SUBSTRATE REPERTOIRES OF MMP-9 HAVE BEEN DEFINED, BUT IT REMAINS A CHALLENGE TO DETERMINE AND PROVE WHICH SUBSTRATES ARE BIOLOGICALLY RELEVANT. THE SUBSTRATE REPERTOIRE HAS BEEN ENLARGED FROM EXTRACELLULAR TO MEMBRANE-BOUND AND EFFICIENT INTRACELLULAR SUBSTRATES, SUCH AS CRYSTALLINS, TUBULINS AND ACTINS. BIOLOGICAL STUDIES OF MMP-9 HAVE TUNED THE FIELD FROM BEING PRIMARILY CANCER-ORIENTED TOWARDS VASCULAR AND INFLAMMATORY RESEARCH. IN TUMOR BIOLOGY, IT HAS BEEN INCREASINGLY APPRECIATED THAT MMP-9 FROM INFLAMMATORY CELLS, PARTICULARLY NEUTROPHILS, CO-DETERMINES PROGNOSIS AND OUTCOME. ASIDE FROM THE CATALYTIC FUNCTIONS EXECUTED BY AMINOTERMINAL DOMAINS OF MMP-9, THE CARBOXYTERMINAL HEMOPEXIN (PEX) DOMAIN OF GELATINASE B EXERTS NON-CATALYTIC ANTI-APOPTOTIC SIGNALING EFFECTS. THE RECOGNITION THAT GELATINASE B IS INDUCED BY MANY PRO-INFLAMMATORY CYTOKINES, WHEREAS ITS INHIBITORS ARE INCREASED BY ANTI-INFLAMMATORY CYTOKINES, HAS GENERATED INTEREST TO TARGET MMP-9 IN ACUTE LETHAL CONDITIONS, SUCH AS BACTERIAL MENINGITIS, SEPSIS AND ENDOTOXIN SHOCK, AND IN ACUTE EXACERBATIONS OF CHRONIC DISEASES. PREVIOUSLY DESCRIBED TRANSCRIPTIONAL REGULATION OF MMP-9 IS COMPLEMENTED BY EPIGENETIC CHECKPOINTS, INCLUDING HISTONE MODIFICATIONS AND MICRORNAS. BECAUSE ACTIVATION OF PROMMP-9 MAY BE EXECUTED BY OTHER MMPS, THE THERAPEUTIC DOGMA THAT MMP INHIBITORS NEED TO BE HIGHLY SELECTIVE MAY BE KEYED DOWN FOR THE TREATMENT OF LIFE-THREATENING CONDITIONS. WHEN INFLAMMATION AND MMP-9 FULFILL BENEFICIAL FUNCTIONS TO CLEAR DAMAGING PROTEIN COMPLEXES, SUCH AS IN SYSTEMIC AUTOIMMUNE DISEASES, THERAPEUTIC MMP INHIBITION HAS TO BE AVOIDED. IN MMP9 GENE KNOCKOUT MICE, SPECIFIC SPONTANEOUS PHENOTYPES EMERGED WITH EFFECTS ON THE SKELETAL, REPRODUCTIVE AND NERVOUS SYSTEMS. THESE FINDINGS NOT ONLY HAVE CLINICAL CORRELATES IN BONE GROWTH AND FERTILITY, BUT ALSO STIMULATE RESEARCH ON THE ROLES OF MMPS AND MMP-9 IN ENDOCRINOLOGY, IMMUNOLOGY AND THE NEUROSCIENCES. MMP9-DEFICIENT MICE ARE VALUABLE TOOLS TO DEFINE MMP-9 SUBSTRATES IN VIVO AND TO STUDY THE ROLE OF THIS ENZYME IN ANIMAL MODELS OF INFLAMMATORY, VASCULAR, NEOPLASTIC AND DEGENERATIVE DISEASES. FUTURE CHALLENGES INCLUDE SOLVING THE CRYSTAL STRUCTURE, DEFINITION OF THE FUNCTIONS OF COVALENT OLIGOMERS AND HETEROMERS IN BIOLOGY AND PATHOLOGY, LIFE-IMAGING OF MMP-9 ACTIVITY, SUBSTRATE DETERMINATION IN SITU AND THE STUDY OF INHIBITOR EFFECTS ON FERTILITY, CANCER AND INFLAMMATION AND IN NEUROBIOLOGY AND REGENERATIVE MEDICINE. SUCH STUDIES WILL BETTER DEFINE CONDITIONS IN WHICH INHIBITION OF MMP-9 IS BENEFICIAL OR HAS TO BE AVOIDED. 2013 2 5078 61 PHYSIOLOGY AND PATHOPHYSIOLOGY OF MATRIX METALLOPROTEASES. MATRIX METALLOPROTEASES (MMPS) COMPRISE A FAMILY OF ENZYMES THAT CLEAVE PROTEIN SUBSTRATES BASED ON A CONSERVED MECHANISM INVOLVING ACTIVATION OF AN ACTIVE SITE-BOUND WATER MOLECULE BY A ZN(2+) ION. ALTHOUGH THE CATALYTIC DOMAIN OF MMPS IS STRUCTURALLY HIGHLY SIMILAR, THERE ARE MANY DIFFERENCES WITH RESPECT TO SUBSTRATE SPECIFICITY, CELLULAR AND TISSUE LOCALIZATION, MEMBRANE BINDING AND REGULATION THAT MAKE THIS A VERY VERSATILE FAMILY OF ENZYMES WITH A MULTITUDE OF PHYSIOLOGICAL FUNCTIONS, MANY OF WHICH ARE STILL NOT FULLY UNDERSTOOD. ESSENTIALLY, ALL MEMBERS OF THE MMP FAMILY HAVE BEEN LINKED TO DISEASE DEVELOPMENT, NOTABLY TO CANCER METASTASIS, CHRONIC INFLAMMATION AND THE ENSUING TISSUE DAMAGE AS WELL AS TO NEUROLOGICAL DISORDERS. THIS HAS STIMULATED A FLURRY OF STUDIES INTO MMP INHIBITORS AS THERAPEUTIC AGENTS, AS WELL AS INTO MEASURING MMP LEVELS AS DIAGNOSTIC OR PROGNOSTIC MARKERS. AS WITH MOST PROTEIN FAMILIES, DECIPHERING THE FUNCTION(S) OF MMPS IS DIFFICULT, AS THEY CAN MODIFY MANY PROTEINS. WHICH OF THESE REACTIONS ARE PHYSIOLOGICALLY OR PATHOPHYSIOLOGICALLY RELEVANT IS OFTEN NOT CLEAR, ALTHOUGH STUDIES ON KNOCKOUT ANIMALS, HUMAN GENETIC AND EPIGENETIC, AS WELL AS BIOCHEMICAL STUDIES USING NATURAL OR SYNTHETIC INHIBITORS HAVE PROVIDED INSIGHT TO A GREAT EXTENT. IN THIS REVIEW, WE WILL GIVE AN OVERVIEW OF 23 MEMBERS OF THE HUMAN MMP FAMILY AND DESCRIBE FUNCTIONS, LINKAGES TO DISEASE AND STRUCTURAL AND MECHANISTIC FEATURES. MMPS CAN BE GROUPED INTO SOLUBLE (INCLUDING MATRILYSINS) AND MEMBRANE-ANCHORED SPECIES. WE ADHERE TO THE 'MMP NOMENCLATURE' AND PROVIDE THE READER WITH REFERENCE TO THE MANY, OFTEN DIVERSE, NAMES FOR THIS ENZYME FAMILY IN THE INTRODUCTION. 2011 3 3348 48 HISTONE DEACETYLASES MEET MICRORNA-ASSOCIATED MMP-9 EXPRESSION REGULATION IN GLUCOCORTICOID-SENSITIVE AND -RESISTANT CELL LINES. GLUCOCORTICOIDS ARE LARGELY USED IN THE TREATMENT OF INFLAMMATORY PATHOLOGIES AND/OR HEMATOLOGICAL MALIGNANCIES AND REGULATE THE EXPRESSION OF A VARIETY OF GENES INVOLVED IN INFLAMMATION OR METASTASIS SUCH AS MATRIX METALLOPROTEINASES (MMP). LONG-TERM EXPOSURE TO GLUCOCORTICOIDS CAN RESULT IN FAILURE OF RESPONSIVENESS, WHICH IS OFTEN ASSOCIATED WITH AN UNWANTED GENE EXPRESSION. EPIGENETIC MECHANISMS ARE INVOLVED IN GENE EXPRESSION MODULATED AFTER DEVELOPMENT OF GLUCOCORTICOID RESISTANCE BUT HOW THESE MECHANISMS TAKE PLACE MUST BE FURTHER STUDIED. THE EFFECTS OF HDAC INHIBITORS (HDACI) IN A CONTEXT OF GLUCOCORTICOID RESISTANCE ARE STILL NOT WELL UNDERSTOOD AND NEED TO BE FURTHER INVESTIGATED. WE HYPOTHESIZED THAT ACQUIRED GLUCOCORTICOID RESISTANCE ASSOCIATED TO HDACI COULD DISTURBS EPIGENETIC LANDSCAPE, ESPECIALLY MIR EXPRESSION, LEADING TO A MODULATION OF MMP-9 GENE EXPRESSION AND/OR PROTEIN SECRETION, DESCRIBED AS LARGELY INVOLVED IN BONE REMODELING AND TUMOR INVASION IN MULTIPLE MYELOMA. TO THIS AIM, WE USED SENSITIVE RPMI-8226 CELL LINE AND ITS DEXAMETHASONE- AND METHYLPREDNISOLONE-RESISTANT DERIVATIVES. THE RESISTANT CELL LINES DISPLAYED AN 'OPEN CHROMATIN' AND AN MMP-9 OVEREXPRESSION COMPARATIVELY TO THE SENSITIVE CELL LINE. HDACI TREATMENT WITH MS-275 INCREASED EVEN MORE MMP-9 OVEREXPRESSION NOT ONLY AT AN MRNA LEVEL BUT ALSO AT THE PROTEIN LEVEL. WE SHOWED THAT MMP-9 EXPRESSION REGULATION WAS NOT DIRECTLY LINKED WITH HAT/HDAC BALANCE ALTERATIONS BUT RATHER WITH THE DEREGULATION OF MMP-9-TARGETING MIRS. THEN, WE FIRST DEMONSTRATED THAT MIR?149 DOWNREGULATION WAS DIRECTLY INVOLVED IN THE MMP-9 OVEREXPRESSION FOLLOWING A CHRONIC GLUCOCORTICOID EXPOSURE AND THAT MS-275 COULD AMPLIFY THIS OVEREXPRESSION BY INHIBITION OF MIR?149 EXPRESSION AND MIR?520C OVEREXPRESSION. TAKEN TOGETHER, THESE RESULTS INDICATE THAT THE USE OF HDACI IN A CONTEXT OF ACQUIRED GLUCOCORTICOID RESISTANCE COULD MODIFY THE EPIGENETIC LANDSCAPE, HIGHLIGHTING THE IMPORTANCE OF TAKING THE GLUCOCORTICOID RESPONSE STATUS INTO CONSIDERATION IN TREATMENT WITH HDACI. 2017 4 4738 47 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 5 1150 52 CONNECTION BETWEEN INFLAMMATION AND CARCINOGENESIS IN GASTROINTESTINAL TRACT: FOCUS ON TGF-BETA SIGNALING. INFLAMMATION IS A PRIMARY DEFENSE PROCESS AGAINST VARIOUS EXTRACELLULAR STIMULI, SUCH AS VIRUSES, PATHOGENS, FOODS, AND ENVIRONMENTAL POLLUTANTS. WHEN CELLS RESPOND TO STIMULI FOR SHORT PERIODS OF TIME, IT RESULTS IN ACUTE OR PHYSIOLOGICAL INFLAMMATION. HOWEVER, IF THE STIMULATION IS SUSTAINED FOR LONGER TIME OR A PATHOLOGICAL STATE OCCURS, IT IS KNOWN AS CHRONIC OR PATHOLOGICAL INFLAMMATION. SEVERAL STUDIES HAVE SHOWN THAT TUMORIGENESIS IN THE GASTROINTESTINAL (GI) TRACT IS CLOSELY ASSOCIATED WITH CHRONIC INFLAMMATION, FOR WHICH ABNORMAL CELLULAR ALTERATIONS THAT ACCOMPANY CHRONIC INFLAMMATION SUCH AS OXIDATIVE STRESSES, GENE MUTATIONS, EPIGENETIC CHANGES, AND INFLAMMATORY CYTOKINES, ARE SHARED WITH CARCINOGENIC PROCESSES, WHICH FORMS A CRITICAL CROSS-LINK BETWEEN CHRONIC INFLAMMATION AND CARCINOGENESIS. TRANSFORMING GROWTH FACTOR (TGF)-BETA IS A MULTI-POTENT CYTOKINE THAT PLAYS AN IMPORTANT ROLE IN REGULATION OF CELL GROWTH, APOPTOSIS AND DIFFERENTIATION. MOST IMPORTANTLY, TGF-BETA IS A STRONG ANTI-INFLAMMATORY CYTOKINE THAT REGULATES THE DEVELOPMENT OF EFFECTOR CELLS. TGF-BETA HAS A SUPPRESSIVE EFFECT ON CARCINOGENESIS UNDER NORMAL CONDITIONS BY INHIBITING ABNORMAL CELL GROWTH, BUT ON THE OTHER HAND, MANY GI CANCERS ORIGINATE FROM UNCONTROLLED CELL GROWTH AND DIFFERENTIATION BY GENETIC LOSS OF TGF-BETA SIGNALING MOLECULES OR PERTURBATION OF TGF-BETA ADAPTORS. ONCE A TUMOR HAS DEVELOPED, TGF-BETA EXERTS A PROMOTING EFFECT ON THE TUMOR ITSELF AND STROMAL CELLS TO ENHANCE CELL GROWTH, ALTER THE RESPONSIVENESS OF TUMOR CELLS TO STIMULATE INVASION AND METASTASIS, AND INHIBITED IMMUNE SURVEILLANCE. THEREFORE, NOVEL DEVELOPMENT OF THERAPEUTIC AGENTS TO INHIBIT TGF-BETA-INDUCED PROGRESSION OF TUMOR AND TO RETAIN ITS GROWTH INHIBITORY ACTIVITIES, IN ADDITION TO ANTI-INFLAMMATORY ACTIONS, COULD BE USEFUL IN ONCOLOGY. IN THIS REVIEW, WE DISCUSS THE ROLE OF TGF-BETA IN INFLAMMATION AND CARCINOGENESIS OF THE GI TRACT RELATED TO ABNORMAL TGF-BETA SIGNALING. 2010 6 4200 50 METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS: REGULATION AND DEFECTS IN HEALTH AND IN INFLAMMATORY DISEASES. THE IMMUNE SYSTEM PROTECTS FROM INFECTIONS AND CANCER THROUGH COMPLEX CELLULAR NETWORKS. FOR THIS PURPOSE, IMMUNE CELLS REQUIRE WELL-DEVELOPED MECHANISMS OF ENERGY GENERATION. HOWEVER, THE IMMUNE SYSTEM ITSELF CAN ALSO CAUSE DISEASES WHEN DEFECTIVE REGULATION RESULTS IN THE EMERGENCE OF AUTOREACTIVE LYMPHOCYTES. RECENT STUDIES PROVIDE INSIGHTS INTO HOW DIFFERENTIAL PATTERNS OF IMMUNE CELL RESPONSES ARE ASSOCIATED WITH SELECTIVE METABOLIC PATHWAYS. THIS REVIEW WILL EXAMINE THE CHANGING METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS AT DIFFERENT STAGES OF THEIR DEVELOPMENT AND ACTIVATION. BOTH CELLS PROVIDE PROTECTION BUT CAN ALSO MEDIATE DISEASES THROUGH THE PRODUCTION OF AUTOANTIBODIES AND THE PRODUCTION OF PROINFLAMMATORY MEDIATORS. IN HEALTH, B CELLS PRODUCE ANTIBODIES AND CYTOKINES AND PRESENT ANTIGENS TO T CELLS TO MOUNT SPECIFIC IMMUNITY. TH17 CELLS, ON THE OTHER HAND, PROVIDE PROTECTION AGAINST EXTRA CELLULAR PATHOGENS AT MUCOSAL SURFACES BUT CAN ALSO DRIVE CHRONIC INFLAMMATION. THE LATTER CELLS CAN ALSO PROMOTE THE DIFFERENTIATION OF B CELLS TO PLASMA CELLS TO PRODUCE MORE AUTOANTIBODIES. METABOLISM-REGULATED CHECKPOINTS AT DIFFERENT STAGES OF THEIR DEVELOPMENT ENSURE THE THAT SELF-REACTIVE B CELLS CLONES AND NEEDLESS PRODUCTION OF INTERLEUKIN (IL-)17 ARE LIMITED. THE METABOLIC REGULATION OF THE TWO CELL TYPES HAS SOME SIMILARITIES, E.G. THE UTILITY OF HYPOXIA INDUCED FACTOR (HIF)1ALPHA DURING LOW OXYGEN TENSION, TO PREVENT AUTOIMMUNITY AND REGULATE INFLAMMATION. THERE ARE ALSO CLEAR DIFFERENCES, AS TH17 CELLS ONLY ARE VULNERABLE TO THE LACK OF CERTAIN AMINO ACIDS. B CELLS, UNLIKE TH17 CELLS, ARE ALSO DEPENDENT OF MECHANISTIC TARGET OF RAPAMYCIN 2 (MTORC2) TO FUNCTION. SIGNIFICANT KNOWLEDGE HAS RECENTLY BEEN GAINED, PARTICULARLY ON TH17 CELLS, ON HOW METABOLISM REGULATES THESE CELLS THROUGH INFLUENCING THEIR EPIGENOME. METABOLIC DYSREGULATION OF TH17 CELLS AND B CELLS CAN LEAD TO CHRONIC INFLAMMATION. DISEASE ASSOCIATED ALTERATIONS IN THE GENOME CAN, IN ADDITION, CAUSE DYSREGULATION TO METABOLISM AND, THEREBY, RESULT IN EPIGENETIC ALTERATIONS IN THESE CELLS. RECENT STUDIES HIGHLIGHT HOW PATHOLOGY CAN RESULT FROM THE COOPERATION BETWEEN THE TWO CELL TYPES BUT ONLY FEW HAVE SO FAR ADDRESSED THE KEY METABOLIC ALTERATIONS IN SUCH SETTINGS. KNOWLEDGE OF THE IMPACT OF METABOLIC DYSFUNCTION ON CHRONIC INFLAMMATION AND PATHOLOGY CAN REVEAL NOVEL THERAPEUTIC TARGETS TO TREAT SUCH DISEASES. 2022 7 2303 41 EPIGENETIC REGULATION OF CANNABINOID-MEDIATED ATTENUATION OF INFLAMMATION AND ITS IMPACT ON THE USE OF CANNABINOIDS TO TREAT AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION IS CONSIDERED TO BE A SILENT KILLER BECAUSE IT IS THE UNDERLYING CAUSE OF A WIDE RANGE OF CLINICAL DISORDERS, FROM CARDIOVASCULAR TO NEUROLOGICAL DISEASES, AND FROM CANCER TO OBESITY. IN ADDITION, THERE ARE OVER 80 DIFFERENT TYPES OF DEBILITATING AUTOIMMUNE DISEASES FOR WHICH THERE ARE NO CURE. CURRENTLY, THE DRUGS THAT ARE AVAILABLE TO SUPPRESS CHRONIC INFLAMMATION ARE EITHER INEFFECTIVE OR OVERTLY SUPPRESS THE INFLAMMATION, THEREBY CAUSING INCREASED SUSCEPTIBILITY TO INFECTIONS AND CANCER. THUS, THE DEVELOPMENT OF A NEW CLASS OF DRUGS THAT CAN SUPPRESS CHRONIC INFLAMMATION IS IMPERATIVE. CANNABINOIDS ARE A GROUP OF COMPOUNDS PRODUCED IN THE BODY (ENDOCANNABINOIDS) OR FOUND IN CANNABIS (PHYTOCANNABINOIDS) THAT ACT THROUGH CANNABINOID RECEPTORS AND VARIOUS OTHER RECEPTORS EXPRESSED WIDELY IN THE BRAIN AND IMMUNE SYSTEM. IN THE LAST DECADE, CANNABINOIDS HAVE BEEN WELL ESTABLISHED EXPERIMENTALLY TO MEDIATE ANTI-INFLAMMATORY PROPERTIES. RESEARCH HAS SHOWN THAT THEY SUPPRESS INFLAMMATION THROUGH MULTIPLE PATHWAYS, INCLUDING APOPTOSIS AND INDUCING IMMUNOSUPPRESSIVE T REGULATORY CELLS (TREGS) AND MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS). INTERESTINGLY, CANNABINOIDS ALSO MEDIATE EPIGENETIC ALTERATIONS IN GENES THAT REGULATE INFLAMMATION. IN THE CURRENT REVIEW, WE HIGHLIGHT HOW THE EPIGENETIC MODULATIONS CAUSED BY CANNABINOIDS LEAD TO THE SUPPRESSION OF INFLAMMATION AND HELP IDENTIFY NOVEL PATHWAYS THAT CAN BE USED TO TARGET AUTOIMMUNE DISEASES. 2021 8 3921 47 LINKING INFLAMMATION TO CELL CYCLE PROGRESSION. RISK OF GASTROINTESTINAL CANCERS IS CLOSELY RELATED TO INCREASED LEVELS OF OXIDANTS IN THE BALANCE BETWEEN OXIDANT AND ANTI-OXIDANT AGENTS. A POSSIBLE EXPLANATION OF THIS EPIDEMIOLOGICAL OBSERVATION IS THE LOCAL LOSS OF THE EPITHELIAL BARRIER FUNCTION WITH A FOCAL INFLAMMATORY RESPONSE. ACCORDINGLY, CHRONIC INFLAMMATORY DISEASES REPRESENT WELL-KNOWN RISK FACTORS FOR CANCER AND, ON THE OTHER HAND, IT IS KNOWN THAT ANTI-INFLAMMATORY AGENTS, DEMULCENTS AND ANTIOXIDANTS MARKEDLY INHIBIT THE DEVELOPMENT OF COLON CANCER IN ANIMAL MODELS AS WELL IN HUMANS. AT MOLECULAR LEVEL A KEY ROLE IN THE PROCESS THAT LINK INFLAMMATION TO CELLULAR TRANSFORMATION SEEMS TO BE PLAYED BY ACTIVATION OF CYCLOOXYGENASE-2 (COX-2) TOGETHER WITH PRODUCTION OF REACTIVE OXYGEN INTERMEDIATE (ROI). BOTH THESE EVENTS HAVE BEEN STRICTLY LINKED WITH CELL PROLIFERATION AND TRANSFORMATION, ALTHOUGH THE INTRACELLULAR PATHWAYS INVOLVED IN THESE PROCESSES ARE STILL NOT COMPLETELY UNDERSTOOD. THE UNCONTROLLED PROLIFERATION, WHICH IS A LANDMARK OF CELLULAR TRANSFORMATION, IS ACCOMPANIED BY THE DEREGULATION OF PROTEINS INVOLVED IN THE CONTROL OF CELL CYCLE CHECKPOINTS. ALTERED EXPRESSION AND FUNCTION OF CYCLOOXYGENASE AND NITRIC OXIDE SYNTHASE SEEM TO INFLUENCE, AMONG OTHERS, THE EXPRESSION OF PROTEINS INVOLVED IN THE REGULATION OF CELL CYCLE PROGRESSION. SIMILARLY, ANTI-INFLAMMATORY AND ANTIOXIDANT AGENTS MAY ALSO ACT ON THE EXPRESSION AND FUNCTION OF SEVERAL CELL CYCLE REGULATING PROTEINS. UNDERSTANDING THE MECHANISMS BY WHICH CHRONIC INFLAMMATION CONTRIBUTES TO GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE REGULATION OF CRITICAL CELL CYCLE CHECKPOINTS MAY HELP TO DEVELOP MORE AND MORE SPECIFIC TREATMENT STRATEGIES FOR REDUCING MALIGNANT TRANSFORMATION OF THESE INFLAMMATORY DISEASES. 2004 9 4987 46 PATTERNS OF CALCIUM SIGNALING: A LINK BETWEEN CHRONIC EMOTIONS AND CANCER. INTRA AND INTER-CELLULAR CALCIUM SIGNALING IS PRESENT IN ALL TYPES OF CELLS AND BODY TISSUES. IN THE HUMAN BRAIN, CALCIUM CURRENTS AND WAVES ARE RELATED TO MENTAL ACTIVITIES, INCLUDING EMOTIONS. WE PRESENT A THEORETICAL INTERPRETATION OF THESE PHENOMENA SUGGESTING THEIR INVOLVEMENT IN CHRONIC EMOTIONAL PATTERNS AND IN THE PATHOLOGY OF CANCER. RECENT DEVELOPMENTS ON BIOPHYSICS, TRANSLATIONAL BIOLOGY AND PSYCHONEUROENDOCRINOIMMUNOLOGY (PNEI) CAN SUPPORT EXPLANATORY HYPOTHESES ABOUT THE LINK BETWEEN EMOTIONAL STRESSES AND THE ORIGIN AND DEVELOPMENT OF DIFFERENT TYPES OF TUMOR CELLS. CHRONIC STRESSES MAY CAUSE PERTURBATIONS OF RHYTHMS OF THE PNEI SYSTEM, EXCESSIVE ACTIVATION OF HPA AXIS AND ABNORMAL ACTIVATION OF CALCIUM SIGNALS IN SOMATIC TISSUES, WITH DELETERIOUS EFFECTS ON DIFFERENT PARTS OF THE BODY. THE INCREASING OF CALCIUM SIGNALING INSIDE CELLS MAY LEAD TO A DEREGULATION OF DIFFERENT PATHWAYS AND EPIGENETIC SYSTEMS THAT PROMOTE THE PRODUCTION OF GENOMIC MUTATIONS IN A SECOND PHASE. IN PARTICULAR, THE HYPERACTIVATION OF THE TRANSCRIPTION NUCLEAR FACTOR KAPPAB (NF-KAPPAB), IF IS NOT COUNTERBALANCED BY THE FOLLOWING ACTIVATION OF THE NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE 2 (NFE2L2 OR NRF2), INCREASES THE PRODUCTION OF OXIDATIVE CATABOLITES, AS THE ADVANCED GLYCATION END PRODUCTS (AGE), WHICH PLAY A KEY ROLE IN THE PROGRESSION OF DIFFERENT TYPES OF CANCER AND OTHER DEGENERATIVE DISEASES. CORTISOL BINDING TO GLUCOCORTICOID RECEPTOR (GR) REDUCES THE ACTIVITY OF BOTH NF-KAPPAB AND NRF2 INSIDE THE CELLS BUT INHIBITS THE CELLULAR IMMUNITY AND THE ANABOLIC PROCESSES OF TISSUE REGENERATION. THE TISSUE ATROPHY AND THE DEFECTIVE ANTI-AGEING MECHANISMS PROMOTES THE TUMORAL CELLS GROWTH AND THEIR ESCAPE FROM THE IMMUNE-SURVEILLANCE. 2017 10 5561 49 ROLE OF HISTONE DEACETYLASES IN MONOCYTE FUNCTION IN HEALTH AND CHRONIC INFLAMMATORY DISEASES. HISTONE DEACETYLASES (HDACS) ARE A FAMILY OF 18 MEMBERS THAT PARTICIPATE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION. IN ADDITION TO HISTONES, SOME HDACS ALSO DEACETYLATE TRANSCRIPTION FACTORS AND SPECIFIC CYTOPLASMIC PROTEINS.MONOCYTES, AS PART OF THE INNATE IMMUNE SYSTEM, MAINTAIN TISSUE HOMEOSTASIS AND HELP FIGHT INFECTIONS AND CANCER. IN THESE CELLS, HDACS ARE INVOLVED IN MULTIPLE PROCESSES INCLUDING PROLIFERATION, MIGRATION, DIFFERENTIATION, INFLAMMATORY RESPONSE, INFECTIONS, AND TUMORIGENESIS. HERE, A SYSTEMATIC DESCRIPTION OF THE ROLE THAT MOST HDACS PLAY IN THESE FUNCTIONS IS REVIEWED. SPECIFICALLY, SOME HDACS INDUCE A PRO-INFLAMMATORY RESPONSE AND PLAY MAJOR ROLES IN HOST DEFENSE. CONVERSELY, OTHER HDACS REPROGRAM MONOCYTES AND MACROPHAGES TOWARDS AN IMMUNOSUPPRESSIVE PHENOTYPE. THE RIGHT BALANCE BETWEEN BOTH TYPES HELPS MONOCYTES TO RESPOND CORRECTLY TO THE DIFFERENT PHYSIOLOGICAL/PATHOLOGICAL STIMULI. HOWEVER, ABERRANT EXPRESSIONS OR ACTIVITIES OF SPECIFIC HDACS ARE ASSOCIATED WITH AUTOIMMUNE DISEASES ALONG WITH OTHER CHRONIC INFLAMMATORY DISEASES, INFECTIONS, OR CANCER.THIS PAPER CRITICALLY REVIEWS THE INTERESTING AND EXTENSIVE KNOWLEDGE REGARDING THE ROLE OF SOME HDACS IN THESE PATHOLOGIES. IT ALSO SHOWS THAT AS YET, VERY LITTLE PROGRESS HAS BEEN MADE TOWARD THE GOAL OF FINDING EFFECTIVE HDAC-TARGETED THERAPIES. HOWEVER, GIVEN THEIR OBVIOUS POTENTIAL, WE CONCLUDE THAT IT IS WORTH THE EFFORT TO DEVELOP MONOCYTE-SPECIFIC DRUGS THAT SELECTIVELY TARGET HDAC SUBTYPES WITH THE AIM OF FINDING EFFECTIVE TREATMENTS FOR DISEASES IN WHICH OUR INNATE IMMUNE SYSTEM IS INVOLVED. 2021 11 45 36 A COMPREHENSIVE REVIEW ON RNA INTERFERENCE-MEDIATED TARGETING OF INTERLEUKINS AND ITS POTENTIAL THERAPEUTIC IMPLICATIONS IN COLON CANCER. COLON CANCER IS THE WORLD'S FOURTH LEADING CAUSE OF DEATH. IT IS CANCER OF THE LATTER PART OF THE LARGE INTESTINE, I.E. THE COLON. CHRONIC INFLAMMATION OVER A LONG PERIOD ALSO LEADS TO THE DEVELOPMENT OF CANCER. CANCER IN THE COLON REGION IS ARDUOUS TO DIAGNOSE AND IS DETECTED AT A LATER STAGE WHEN IT METASTASIZES TO OTHER PARTS OF THE BODY LIKE THE LIVER, LUNGS, PERITONEUM, ETC. COLON CANCER IS A GREAT EXAMPLE OF SOLID TUMOURS ASSOCIATED WITH CHRONIC INFLAMMATION. ALTHOUGH CONVENTIONAL THERAPIES ARE EFFECTIVE, THEY LOSE THEIR EFFECTIVENESS BEYOND A CERTAIN POINT. RELAPSE OF THE DISEASE OCCURS FREQUENTLY. RNA INTERFERENCE (RNAI) IS EMERGING AS A GREAT TOOL TO SPECIFICALLY ATTACK THE CANCER CELLS OF A TARGET SITE LIKE THE COLON. RNAI DEALS WITH EPIGENETIC CHANGES MADE IN THE DEFECTIVE CELLS WHICH ULTIMATELY LEADS TO THEIR DEATH WITHOUT HARMING THE HEALTHY CELLS. IN THIS REVIEW, TWO TYPES OF EPIGENETIC MODULATORS HAVE BEEN CONSIDERED, NAMELY SIRNA AND MIRNA, AND THEIR EFFECT ON INTERLEUKINS. INTERLEUKINS, A CLASS OF CYTOKINES, ARE MAJOR INFLAMMATORY RESPONSES OF THE BODY THAT ARE RELEASED BY IMMUNE CELLS LIKE LEUKOCYTES AND MACROPHAGES. SOME OF THESE INTERLEUKINS ARE PRO-INFLAMMATORY, THEREBY PROMOTING INFLAMMATION WHICH EVENTUALLY CAUSES CANCER. RNAI CAN PREVENT COLON CANCER BY INHIBITING PRO-INFLAMMATORY INTERLEUKINS. 2023 12 6394 59 THE ROLE OF THE HOST-NEUTROPHIL BIOLOGY. NEUTROPHILIC POLYMORPHONUCLEAR LEUKOCYTES (NEUTROPHILS) ARE MYELOID CELLS PACKED WITH LYSOSOMAL GRANULES (HENCE ALSO CALLED GRANULOCYTES) THAT CONTAIN A FORMIDABLE ANTIMICROBIAL ARSENAL. THEY ARE TERMINALLY DIFFERENTIATED CELLS THAT PLAY A CRITICAL ROLE IN ACUTE AND CHRONIC INFLAMMATION, AS WELL AS IN THE RESOLUTION OF INFLAMMATION AND WOUND HEALING. NEUTROPHILS EXPRESS A DENSE ARRAY OF SURFACE RECEPTORS FOR MULTIPLE LIGANDS, RANGING FROM INTEGRINS TO SUPPORT THEIR EGRESS FROM BONE MARROW INTO THE CIRCULATION AND FROM THE CIRCULATION INTO TISSUES, TO CYTOKINE/CHEMOKINE RECEPTORS THAT DRIVE THEIR NAVIGATION TO THE SITE OF INFECTION OR TISSUE DAMAGE AND ALSO PRIME THEM FOR A SECOND STIMULUS, TO PATTERN RECOGNITION RECEPTORS AND IMMUNOGLOBULIN RECEPTORS TO FACILITATE THE DESTRUCTION AND REMOVAL OF INFECTIVE AGENTS OR DEBRIDEMENT OF DAMAGED TISSUES. WHEN AFFERENT NEUTROPHIL SIGNALS ARE PROPORTIONATE AND COORDINATED THEY WILL PHAGOCYTOSE OPSONIZED AND UNOPSONIZED BACTERIA, ACTIVATING THE NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE (RESPIRATORY BURST) TO GENERATE REACTIVE OXYGEN SPECIES, WHICH AUGMENT THE PROTEOLYTIC DESTRUCTION OF MICROBES SECURED WITHIN THE PHAGOSOME. A HIGHLY ORCHESTRATED PROCESS OF APOPTOSIS FOLLOWS, FORMING MEMBRANE-BOUND SUBSTRUCTURES THAT ARE REMOVED BY MACROPHAGES. NEUTROPHILS ARE CAPABLE OF VARIOUS OTHER FORMS OF PROGRAMMED CELL DEATH, SUCH AS NETOSIS AND PYROPTOTIC CELL DEATH, AS WELL AS NONPROGRAMMED CELL DEATH BY NECROSIS. IN RECENT YEARS, RESEARCH HAS REVEALED THAT NEUTROPHILS ARE CAPABLE OF FAR MORE SUBTLE CELL-CELL INTERACTIONS THAN PREVIOUSLY THOUGHT POSSIBLE. THIS INCLUDES SYNTHESIS OF VARIOUS INFLAMMATORY MEDIATORS AND ALSO MYELOID CELL TRAINING WITHIN BONE MARROW, WHERE EPIGENETIC AND METABOLIC SIGNALS ASSOCIATED WITH RETURNING NEUTROPHILS THAT UNDERGO REVERSE EGRESS FROM TISSUES INTO THE VASCULATURE AND BACK TO BONE MARROW PROGRAM A HYPERREACTIVE SUBSET OF NEUTROPHILS DURING MYELOPOIESIS THAT ARE CAPABLE OF HYPERSENSITIVE REACTIONS TO MICROBIAL AGGRESSORS. THESE CHARACTERISTICS ARE EVIDENT IN VARIOUS NEUTROPHIL SUBSETS/SUBPOPULATIONS, CREATING BROAD HETEROGENEITY IN THE BEHAVIOR AND BIOLOGICAL REPERTOIRE OF THESE SEEMINGLY SCHIZOPHRENIC IMMUNE CELLS. MOREOVER, NEUTROPHILS ARE CRITICAL EFFECTOR CELLS OF ADAPTIVE AND INNATE IMMUNITY, BINDING TO OPSONIZED BACTERIA AND DESTROYING THEM BY EXTRACELLULAR AND INTRACELLULAR METHODS. THE FORMER CREATES SUBSTANTIAL COLLATERAL HOST TISSUE DAMAGE, AS THEY ARE LESS SPECIFIC THAN T-CYTOTOXIC CELL-KILLING MECHANISMS, AND IN CONDITIONS SUCH AS PERI-IMPLANTITIS, WHERE PLASMA CELLS AND NEUTROPHILS DOMINATE THE IMMUNE INFILTRATE, BONE AND TISSUE DESTRUCTION ARE RAPID AND APPEAR RELENTLESS. FINALLY, THE ROLE OF NEUTROPHILS AS CONDUITS FOR PERIODONTAL-SYSTEMIC DISEASE CONNECTIONS AND FOR OXIDATIVE DAMAGE TO ACT AS A CAUSAL LINK BETWEEN THE TWO HAS ONLY RECENTLY BEEN REALIZED. IN THIS CHAPTER, WE ATTEMPT TO EXPAND ON THESE ISSUES, EMPHASIZING THE CONTRIBUTIONS OF EUROPEAN SCIENTISTS THROUGHOUT A DETAILED APPRAISAL OF THE BENEFITS AND SIDE EFFECTS OF NEUTROPHILIC INFLAMMATION AND IMMUNE FUNCTION. 2023 13 3355 44 HISTONE EXTRACTION FROM HUMAN ARTICULAR CARTILAGE FOR THE STUDY OF EPIGENETIC REGULATION IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A CHRONIC DISEASE THAT AFFECTS ARTICULAR CARTILAGE, CAUSING ITS DEGENERATION. ALTHOUGH OA IS ONE OF THE MOST PREVALENT PATHOLOGIES GLOBALLY, THERE ARE NO DEFINITIVE TREATMENTS AVAILABLE. RECENTLY, RESEARCH HAS FOCUSED ON ELUCIDATING THE COMPLEX INTERPLAY THAT TAKES PLACE BETWEEN INFLAMMATORY PROCESSES AND EPIGENETIC REGULATION, SHOWING THAT HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS) CAN EXERT A PRONOUNCED EFFECT ON THE EXPRESSION OF OA-RELATED GENES. OA CHONDROCYTES ENHANCE THE PRODUCTION OF INTERLEUKIN 1BETA (IL-1BETA) AND INTERLEUKIN 8 (IL-8), WHICH ARE EPIGENETICALLY REGULATED. THESE CYTOKINES UPREGULATE THE SYNTHESIS OF MATRIX METALLOPROTEINASES (MMPS) AND AGGRECANASES, WHICH PROMOTE THE EXTRACELLULAR MATRIX (ECM) DESTRUCTION. THIS MOTIVATES THE STUDY OF HISTONE PTMS TO INVESTIGATE THE EPIGENETIC REGULATION OF PROINFLAMMATORY MOLECULES, BUT THE ABSENCE OF SPECIFIC PROTOCOLS TO EXTRACT HISTONES FROM HUMAN ARTICULAR CARTILAGE HAS COMPLICATED THIS TASK. THE LACK OF EFFECTIVE METHODS CAN BE EXPLAINED BY THE STRUCTURAL COMPLEXITY AND LOW CELLULARITY OF THIS TISSUE, WHICH ARE RESPONSIBLE FOR THE BIOMECHANICAL PROPERTIES THAT ALLOW THE MOVEMENT OF THE JOINT BUT ALSO COMPLICATE HISTONE ISOLATION. HERE, WE PROVIDE A HISTONE EXTRACTION PROCEDURE SPECIFICALLY ADAPTED FOR CRYOPRESERVED HUMAN ARTICULAR CARTILAGE THAT CAN BE USEFUL TO UNDERSTAND EPIGENETIC REGULATION IN OA AND ACCELERATE THE SEARCH FOR NOVEL STRATEGIES. 2022 14 6449 58 THERAPEUTIC TARGETING OF TELOMERASE. TELOMERE LENGTH AND CELL FUNCTION CAN BE PRESERVED BY THE HUMAN REVERSE TRANSCRIPTASE TELOMERASE (HTERT), WHICH SYNTHESIZES THE NEW TELOMERIC DNA FROM A RNA TEMPLATE, BUT IS NORMALLY RESTRICTED TO CELLS NEEDING A HIGH PROLIFERATIVE CAPACITY, SUCH AS STEM CELLS. CONSEQUENTLY, TELOMERASE-BASED THERAPIES TO ELONGATE SHORT TELOMERES ARE DEVELOPED, SOME OF WHICH HAVE SUCCESSFULLY REACHED THE STAGE I IN CLINICAL TRIALS. TELOMERASE IS ALSO PERMISSIVE FOR TUMORIGENESIS AND 90% OF ALL MALIGNANT TUMORS USE TELOMERASE TO OBTAIN IMMORTALITY. THUS, REVERSAL OF TELOMERASE UPREGULATION IN TUMOR CELLS IS A POTENTIAL STRATEGY TO TREAT CANCER. NATURAL AND SMALL-MOLECULE TELOMERASE INHIBITORS, IMMUNOTHERAPEUTIC APPROACHES, OLIGONUCLEOTIDE INHIBITORS, AND TELOMERASE-DIRECTED GENE THERAPY ARE USEFUL TREATMENT STRATEGIES. TELOMERASE IS MORE WIDELY EXPRESSED THAN ANY OTHER TUMOR MARKER. THE LOW EXPRESSION IN NORMAL TISSUES, TOGETHER WITH THE LONGER TELOMERES IN NORMAL STEM CELLS VERSUS CANCER CELLS, PROVIDES SOME DEGREE OF SPECIFICITY WITH LOW RISK OF TOXICITY. HOWEVER, LONG TERM TELOMERASE INHIBITION MAY ELICIT NEGATIVE EFFECTS IN HIGHLY-PROLIFERATIVE CELLS WHICH NEED TELOMERASE FOR SURVIVAL, AND IT MAY INTERFERE WITH TELOMERE-INDEPENDENT PHYSIOLOGICAL FUNCTIONS. MOREOVER, ONLY A FEW HTERT MOLECULES ARE REQUIRED TO OVERCOME SENESCENCE IN CANCER CELLS, AND TELOMERASE INHIBITION REQUIRES PROLIFERATING CELLS OVER A SUFFICIENT NUMBER OF POPULATION DOUBLINGS TO INDUCE TUMOR SUPPRESSIVE SENESCENCE. THESE LIMITATIONS MAY EXPLAIN THE MODERATE SUCCESS RATES IN MANY CLINICAL STUDIES. DESPITE EXTENSIVE STUDIES, ONLY ONE VACCINE AND ONE TELOMERASE ANTAGONIST ARE ROUTINELY USED IN CLINICAL WORK. FOR COMPLETE ERADICATION OF ALL SUBPOPULATIONS OF CANCER CELLS A SIMULTANEOUS TARGETING OF SEVERAL MECHANISMS WILL LIKELY BE NEEDED. POSSIBLE TECHNICAL IMPROVEMENTS HAVE BEEN PROPOSED INCLUDING THE DEVELOPMENT OF MORE SPECIFIC INHIBITORS, METHODS TO INCREASE THE EFFICACY OF VACCINATION METHODS, AND PERSONALIZED APPROACHES. TELOMERASE ACTIVATION AND CELL REJUVENATION IS SUCCESSFULLY USED IN REGENERATIVE MEDICINE FOR TISSUE ENGINEERING AND RECONSTRUCTIVE SURGERY. HOWEVER, THERE ARE ALSO A NUMBER OF PITFALLS IN THE TREATMENT WITH TELOMERASE ACTIVATING PROCEDURES FOR THE WHOLE ORGANISM AND FOR LONGER PERIODS OF TIME. EXTENDED CELL LIFESPAN MAY ACCUMULATE RARE GENETIC AND EPIGENETIC ABERRATIONS THAT CAN CONTRIBUTE TO MALIGNANT TRANSFORMATION. THEREFORE, NOVEL VECTOR SYSTEMS HAVE BEEN DEVELOPED FOR A 'MILD' INTEGRATION OF TELOMERASE INTO THE HOST GENOME AND LOSS OF THE VECTOR IN RAPIDLY-PROLIFERATING CELLS. IT IS CURRENTLY UNCLEAR IF THIS TECHNIQUE CAN ALSO BE USED IN HUMAN BEINGS TO TREAT CHRONIC DISEASES, SUCH AS ATHEROSCLEROSIS. 2016 15 6906 39 [THE ROLE OF GLYCANS IN CANCER DEVELOPMENT AND PROGRESSION. CLINICAL APPLICATIONS]. CHANGES IN GLYCOSYLATION PATTERN OF CELL SURFACE, BODY FLUIDS AND EXTRACELLULAR MATRIX GLYCOCONJUGATES IS A CHARACTERISTIC FEATURE OF TUMOR CELL MALIGNANCY. THESE CHANGES ARE THE RESULT OF MUTATIONS OF TUMOR-ASSOCIATED GENES AS WELL AS EPIGENETIC CHANGES IN THE TUMOR ENVIRONMENT, INCLUDING NUTRIENT INFLUX, HYPOXIA, CYTOKINE EXPRESSION AND STIMULATION OF CHRONIC INFLAMMATION. THE UNIQUE SET OF CELL SURFACE GLYCOANTIGENS ON NEOPLASTIC CELLS IS RECOGNIZED BY ENDOGENOUS LECTINS LOCATED IN THE EXTRACELLULAR MATRIX, VASCULAR ENDOTHELIUM, ON LEUKOCYTES OR PLATELETS, AND HAS AN IMPACT ON DISRUPTING BASIC CELLULAR PROCESSES, SUCH AS INTERCELLULAR RECOGNITION, CELL-CELL ADHESION OR CELL-ECM INTERACTION. THESE CHANGES HAVE A CRITICAL IMPACT ON THE MIGRATION, INVASIVE AND METASTATIC POTENTIAL OF NEOPLASTIC CELLS AND MODULATE THE IMMUNE RESPONSE. THIS UNIQUE PATTERN OF SUGAR ANTIGENS ON THE CANCER CELLS CAN BE A VAULABLE MARKER TO IDENTIFY THEM, DETERMINE THE STAGE OF THE DISEASE AS WELL AS BE A TARGET OF ANTI-CANCER THERAPY. 2021 16 3123 52 GETTING AN INSIGHT INTO THE COMPLEXITY OF MAJOR CHRONIC INFLAMMATORY AND DEGENERATIVE DISEASES: A POTENTIAL NEW SYSTEMIC APPROACH TO THEIR TREATMENT. AS THE MODERN SOCIETY IS TROUBLED BY MULTI-FACTORIAL DISEASES, RESEARCH HAS BEEN CONDUCTED ON COMPLEX REALITIES INCLUDING CHRONIC INFLAMMATION, CANCER, OBESITY, HIV INFECTION, METABOLIC SYNDROME AND ITS DETRIMENTAL CARDIOVASCULAR COMPLICATIONS AS WELL AS DEPRESSION AND OTHER BRAIN DISORDERS. DETERIORATION OF CRUCIAL HOMEOSTATIC MECHANISMS IN SUCH DISEASES INVARIABLY RESULTS IN ACTIVATION OF INFLAMMATORY MEDIATORS, CHRONIC INFLAMMATION, LOSS IN IMMUNOLOGICAL FUNCTION, INCREASED SUSCEPTIBILITY TO DISEASES, ALTERATION OF METABOLISM, DECREASE OF ENERGY PRODUCTION AND NEURO-COGNITIVE DECLINE. REGULATION OF GENES EXPRESSION BY EPIGENETIC CODE IS THE DOMINANT MECHANISM FOR THE TRANSDUCTION OF ENVIRONMENTAL INPUTS, SUCH AS STRESS AND INFLAMMATION TO LASTING PHYSIOLOGICAL CHANGES. ACUTE AND CHRONIC STRESS DETERMINES DNA METHYLATION AND HISTONE MODIFICATIONS IN BRAIN REGIONS WHICH MAY CONTRIBUTE TO NEURO-DEGENERATIVE DISORDERS. NUCLEAR GLUCOCORTICOIDS RECEPTOR INTERACTS WITH THE EPIGENOMA RESULTING IN A CORTISOL RESISTANCE STATUS ASSOCIATED WITH A DETERIORATION OF THE METABOLIC AND IMMUNE FUNCTIONS. GONADAL STEROIDS RECEPTORS HAVE A SIMILAR CAPACITY TO PRODUCE EPIGENOMIC REORGANIZATION OF CHROMATINE STRUCTURE. EPIGENOMIC-INDUCED REDUCTION IN IMMUNE CELLS TELOMERES LENGTH HAS BEEN OBSERVED IN MANY DEGENERATIVE DISEASES, INCLUDING ALL TYPES OF CANCER. THE FINAL RESULT OF THESE EPIGENETIC ALTERATIONS IS A SERIOUS DAMAGE TO THE NEURO-ENDOCRINE-IMMUNE-METABOLIC ADAPTIVE SYSTEMS. IN THIS STUDY, WE PROPOSE A TREATMENT WITH STEM CELLS DIFFERENTIATION STAGE FACTORS TAKEN FROM ZEBRAFISH EMBRYOS WHICH ARE ABLE TO REGULATE THE GENES EXPRESSION OF NORMAL AND PATHOLOGICAL STEM CELLS IN A DIFFERENT SPECIFIC WAY. 2015 17 2694 38 EVOLVING SPECTRUM OF DIABETIC WOUND: MECHANISTIC INSIGHTS AND THERAPEUTIC TARGETS. DIABETES MELLITUS IS A CHRONIC METABOLIC DISORDER RESULTING IN AN INCREASED BLOOD GLUCOSE LEVEL AND PROLONGED HYPERGLYCEMIA, CAUSES LONG TERM HEALTH CONSE-QUENCES. CHRONIC WOUND IS FREQUENTLY OCCURRING IN DIABETES PATIENTS DUE TO COMPROMISED WOUND HEALING CAPABILITY. MANAGEMENT OF WOUNDS IN DIABETIC PATIENTS REMAINS A CLINICAL CHALLENGE DESPITE MANY ADVANCEMENTS IN THE FIELD OF SCIENCE AND TECHNOLOGY. INCREASING EVIDENCE INDICATES THAT ALTERATION OF THE BIOCHEMICAL MILIEU RESULTING FROM ALTERATION IN INFLAMMATORY CYTOKINES AND MATRIX METALLOPROTEINASE, DECREASE IN FIBROBLAST AND KERATINOCYTE FUNCTIONING, NEUROPATHY, ALTERED LEUKOCYTE FUNCTIONING, INFECTION, ETC., PLAYS A SIGNIFICANT ROLE IN IMPAIRED WOUND HEALING IN DIABETIC PEOPLE. APART FROM THE CURRENT PHARMACOTHERAPY, DIFFERENT OTHER APPROACHES LIKE THE USE OF CONVENTIONAL DRUGS, ANTIDIABETIC MEDICATION, ANTIBIOTICS, DEBRIDEMENT, OFFLOADING, PLATELET-RICH PLASMA, GROWTH FACTOR, OXYGEN THERAPY, NEGATIVE PRESSURE WOUND THERAPY, LOW-LEVEL LASER, EXTRACORPOREAL SHOCK WAVE BIOENGINEERED SUBSTITUTE CAN BE CONSIDERED IN THE MANAGEMENT OF DIABETIC WOUNDS. DRUGS/THERAPEUTIC STRATEGY THAT INDUCE ANGIOGENESIS AND COLLAGEN SYNTHESIS, INHIBITION OF MMPS, REDUCTION OF OXIDATIVE STRESS, CONTROLLING HYPERGLYCEMIA, INCREASE GROWTH FACTORS, REGULATE INFLAMMATORY CYTOKINES, CAUSE NO INDUCTION, INDUCE FIBROBLAST AND KERATINOCYTE PROLIFERATION, CONTROL MICROBIAL INFECTIONS ARE CONSIDERED IMPORTANT IN CONTROLLING DIABETIC WOUND. FURTHER, MEDICINAL PLANTS AND/OR PHYTOCONSTITUENTS ALSO OFFER A VIABLE ALTERNATIVE IN THE TREATMENT OF DIABETIC WOUND. THE FOCUS OF THE PRESENT REVIEW IS TO HIGHLIGHT THE MOLECULAR AND CELLULAR MECHANISMS, AND DISCUSS THE DRUG TARGETS AND TREATMENT STRATEGIES INVOLVED IN THE DIABETIC WOUND. 2022 18 4773 41 NUCLEAR TRAFFICKING OF BACTERIAL EFFECTOR PROTEINS. BACTERIAL PATHOGENS CAN SUBVERT HOST RESPONSES BY PRODUCING EFFECTOR PROTEINS THAT DIRECTLY TARGET THE NUCLEUS OF EUKARYOTIC CELLS IN ANIMALS AND PLANTS. NUCLEAR-TARGETING PROTEINS ARE CATEGORISED AS EITHER: "NUCLEOMODULINS," WHICH HAVE EPIGENETIC-MODULATING ACTIVITIES; OR "CYCLOMODULINS," WHICH SPECIFICALLY INTERFERE WITH THE HOST CELL CYCLE. BACTERIA CAN DELIVER THESE EFFECTOR PROTEINS TO EUKARYOTIC CELLS VIA A RANGE OF STRATEGIES. DESPITE AN INCREASING NUMBER OF REPORTS DESCRIBING THE EFFECTS OF BACTERIAL EFFECTOR PROTEINS ON NUCLEAR PROCESSES IN HOST CELLS, THE INTRACELLULAR PATHWAYS USED BY THESE PROTEINS TO TRAFFIC TO THE NUCLEUS HAVE YET TO BE FULLY ELUCIDATED. THIS REVIEW WILL DESCRIBE CURRENT KNOWLEDGE ABOUT HOW NUCLEOMODULINS AND CYCLOMODULINS ENTER EUKARYOTIC CELLS, EXPLOIT ENDOCYTIC PATHWAYS AND TRANSLOCATE TO THE NUCLEUS. WE WILL ALSO DISCUSS THE SECRETION OF NUCLEAR-TARGETING PROTEINS OR THEIR RELEASE IN BACTERIAL MEMBRANE VESICLES AND THE TRAFFICKING PATHWAYS EMPLOYED BY EACH OF THESE FORMS. BESIDES THEIR IMPORTANCE FOR BACTERIAL PATHOGENESIS, SOME NUCLEAR-TARGETING PROTEINS HAVE BEEN IMPLICATED IN THE DEVELOPMENT OF CHRONIC DISEASES AND EVEN CANCER. A GREATER UNDERSTANDING OF NUCLEAR-TARGETING PROTEINS AND THEIR ACTIONS WILL PROVIDE NEW INSIGHTS INTO THE PATHOGENESIS OF INFECTIOUS DISEASES, AS WELL AS CONTRIBUTE TO ADVANCES IN THE DEVELOPMENT OF NOVEL THERAPIES AGAINST BACTERIAL INFECTIONS AND POSSIBLY CANCER. 2021 19 834 45 CHEMICAL BIOLOGY OF LYSINE DEMETHYLASES. ABNORMAL LEVELS OF DNA METHYLATION AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. METHYLATION OF LYSINES WITHIN HISTONE TAILS IS A KEY MODIFICATION THAT CONTRIBUTES TO INCREASED GENE EXPRESSION OR REPRESSION DEPENDING ON THE SPECIFIC RESIDUE AND DEGREE OF METHYLATION, WHICH IS IN TURN CONTROLLED BY THE INTERPLAY OF LYSINE METHYL TRANSFERASES AND DEMETHYLASES. DRUGS THAT TARGET THESE AND OTHER ENZYMES CONTROLLING CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS ACTING ON DOWNSTREAM BIOCHEMICAL PATHWAYS THAT ARE SUSCEPTIBLE TO DEGENERACY. LYSINE DEMETHYLASES, FIRST DISCOVERED IN 2004, ARE THE SUBJECT OF INCREASING INTEREST AS THERAPEUTIC TARGETS. THIS REVIEW PROVIDES AN OVERVIEW OF RECENT FINDINGS IMPLICATING LYSINE DEMETHYLASES IN A RANGE OF THERAPEUTIC AREAS INCLUDING ONCOLOGY, IMMUNOINFLAMMATION, METABOLIC DISORDERS, NEUROSCIENCE, VIROLOGY AND REGENERATIVE MEDICINE, TOGETHER WITH A SUMMARY OF RECENT ADVANCES IN STRUCTURAL BIOLOGY AND SMALL MOLECULE INHIBITOR DISCOVERY, SUPPORTING THE TRACTABILITY OF THE PROTEIN FAMILY FOR THE DEVELOPMENT OF SELECTIVE DRUGLIKE INHIBITORS. 2011 20 6395 44 THE ROLE OF THE MEDIATORS OF INFLAMMATION IN CANCER DEVELOPMENT. EPIGENETIC DISORDERS SUCH AS POINT MUTATIONS IN CELLULAR TUMOR SUPPRESSOR GENES, DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS ARE NEEDED TO TRANSFORMATION OF NORMAL CELLS INTO CANCER CELLS. THESE EVENTS RESULT IN ALTERATIONS IN CRITICAL PATHWAYS RESPONSIBLE FOR MAINTAINING THE NORMAL CELLULAR HOMEOSTASIS, TRIGGERING TO AN INFLAMMATORY RESPONSE WHICH CAN LEAD THE DEVELOPMENT OF CANCER. THE INFLAMMATORY RESPONSE IS A UNIVERSAL DEFENSE MECHANISM ACTIVATED IN RESPONSE TO AN INJURY TISSUE, OF ANY NATURE, THAT INVOLVES BOTH INNATE AND ADAPTIVE IMMUNE RESPONSES, THROUGH THE COLLECTIVE ACTION OF A VARIETY OF SOLUBLE MEDIATORS. MANY INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN SEVERAL TYPES OF CANCER, LINKING CHRONIC INFLAMMATION TO TUMORIGENESIS PROCESS. THUS, INFLAMMATORY RESPONSES PLAY DECISIVE ROLES AT DIFFERENT STAGES OF TUMOR DEVELOPMENT, INCLUDING INITIATION, PROMOTION, GROWTH, INVASION, AND METASTASIS, AFFECTING ALSO THE IMMUNE SURVEILLANCE. IMMUNE CELLS THAT INFILTRATE TUMORS ENGAGE IN AN EXTENSIVE AND DYNAMIC CROSSTALK WITH CANCER CELLS, AND SOME OF THE MOLECULAR EVENTS THAT MEDIATE THIS DIALOG HAVE BEEN REVEALED. A RANGE OF INFLAMMATION MEDIATORS, INCLUDING CYTOKINES, CHEMOKINES, FREE RADICALS, PROSTAGLANDINS, GROWTH AND TRANSCRIPTION FACTORS, MICRORNAS, AND ENZYMES AS, CYCLOOXYGENASE AND MATRIX METALLOPROTEINASE, COLLECTIVELY ACTS TO CREATE A FAVORABLE MICROENVIRONMENT FOR THE DEVELOPMENT OF TUMORS. IN THIS REVIEW ARE PRESENTED THE MAIN MEDIATORS OF THE INFLAMMATORY RESPONSE AND DISCUSSED THE LIKELY MECHANISMS THROUGH WHICH, THEY INTERACT WITH EACH OTHER TO CREATE A CONDITION FAVORABLE TO DEVELOPMENT OF CANCER. 2015