1 4583 68 N6-METHYLADENINE RNA METHYLATION EPIGENETIC MODIFICATION AND KIDNEY DISEASES. RNA METHYLATION MODIFICATION IS A RAPIDLY DEVELOPING FIELD IN EPIGENETICS. N6-METHYLADENSINE (M(6)A) IS THE MOST COMMON INTERNAL MODIFICATION IN EUKARYOTIC MRNA. M(6)A GROUP REGULATES RNA SPLICING, STABILITY, TRANSLOCATION, AND TRANSLATION. ENZYMES CATALYZING THIS PROCESS WERE TERMED AS WRITERS, ERASERS, AND READERS. RECENT STUDIES HAVE FOCUSED ON EXPLORING THE ROLE OF RNA METHYLATION IN HUMAN DISEASES. RNA METHYLATION MODIFICATIONS, PARTICULARLY M(6)A, PLAY IMPORTANT ROLES IN THE PATHOGENESIS OF KIDNEY DISEASES. IN THIS REVIEW, WE PROVIDE A BRIEF DESCRIPTION OF M(6)A AND SUMMARIZE THE IMPACT OF M(6)A ON ACUTE AND CHRONIC KIDNEY DISEASE (CKD) AND POSSIBLE FUTURE STUDY DIRECTIONS FOR THIS RESEARCH. 2023 2 1720 37 DYSREGULATED N6-METHYLADENOSINE (M(6)A) PROCESSING IN HEPATOCELLULAR CARCINOMA. N6-METHYLADENOSINE (M(6)A) IS THE MOST THOROUGHLY STUDIED TYPE OF INTERNAL RNA MODIFICATION, AS THIS EPIGENETIC MODIFICATION IS THE MOST ABUNDANT IN EUKARYOTIC RNAS TO DATE. THIS MODIFICATION OCCURS IN VARIOUS TYPES OF RNAS AND PLAYS SIGNIFICANT ROLES IN DOMINANT RNA-RELATED PROCESSES, SUCH AS TRANSLATION, SPLICING, EXPORT AND DEGRADATION. THESE PROCESSES ARE CATALYZED BY THREE TYPES OF PROMINENT ENZYMES: WRITERS, ERASERS AND READERS. INCREASING EVIDENCE HAS SHOWN THAT M(6)A MODIFICATION IS VITAL FOR THE REGULATION OF GENE EXPRESSION, CARCINOGENESIS, TUMOR PROGRESSION AND OTHER ABNORMAL CHANGES, AND RECENT STUDIES HAVE SHOWN THAT M(6)A IS IMPORTANT IN THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). HEREIN, WE SUMMARIZE THE NATURE AND REGULATORY MECHANISMS OF M(6)A MODIFICATION, INCLUDING ITS ROLE IN THE PATHOGENESIS OF HCC AND RELATED CHRONIC LIVER DISEASES. WE ALSO HIGHLIGHT THE CLINICAL SIGNIFICANCE AND FUTURE STRATEGIES INVOLVING RNA M(6)A MODIFICATIONS IN HCC. 2021 3 6144 27 THE EVOLVING LANDSCAPE OF N(6)-METHYLADENOSINE MODIFICATION IN THE TUMOR MICROENVIRONMENT. THE TUMOR MICROENVIRONMENT (TME), CONTROLLED BY INTRINSIC MECHANISMS OF CARCINOGENESIS AND EPIGENETIC MODIFICATIONS, HAS, IN RECENT YEARS, BECOME A HEAVILY RESEARCHED TOPIC. THE TME CAN BE DESCRIBED IN TERMS OF HYPOXIA, METABOLIC DYSREGULATION, IMMUNE ESCAPE, AND CHRONIC INFLAMMATION. RNA METHYLATION, AN EPIGENETIC MODIFICATION, HAS RECENTLY BEEN FOUND TO HAVE A PIVOTAL ROLE IN SHAPING THE TME. THE N(6)-METHYLATION OF ADENOSINE (M(6)A) MODIFICATION IS THE MOST COMMON TYPE OF RNA METHYLATION THAT OCCURS IN THE N(6)-POSITION OF ADENOSINE, WHICH IS THE PRIMARY INTERNAL MODIFICATION OF EUKARYOTIC MRNA. COMPELLING EVIDENCE HAS DEMONSTRATED THAT M(6)A REGULATES TRANSCRIPTIONAL AND PROTEIN EXPRESSION THROUGH SPLICING, TRANSLATION, DEGRADATION, AND EXPORT, THEREBY MEDIATING THE BIOLOGICAL PROCESSES OF CANCER CELLS AND/OR STROMAL CELLS AND CHARACTERIZING THE TME. THE TME ALSO HAS A CRUCIAL ROLE IN THE COMPLICATED REGULATORY NETWORK OF M(6)A MODIFICATIONS AND, SUBSEQUENTLY, INFLUENCES TUMOR INITIATION, PROGRESSION, AND THERAPY RESPONSES. IN THIS REVIEW, WE DESCRIBE THE FEATURES OF THE TME AND HOW THE M(6)A MODIFICATION MODULATES AND INTERACTS WITH IT. WE ALSO FOCUS ON VARIOUS FACTORS AND PATHWAYS INVOLVED IN M(6)A METHYLATION. FINALLY, WE DISCUSS POTENTIAL THERAPEUTIC STRATEGIES AND PROGNOSTIC BIOMARKERS WITH RESPECT TO THE TME AND M(6)A MODIFICATION. 2021 4 4034 21 M6A METHYLATION PROMOTES WHITE-TO-BEIGE FAT TRANSITION BY FACILITATING HIF1A TRANSLATION. OBESITY MAINLY RESULTS FROM A CHRONIC ENERGY IMBALANCE. PROMOTING BROWNING OF WHITE ADIPOCYTES IS A PROMISING STRATEGY TO ENHANCE ENERGY EXPENDITURE AND COMBAT OBESITY. N6-METHYLADENOSINE (M6A), THE MOST ABUNDANT MRNA MODIFICATION IN EUKARYOTES, PLAYS AN IMPORTANT ROLE IN REGULATING ADIPOGENESIS. HOWEVER, WHETHER M6A REGULATES WHITE ADIPOCYTE BROWNING WAS UNKNOWN. HERE, WE REPORT THAT ADIPOSE TISSUE-SPECIFIC DELETION OF FTO, AN M6A DEMETHYLASE, PREDISPOSES MICE TO PREVENT HIGH-FAT DIET (HFD)-INDUCED OBESITY BY ENHANCING ENERGY EXPENDITURE. ADDITIONALLY, DELETION OF FTO IN VITRO PROMOTES THERMOGENESIS AND WHITE-TO-BEIGE ADIPOCYTE TRANSITION. MECHANISTICALLY, FTO DEFICIENCY INCREASES THE M6A LEVEL OF HIF1A MRNA, WHICH IS RECOGNIZED BY M6A-BINDING PROTEIN YTHDC2, FACILITATING MRNA TRANSLATION AND INCREASING HIF1A PROTEIN ABUNDANCE. HIF1A ACTIVATES THE TRANSCRIPTION OF THERMOGENIC GENES, INCLUDING PPAGGC1A, PRDM16, AND PPARG, THEREBY PROMOTING UCP1 EXPRESSION AND THE BROWNING PROCESS. COLLECTIVELY, THESE RESULTS UNVEIL AN EPIGENETIC MECHANISM BY WHICH M6A-FACILITATED HIF1A EXPRESSION CONTROLS BROWNING OF WHITE ADIPOCYTES AND THERMOGENESIS, PROVIDING A POTENTIAL TARGET TO COUNTERACT OBESITY AND METABOLIC DISEASE. 2021 5 4033 23 M6A HYPOMETHYLATION OF DNMT3B REGULATED BY ALKBH5 PROMOTES INTERVERTEBRAL DISC DEGENERATION VIA E4F1 DEFICIENCY. BACKGROUND: THE INTERVERTEBRAL DISC (IVD) DEGENERATION IS THE LEADING CAUSE OF LOW BACK PAIN, WHICH ACCOUNTS FOR A MAIN CAUSE OF DISABILITY. N6-METHYLADENOSINE (M6A) IS THE MOST ABUNDANT INTERNAL MODIFICATION IN EUKARYOTIC MESSENGER RNAS AND IS INVOLVED IN VARIOUS DISEASES AND CELLULAR PROCESSES BY MODULATING MRNA FATE. HOWEVER, THE CRITICAL ROLE OF M6A REGULATION IN IVD DEGENERATION REMAINS UNCLEAR. NUCLEUS PULPOSUS CELL (NPC) SENESCENCE IS CRITICAL FOR THE PROGRESSION OF IVD DEGENERATION. HERE, WE UNCOVERED THE ROLE AND EXPLORED THE REGULATORY MECHANISM OF M6A IN NPC SENESCENCE DURING IVD DEGENERATION. METHODS: IDENTIFICATION OF NPC SENESCENCE DURING IVD DEGENERATION WAS BASED ON THE ANALYSIS OF TISSUE SAMPLES AND THE CELLULAR MODEL. ALKBH5 UPREGULATION INDUCING CELLULAR SENESCENCE WAS CONFIRMED BY FUNCTIONAL EXPERIMENTS IN VIVO AND IN VITRO. CHIP-QPCR AND DNA-PULLDOWN WERE USED TO REVEAL INCREASED ALKBH5 WAS REGULATED BY KDM4A-MEDIATED H3K9ME3. FURTHERMORE, ME-RIP-SEQ WAS PERFORMED TO IDENTIFY M6A HYPOMETHYLATION OF DNMT3B TRANSCRIPTS IN SENESCENT NPCS. STABILITY ANALYSIS SHOWED THAT DNMT3B EXPRESSION WAS ENHANCED FOR LESS YTHDF2 RECOGNITION AND INCREASED DNMT3B PROMOTED NPC SENESCENCE AND IVD DEGENERATION VIA E4F1 METHYLATION BY IN VIVO AND IN VITRO ANALYSES. RESULTS: EXPRESSION OF ALKBH5 IS ENHANCED DURING IVD DEGENERATION AND NPC SENESCENCE, DUE TO DECREASED KDM4A-MEDIATED H3K9ME3 MODIFICATION. FUNCTIONALLY, ALKBH5 CAUSES NPC SENESCENCE BY DEMETHYLATING DNMT3B TRANSCRIPTS AND IN TURN PROMOTING ITS EXPRESSION VIA LESS YTHDF2 RECOGNITION AND FOLLOWING DEGRADATION DUE TO TRANSCRIPT HYPOMETHYLATION IN VITRO AND IN VIVO. INCREASED DNMT3B PROMOTES THE DEVELOPMENT OF IVD DEGENERATION AND NPC SENESCENCE, MECHANISTICALLY BY METHYLATING CPG ISLANDS OF E4F1 AT THE PROMOTER REGION AND THUS RESTRAINING ITS TRANSCRIPTION AND EXPRESSION. CONCLUSIONS: COLLECTIVELY, OUR FINDINGS REVEAL AN EPIGENETIC INTERPLAY MECHANISM IN NPC SENESCENCE AND IVD DEGENERATION, PRESENTING A CRITICAL PRO-SENESCENCE ROLE OF ALKBH5 AND M6A HYPOMETHYLATION, HIGHLIGHTING THE THERAPEUTIC POTENTIAL OF TARGETING THE M6A/DNMT3B/E4F1 AXIS FOR TREATING IVD DEGENERATION. 2022 6 6881 29 [RESEARCH PROGRESS OF M6A METHYLATION MODIFICATION IN HEMATOLOGICAL TUMORS--REVIEW]. N6-METHYLADENOSINE (M6A) IS ONE OF THE MOST COMMON EPIGENETIC MODIFICATIONS OF EUKARYOTIC MRNAS, WHICH IS INVOLVED IN THE REGULATION OF GENE EXPRESSIONS AND BIOLOGICAL PROCESSES IN A VARIETY OF CELLS WITH DYNAMIC AND REVERSIBLE METHYLATION PROCESSES. IN RECENT YEARS, MANY STUDIES HAVE SHOWN THAT M6A METHYLATION MODIFICATION NOT ONLY ACTS ON THE GROWTH, PROLIFERATION, AND MEDULLARY DIFFERENTIATION OF ACUTE MYELOID LEUKEMIA CELLS, BUT ALSO PARTICIPATES IN THE REGULATION OF THE PROLIFERATION AND APOPTOSIS OF OTHER HEMATOLOGICAL TUMOR CELLS SUCH AS CHRONIC MYELOID LEUKEMIA AND DIFFUSE LARGE B-CELL LYMPHOMA, AND IT CAN EVEN WEAKEN THE EFFICACY OF ANTI-HEMATOLOGICAL TUMOR IMMUNOTHERAPY AND INDUCE IMMUNE ESCAPE LEADING TO TUMOR RESISTANCE. WITH THE SUCCESSIVE DEVELOPMENT OF A VARIETY OF M6A METHYLATION-RELATED ENZYME INHIBITORS, IT WILL PROVIDE NEW THERAPEUTIC IDEAS FOR PATIENTS WITH RELAPSED AND REFRACTORY HEMATOLOGICAL TUMORS. IN THIS PAPER, WE REVIEW THE RESEARCH PROGRESS ON THE MECHANISM OF M6A METHYLATION ON THE OCCURRENCE, DEVELOPMENT, AND TUMOR IMMUNITY OF VARIOUS HEMATOLOGICAL TUMORS. 2022 7 4773 22 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 8 2821 17 FINE-TUNING AUTOPHAGY: FROM TRANSCRIPTIONAL TO POSTTRANSLATIONAL REGULATION. MACROAUTOPHAGY (HEREAFTER CALLED AUTOPHAGY) IS A VACUOLAR LYSOSOMAL PATHWAY FOR DEGRADATION OF INTRACELLULAR MATERIAL IN EUKARYOTIC CELLS. AUTOPHAGY PLAYS CRUCIAL ROLES IN TISSUE HOMEOSTASIS, IN ADAPTATION TO STRESS SITUATIONS, AND IN IMMUNE AND INFLAMMATORY RESPONSES. ALTERATION OF AUTOPHAGY IS ASSOCIATED WITH CANCER, DIABETES AND OBESITY, CARDIOVASCULAR DISEASE, NEURODEGENERATIVE DISEASE, AUTOIMMUNE DISEASE, INFECTION, AND CHRONIC INFLAMMATORY DISEASE. AUTOPHAGY IS CONTROLLED BY AUTOPHAGY-RELATED (ATG) PROTEINS THAT ACT IN A COORDINATED MANNER TO BUILD UP THE INITIAL AUTOPHAGIC VACUOLE NAMED THE AUTOPHAGOSOME. IT IS NOW KNOWN THAT THE ACTIVITIES OF ATG PROTEINS ARE MODULATED BY POSTTRANSLATIONAL MODIFICATIONS SUCH AS PHOSPHORYLATION, UBIQUITINATION, AND ACETYLATION. MOREOVER, TRANSCRIPTIONAL AND EPIGENETIC CONTROLS ARE INVOLVED IN THE REGULATION OF AUTOPHAGY IN STRESS SITUATIONS. HERE WE SUMMARIZE AND DISCUSS HOW POSTTRANSLATIONAL MODIFICATIONS AND TRANSCRIPTIONAL AND EPIGENETIC CONTROLS REGULATE THE INVOLVEMENT OF AUTOPHAGY IN THE PROTEOSTASIS NETWORK. 2016 9 1838 22 EFFECTS OF POLYPHENOLS ON NCRNAS IN CANCER-AN UPDATE. IN RECENT YEARS, ONCOTHERAPY HAS RECEIVED CONSIDERABLE ATTENTION CONCERNING PLANT POLYPHENOLS. INCREASING EVIDENCE SUGGESTS THAT BECAUSE OF THE EFFICIENCY OF POLYPHENOLS, THEY MAY HAVE ANTI-TUMOUR EFFECTS IN VARIOUS CANCERS. HOWEVER, THEIR REGULATORY STRUCTURES REMAIN ELUSIVE. LONG NON-CODING RNAS (LNCRNAS) HAVE BEEN IDENTIFIED IN THE REGULATION OF VARIOUS FORMS OF TUMORIGENESIS AND TUMOUR DEVELOPMENT. LONG NON-CODING RNAS HAVE RECENTLY EMERGED AS REGULATORY EUKARYOTIC TRANSCRIPTS AND THERAPEUTIC TARGETS WITH IMPORTANT AND DIVERSE FUNCTIONS IN HEALTH AND DISEASES. LNCRNAS MAY BE ASSOCIATED WITH THE INITIATION, DEVELOPMENT, AND PROGRESSION OF CANCER. THIS REVIEW SUMMARIZES THE RESEARCH ON THE MODULATORY EFFECTS OF INCRNAS AND THEIR ROLES IN MEDIATING CELLULAR PROCESSES. THE MECHANISMS OF ACTION OF POLYPHENOLS UNDERLYING THEIR THERAPEUTIC EFFECTS ON CANCERS ARE ALSO DISCUSSED. BASED ON OUR REVIEW, POLYPHENOLS MIGHT FACILITATE A SIGNIFICANT EPIGENETIC MODIFICATION AS PART OF THEIR TISSUE- AND/OR CELL-RELATED BIOLOGICAL EFFECTS. THIS FINDING MAY BE ATTRIBUTED TO THEIR INTERACTION WITH CELLULAR SIGNALLING PATHWAYS INVOLVED IN CHRONIC DISEASES. CERTAIN LNCRNAS MIGHT BE THE TARGET OF SPECIFIC POLYPHENOLS, AND SOME CRITICAL SIGNALLING PROCESSES INVOLVED IN THE INTERVENTION OF CANCERS MIGHT MEDIATE THE THERAPEUTIC ROLES OF POLYPHENOLS. 2022 10 2686 14 EVIDENCE FOR THE INVOLVEMENT OF EPIGENETICS IN THE PROGRESSION OF RENAL FIBROGENESIS. EPIGENETICS ARE OMNIPRESENT IN EUKARYOTIC CELLS AND INFLUENCE CELL DIFFERENTIATION AND MAINTENANCE OF CELL METABOLISM IN HEALTH AND DISEASE. HERE, WE DISCUSS HOW THE 'SECOND GENETIC CODE' IMPACTS THE FATE OF THE INJURED KIDNEY. WE PROVIDE A GLIMPSE OF HOW RECENT INSIGHTS INTO EPIGENETIC MECHANISMS OF CHRONIC KIDNEY DISEASE MIGHT LEAD TO NOVEL DIAGNOSTIC AND THERAPEUTIC TOOLS. 2014 11 5529 28 RNA N(6) -METHYLADENOSINE MODIFICATIONS AND POTENTIAL TARGETED THERAPEUTIC STRATEGIES IN KIDNEY DISEASE. EPIGENETIC MODIFICATIONS HAVE RECEIVED INCREASING ATTENTION AND HAVE BEEN SHOWN TO BE EXTENSIVELY INVOLVED IN KIDNEY DEVELOPMENT AND DISEASE PROGRESSION. AMONG THEM, THE MOST COMMON RNA MODIFICATION, N(6) -METHYLADENOSINE (M(6) A), HAS BEEN SHOWN TO DYNAMICALLY AND REVERSIBLY EXERT ITS FUNCTIONS IN MULTIPLE WAYS, INCLUDING SPLICING, EXPORT, DECAY AND TRANSLATION INITIATION EFFICIENCY TO REGULATE MRNA FATE. MOREOVER, M(6) A HAS ALSO BEEN REPORTED TO EXERT BIOLOGICAL EFFECTS BY DESTABILIZING BASE PAIRING TO MODULATE VARIOUS FUNCTIONS OF RNAS. MOST IMPORTANTLY, AN INCREASING NUMBER OF KIDNEY DISEASES, SUCH AS RENAL CELL CARCINOMA, ACUTE KIDNEY INJURY AND CHRONIC KIDNEY DISEASE, HAVE BEEN FOUND TO BE ASSOCIATED WITH ABERRANT M(6) A PATTERNS. IN THIS REVIEW, WE COMPREHENSIVELY REVIEW THE CRITICAL ROLES OF M(6) A IN KIDNEY DISEASES AND DISCUSS THE POSSIBILITIES AND RELEVANCE OF M(6) A-TARGETED EPIGENETIC THERAPY, WITH AN INTEGRATED COMPREHENSIVE DESCRIPTION OF THE DETAILED ALTERATIONS IN SPECIFIC LOCI THAT CONTRIBUTE TO CELLULAR PROCESSES THAT ARE ASSOCIATED WITH KIDNEY DISEASES. 2023 12 2188 22 EPIGENETIC MECHANISMS UNDERLYING THE BENEFITS OF FLAVONOIDS IN CARDIOVASCULAR HEALTH AND DISEASES: ARE LONG NON-CODING RNAS RISING STARS? CARDIOVASCULAR DISEASES (CVDS) RANK AS THE FIRST LEADING CAUSE OF DEATH GLOBALLY. HIGH DIETARY POLYPHENOL (ESPECIALLY FLAVONOIDS) INTAKE HAS STRONGLY BEEN ASSOCIATED WITH LOW INCIDENCE OF THE PRIMARY OUTCOME, OVERALL MORTALITY, BLOOD PRESSURE, INFLAMMATORY BIOMARKERS, ONSET OF NEW-ONSET TYPE 2 DIABETES MELLITUS (T2DM), AND OBESITY. PHYTOGENIC FLAVONOIDS AFFECT THE PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES OF CVDS BY MODULATING VARIOUS BIOCHEMICAL SIGNALING PATHWAYS. NON-CODING RNAS (NCRNAS) HAVE ATTRACTED INCREASING ATTENTION AS FUNDAMENTAL REGULATOR OF GENE EXPRESSION INVOLVED IN CVDS. AMONG THE DIFFERENT NCRNA SUBGROUPS, LONG NCRNAS (LNCRNAS) HAVE RECENTLY EMERGED AS REGULATORY EUKARYOTIC TRANSCRIPTS AND THERAPEUTIC TARGETS WITH IMPORTANT AND DIVERSE FUNCTIONS IN HEALTH AND DISEASES. LNCRNAS MAY BE ASSOCIATED WITH THE INITIATION, DEVELOPMENT AND PROGRESSION OF CVDS BY MODULATING ACUTE AND CHRONIC INFLAMMATION, ADIPOGENESIS AND LIPID METABOLISM, AND CELLULAR PHYSIOLOGY. THIS REVIEW SUMMARIZES THIS RESEARCH ON THE MODULATORY EFFECTS OF LNCRNAS AND THEIR ROLES IN MEDIATING CELLULAR PROCESSES. THE MECHANISMS OF ACTION OF FLAVONOIDS UNDERLYING THEIR THERAPEUTIC EFFECTS ON CVDS ARE ALSO DISCUSSED. BASED ON OUR REVIEW, FLAVONOIDS MIGHT FACILITATE A SIGNIFICANT EPIGENETIC MODIFICATION AS PART (IF NOT FULL) OF THEIR TISSUE-/CELL-RELATED BIOLOGICAL EFFECTS. THIS FINDING MAY BE ATTRIBUTED TO THEIR INTERACTION WITH CELLULAR SIGNALING PATHWAYS INVOLVED IN CHRONIC DISEASES. CERTAIN LNCRNAS MIGHT BE THE TARGET OF SPECIFIC FLAVONOIDS, AND SOME CRITICAL SIGNALING PROCESSES INVOLVED IN THE INTERVENTION OF CVDS MIGHT MEDIATE THE THERAPEUTIC ROLES OF FLAVONOIDS. 2022 13 6058 23 THE DEFICIENCY OF N6-METHYLADENOSINE DEMETHYLASE ALKBH5 ENHANCES THE NEURODEGENERATIVE DAMAGE INDUCED BY COBALT. COBALT EXPOSURE, EVEN AT LOW CONCENTRATIONS, INDUCES NEURODEGENERATIVE DAMAGE, SUCH AS ALZHEIMER'S DISEASE (AD). THE SPECIFIC UNDERLYING MECHANISMS REMAIN UNCLEAR. OUR PREVIOUS STUDY DEMONSTRATED THAT M(6)A METHYLATION ALTERATION IS INVOLVED IN COBALT-INDUCED NEURODEGENERATIVE DAMAGE, SUCH AS IN AD. HOWEVER, THE ROLE OF M(6)A RNA METHYLATION AND ITS UNDERLYING MECHANISMS ARE POORLY UNDERSTOOD. IN THIS STUDY, BOTH EPIDEMIOLOGICAL AND LABORATORY STUDIES SHOWED THAT COBALT EXPOSURE COULD DOWNREGULATE THE EXPRESSION OF THE M(6)A DEMETHYLASE ALKBH5, SUGGESTING A KEY ROLE FOR ALKBH5. MOREOVER, METHYLATED RNA IMMUNOPRECIPITATION AND SEQUENCING (MERIP-SEQ) ANALYSIS REVEALED THAT ALKBH5 DEFICIENCY IS ASSOCIATED WITH NEURODEGENERATIVE DISEASES. KEGG PATHWAY AND GENE ONTOLOGY ANALYSES FURTHER REVEALED THAT THE DIFFERENTIALLY M(6)A-MODIFIED GENES RESULTING FROM ALKBH5 DOWNREGULATION AND COBALT EXPOSURE WERE AGGREGATED IN THE PATHWAYS OF PROLIFERATION, APOPTOSIS, AND AUTOPHAGY. SUBSEQUENTLY, ALKBH5 DEFICIENCY WAS SHOWN TO EXACERBATE CELL VIABILITY DECLINE, MOTIVATE CELL APOPTOSIS AND ATTENUATE CELL AUTOPHAGY INDUCED BY COBALT WITH EXPERIMENTAL TECHNIQUES OF GENE OVEREXPRESSION/INHIBITION. IN ADDITION, MORPHOLOGICAL CHANGES IN NEURONS AND THE EXPRESSION OF AD-RELATED PROTEINS, SUCH AS APP, P-TAU, AND TAU, IN THE CEREBRAL HIPPOCAMPUS OF WILD-TYPE AND ALKBH5 KNOCKOUT MICE AFTER CHRONIC COBALT EXPOSURE WERE ALSO INVESTIGATED. BOTH IN VITRO AND IN VIVO RESULTS SHOWED THAT LOWER EXPRESSION OF ALKBH5 AGGRAVATED COBALT-INDUCED NEURODEGENERATIVE DAMAGE. THESE RESULTS SUGGEST THAT ALKBH5, AS AN EPIGENETIC REGULATOR, COULD BE A POTENTIAL TARGET FOR ALLEVIATING COBALT-INDUCED NEURODEGENERATIVE DAMAGE. IN ADDITION, WE PROPOSE A NOVEL STRATEGY FOR THE PREVENTION AND TREATMENT OF ENVIRONMENTAL TOXICANT-RELATED NEURODEGENERATION FROM AN EPIGENETIC PERSPECTIVE. 2023 14 5125 23 POST-TRANSLATIONAL MODIFICATIONS OF TRYPANOSOMA CRUZI CANONICAL AND VARIANT HISTONES. CHAGAS DISEASE, CAUSED BY TRYPANOSOMA CRUZI, STILL AFFECTS MILLIONS OF PEOPLE AROUND THE WORLD. NO VACCINES NOR TREATMENT FOR CHRONIC CHAGAS DISEASE ARE AVAILABLE, AND CHEMOTHERAPY FOR THE ACUTE PHASE IS HINDERED BY LIMITED EFFICACY AND SEVERE SIDE EFFECTS. THE PROCESSES BY WHICH THE PARASITE ACQUIRES INFECTIVITY AND SURVIVES IN DIFFERENT HOSTS INVOLVE TIGHT REGULATION OF GENE EXPRESSION, MAINLY POST-TRANSCRIPTIONALLY. NEVERTHELESS, CHROMATIN STRUCTURE/ORGANIZATION OF TRYPANOSOMATIDS IS SIMILAR TO OTHER EUKARYOTES, INCLUDING HISTONE VARIANTS AND POST-TRANSLATIONAL MODIFICATIONS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS ALSO PLAY AN IMPORTANT ROLE IN THE BIOLOGY/PATHOGENESIS OF THESE PARASITES, MAKING EPIGENETIC TARGETS SUITABLE CANDIDATES TO DRUG DISCOVERY. HERE, WE PRESENT THE FIRST COMPREHENSIVE MAP OF POST-TRANSLATIONAL MODIFICATIONS OF T. CRUZI CANONICAL AND VARIANT HISTONES AND SHOW THAT ITS HISTONE CODE CAN BE AS SOPHISTICATED AS THAT OF OTHER EUKARYOTES. A TOTAL OF 13 DISTINCT MODIFICATION TYPES WERE IDENTIFIED, INCLUDING RATHER NOVEL AND UNUSUAL ONES SUCH AS ALTERNATIVE LYSINE ACYLATIONS, SERINE/THREONINE ACETYLATION, AND N-TERMINAL METHYLATION. SOME HISTONE MARKS CORRELATE TO THOSE DESCRIBED FOR OTHER ORGANISMS, SUGGESTING THAT SIMILAR REGULATORY MECHANISMS MAY BE IN PLACE. OTHERS, HOWEVER, ARE UNIQUE TO T. CRUZI OR TO TRYPANOSOMATIDS AS A GROUP AND MIGHT REPRESENT GOOD CANDIDATES FOR THE DEVELOPMENT OF ANTIPARASITIC DRUGS. 2017 15 6534 24 TRANSCRIPTIONAL REGULATION OF NMDA RECEPTOR EXPRESSION. THE N-METHYL-D-ASPARTATE (NMDA) SUBTYPES OF GLUTAMATE RECEPTORS ARE INTIMATELY INVOLVED IN A NUMBER OF IMPORTANT NEURONAL ACTIVITIES IN MAMMALIAN NERVOUS SYSTEMS INCLUDING NEURONAL MIGRATION, SYNAPTOGENESIS, NEURONAL PLASTICITY, NEURONAL SURVIVAL, AND EXCITOTOXICITY. THROUGH THESE ACTIVITIES, NMDA RECEPTORS (NRS) PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF DRUG ADDICTION, PAIN PERCEPTION, AND THE PATHOGENESIS OF NEUROLOGICAL DISORDERS SUCH AS SCHIZOPHRENIA AND HUNTINGTON'S DISEASE [1-10]. IT IS GENERALLY BELIEVED THAT ABERRANT OR PATHOLOGICAL NR EFFECTS OCCUR MAINLY VIA ABNORMAL RECEPTOR ACTIVITY, RESULTING FROM ALTERED AVAILABILITY OF AGONISTS OR MODIFIED QUALITY OR QUANTITY OF MEMBRANE-ASSOCIATED RECEPTORS. IN MAMMALS, FUNCTIONAL NRS ARE HETEROTETRAMERS OF SUBUNITS ENCODED BY THREE GENE FAMILIES, I.E., NMDAR1 (NR1 OR GRIN1), NMDAR2 (NR2 OR GRIN2), AND NMDAR3 (NR3 OR GRIN3) [3,4,11]. THE NR1 FAMILY HAS ONE GENE; THE NR2 FAMILY HAS FOUR (DESIGNATED A THROUGH D); AND THE NR3 FAMILY HAS TWO (A AND B). STRUCTURALLY, NR1 IS AN ESSENTIAL COMPONENT FOUND IN ALL TETRAMERS, WHILE DIFFERENT NR2 MEMBERS ARE INCORPORATED BASED ON AGE AND NERVOUS SYSTEM REGION. NR3 PROTEINS FUNCTION AS NEGATIVE COMPONENTS WHEN INCLUDED IN THE STRUCTURES [3,4,11,12]. EIGHT VARIANTS OF NR1 PROTEIN ARE PRODUCED BY ALTERNATIVE SPLICING AND DISTRIBUTED DIFFERENTIALLY IN NERVOUS SYSTEMS [13-15]. THIS COMPLEX COMPOSITION OF DIFFERENT SUBUNITS AND SPLICING VARIANTS FORMS THE PRIMARY BASIS OF THE FUNCTIONAL DIVERSITY OF NRS. FROM JANUARY 1992 TO JUNE 2007, MORE THAN 1000 RESEARCH ARTICLES RELEVANT TO NR EXPRESSION WERE PUBLISHED. IN SUM, THEY CONCLUDED THAT THE EXPRESSION OF NR GENES IS CELL- OR TISSUE-SPECIFIC, RELATIVELY STABLE, AND REGULATED DIFFERENTIALLY BY VARIOUS PHYSIOLOGICAL, PHARMACOLOGICAL, AND PATHOLOGICAL FACTORS. MOST OF THESE CONCLUSIONS WERE BASED ON ASSESSMENTS OF CHANGES OF THE STEADY STATE LEVELS OF MRNA AND PROTEIN THAT MAY BE DRIVEN BY NUMEROUS SOPHISTICATED MECHANISMS. TRANSCRIPTION IS THE INITIAL STEP AND GENERALLY THE MOST SENSITIVE TO CELLULAR NEEDS AND ENVIRONMENTAL CUES. THUS, IT SERVES AS A MAJOR MECHANISM CONTROLLING GENE EXPRESSION [16]. PRECISE SPATIAL AND TEMPORAL EXPRESSION OF A SELECTIVE SET OF GENES DETERMINES PHENOTYPIC DIFFERENCES AMONG DISTINCT TISSUES AND CELLS IN HIGHER EUKARYOTES [16-18]. IN THE CASE OF THE NR GENE FAMILIES, TRANSCRIPTION OF EACH SUBUNIT GENE IN A GIVEN NEURON OR CELL MUST BE COORDINATELY CONTROLLED BUT DIFFERENTIALLY RESPONSIVE TO CELL TYPE, DEVELOPMENTAL STAGE, AND ENVIRONMENTAL SIGNALS TO MAINTAIN HEALTHY CELLULAR FUNCTION. HOW THIS COORDINATED CONTROL TAKES PLACE IS AN IMPORTANT AND CHALLENGING QUESTION. THIS CHAPTER REVIEWS STUDIES THAT EXPLORE THE TRANSCRIPTIONAL CONTROL OF NR GENES. IT DISCUSSES STUDIES OF PROMOTER AND REGULATORY SEQUENCES, REGULATORY UNITS, DEVELOPMENTAL REGULATION, CELL TYPE SPECIFICITY, GROWTH FACTOR REGULATION, NEUROLOGICAL DISORDERS, AND EPIGENETIC MECHANISMS. 2009 16 5495 31 REVIEW ON CIRCULAR RNAS AND NEW INSIGHTS INTO THEIR ROLES IN CANCER. CIRCULAR RNAS (CIRCRNAS) ARE A VERY INTERESTING CLASS OF CONSERVED SINGLE-STRANDED RNA MOLECULES DERIVED FROM EXONIC OR INTRONIC SEQUENCES BY PRECURSOR MRNA BACK-SPLICING. UNLIKE CANONICAL LINEAR RNAS, CIRCRNAS FORM COVALENTLY CLOSED, CONTINUOUS STABLE LOOPS WITHOUT A 5'END CAP AND 3'END POLY(A) TAIL, AND THEREFORE ARE RESISTANT TO EXONUCLEASE DIGESTION. THE MAJORITY OF CIRCRNAS ARE HIGHLY ABUNDANT, AND CONSERVED ACROSS DIFFERENT SPECIES WITH A TISSUE OR DEVELOPMENTAL-STAGE-SPECIFIC EXPRESSION. CIRCRNAS HAVE BEEN SHOWN TO PLAY IMPORTANT ROLES AS MICRORNA SPONGES, REGULATORS OF GENE SPLICING AND TRANSCRIPTION, RNA-BINDING PROTEIN SPONGES AND PROTEIN/PEPTIDE TRANSLATORS. EMERGING EVIDENCE REVEALS THAT CIRCRNAS FUNCTION IN VARIOUS HUMAN DISEASES, PARTICULARLY CANCERS, AND MAY FUNCTION AS BETTER PREDICTIVE BIOMARKERS AND THERAPEUTIC TARGETS FOR CANCER TREATMENT. IN CONSIDERATION OF THEIR POTENTIAL CLINICAL RELEVANCE, CIRCRNAS HAVE BECOME A NEW RESEARCH HOTSPOT IN THE FIELD OF TUMOR PATHOLOGY. IN THE PRESENT STUDY, THE CURRENT UNDERSTANDING OF THE BIOGENESIS, CHARACTERISTICS, DATABASES, RESEARCH METHODS, BIOLOGICAL FUNCTIONS SUBCELLULAR DISTRIBUTION, EPIGENETIC REGULATION, EXTRACELLULAR TRANSPORT AND DEGRADATION OF CIRCRNAS WAS DISCUSSED. IN PARTICULAR, THE MULTIPLE DATABASES AND METHODS INVOLVED IN CIRCRNA RESEARCH WERE FIRST SUMMARIZED, AND THE RECENT ADVANCES IN DETERMINING THE POTENTIAL ROLES OF CIRCRNAS IN TUMOR GROWTH, MIGRATION AND INVASION, WHICH RENDER CIRCRNAS BETTER PREDICTIVE BIOMARKERS, WERE DESCRIBED. FURTHERMORE, FUTURE PERSPECTIVES FOR THE CLINICAL APPLICATION OF CIRCRNAS IN THE MANAGEMENT OF PATIENTS WITH CANCER WERE PROPOSED, WHICH COULD PROVIDE NEW INSIGHTS INTO CIRCRNAS IN THE FUTURE. 2021 17 5966 17 TERMINAL ADDITION IN A CELLULAR WORLD. RECENT ADVANCES IN OUR UNDERSTANDING OF EVOLUTIONARY DEVELOPMENT PERMIT A REFRAMED APPRAISAL OF TERMINAL ADDITION AS A CONTINUOUS HISTORICAL PROCESS OF CELLULAR-ENVIRONMENTAL COMPLEMENTARITY. WITHIN THIS FRAME OF REFERENCE, EVOLUTIONARY TERMINAL ADDITIONS CAN BE IDENTIFIED AS ENVIRONMENTAL INDUCTION OF EPISODIC ADJUSTMENTS TO CELL-CELL SIGNALING PATTERNS THAT YIELD THE CELLULAR-MOLECULAR PATHWAYS THAT LEAD TO DIFFERING DEVELOPMENTAL FORMS. PHENOTYPES DERIVE, THEREBY, THROUGH CELLULAR MUTUALISTIC/COMPETITIVE NICHE CONSTRUCTIONS IN RECIPROCATING RESPONSIVENESS TO ENVIRONMENTAL STRESSES AND EPIGENETIC IMPACTS. IN SUCH TERMS, TERMINAL ADDITION FLOWS ACCORDING TO A LOGIC OF CELLULAR NEEDS CONFRONTING ENVIRONMENTAL CHALLENGES OVER SPACE-TIME. A RECONCILIATION OF EVOLUTIONARY DEVELOPMENT AND TERMINAL ADDITION CAN BE ACHIEVED THROUGH A COMBINED FOCUS ON CELL-CELL SIGNALING, MOLECULAR PHYLOGENIES AND A BROADER UNDERSTANDING OF EPIGENETIC PHENOMENA AMONG EUKARYOTIC ORGANISMS. WHEN UNDERSTOOD IN THIS MANNER, TERMINAL ADDITION HAS AN IMPORTANT ROLE IN EVOLUTIONARY DEVELOPMENT, AND CHRONIC DISEASE MIGHT BE CONSIDERED AS A FORM OF 'REVERSE EVOLUTION' OF THE SELF-SAME PROCESSES. 2018 18 2315 18 EPIGENETIC REGULATION OF FERROPTOSIS-ASSOCIATED GENES AND ITS IMPLICATION IN CANCER THERAPY. FERROPTOSIS IS AN EVOLUTIONARILY CONSERVED FORM OF REGULATED CELL DEATH TRIGGERED BY IRON-DEPENDENT PHOSPHOLIPID PEROXIDATION. FERROPTOSIS CONTRIBUTES TO THE MAINTENANCE OF TISSUE HOMEOSTASIS UNDER PHYSIOLOGICAL CONDITIONS WHILE ITS ABERRATION IS TIGHTLY CONNECTED WITH LOTS OF PATHOPHYSIOLOGICAL PROCESSES SUCH AS ACUTE TISSUE INJURY, CHRONIC DEGENERATIVE DISEASE, AND TUMORIGENESIS. EPIGENETIC REGULATION CONTROLS CHROMATIN STRUCTURE AND GENE EXPRESSION BY WRITING/READING/ERASING THE COVALENT MODIFICATIONS ON DNA, HISTONE, AND RNA, WITHOUT ALTERING THE DNA SEQUENCE. ACCUMULATING EVIDENCES SUGGEST THAT EPIGENETIC REGULATION IS INVOLVED IN THE DETERMINATION OF CELLULAR VULNERABILITY TO FERROPTOSIS. HERE, WE SUMMARIZE THE RECENT ADVANCES ON THE EPIGENETIC MECHANISMS THAT CONTROL THE EXPRESSION OF FERROPTOSIS-ASSOCIATED GENES AND THEREBY THE FERROPTOSIS PROCESS. MOREOVER, THE POTENTIAL VALUE OF EPIGENETIC DRUGS IN TARGETING OR SYNERGIZING FERROPTOSIS DURING CANCER THERAPY IS ALSO DISCUSSED. 2022 19 3374 15 HISTONE POST-TRANSLATIONAL MODIFICATIONS AS POTENTIAL THERAPEUTIC TARGETS FOR PAIN MANAGEMENT. EFFECTIVE PHARMACOLOGICAL MANAGEMENT OF PAIN ASSOCIATED WITH TISSUE PATHOLOGY IS AN UNMET MEDICAL NEED. TRANSCRIPTIONAL MODIFICATIONS IN NOCICEPTIVE PATHWAYS ARE PIVOTAL FOR THE DEVELOPMENT AND THE MAINTENANCE OF PAIN ASSOCIATED WITH TISSUE DAMAGE. ACCUMULATING EVIDENCE HAS SHOWN THE IMPORTANCE OF THE EPIGENETIC CONTROL OF TRANSCRIPTION IN NOCICEPTIVE PATHWAYS VIA HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS). HENCE, HISTONE PTMS COULD BE TARGETS FOR NOVEL EFFECTIVE ANALGESICS. HERE, WE DISCUSS THE CURRENT UNDERSTANDING OF HISTONE PTMS IN THE MODULATION OF GENE EXPRESSION AFFECTING NOCICEPTION AND PAIN PHENOTYPES FOLLOWING TISSUE INJURY. WE ALSO PROVIDE A CRITICAL VIEW OF THE TRANSLATIONAL IMPLICATIONS OF PRECLINICAL MODELS AND DISCUSS OPPORTUNITIES AND CHALLENGES OF TARGETING HISTONE PTMS TO RELIEVE PAIN IN CLINICALLY RELEVANT TISSUE INJURIES. 2021 20 554 28 AUTOPHAGY IN HUMAN HEALTH AND DISEASE: NOVEL THERAPEUTIC OPPORTUNITIES. SIGNIFICANCE: IN EUKARYOTES, AUTOPHAGY REPRESENTS A HIGHLY EVOLUTIONARY CONSERVED PROCESS, THROUGH WHICH MACROMOLECULES AND CYTOPLASMIC MATERIAL ARE DEGRADED INTO LYSOSOMES AND RECYCLED FOR BIOSYNTHETIC OR ENERGETIC PURPOSES. DYSFUNCTION OF THE AUTOPHAGIC PROCESS HAS BEEN ASSOCIATED WITH THE ONSET AND DEVELOPMENT OF MANY HUMAN CHRONIC PATHOLOGIES, SUCH AS CARDIOVASCULAR, METABOLIC, AND NEURODEGENERATIVE DISEASES AS WELL AS CANCER. RECENT ADVANCES: CURRENTLY, COMPREHENSIVE RESEARCH IS BEING CARRIED OUT TO DISCOVER NEW THERAPEUTIC AGENTS THAT ARE ABLE TO MODULATE THE AUTOPHAGIC PROCESS IN VIVO. RECENT EVIDENCE HAS SHOWN THAT A LARGE NUMBER OF NATURAL BIOACTIVE COMPOUNDS ARE INVOLVED IN THE REGULATION OF AUTOPHAGY BY MODULATING SEVERAL TRANSCRIPTIONAL FACTORS AND SIGNALING PATHWAYS. CRITICAL ISSUES: CRITICAL ISSUES THAT DESERVE PARTICULAR ATTENTION ARE THE INADEQUATE UNDERSTANDING OF THE COMPLEX ROLE OF AUTOPHAGY IN DISEASE PATHOGENESIS, THE LIMITED AVAILABILITY OF THERAPEUTIC DRUGS, AND THE LACK OF CLINICAL TRIALS. IN THIS CONTEXT, THE EFFECTS THAT NATURAL BIOACTIVE COMPOUNDS EXERT ON AUTOPHAGIC MODULATION SHOULD BE CLEARLY HIGHLIGHTED, SINCE THEY DEPEND ON THE TYPE AND STAGE OF THE PATHOLOGICAL CONDITIONS OF DISEASES. FUTURE DIRECTIONS: RESEARCH EFFORTS SHOULD NOW FOCUS ON UNDERSTANDING THE SURVIVAL-SUPPORTING AND DEATH-PROMOTING ROLES OF AUTOPHAGY, HOW NATURAL COMPOUNDS INTERACT EXACTLY WITH THE AUTOPHAGIC TARGETS SO AS TO INDUCE OR INHIBIT AUTOPHAGY AND ON THE EVALUATION OF THEIR PHARMACOLOGICAL EFFECTS IN A MORE IN-DEPTH AND MECHANISTIC WAY. IN ADDITION, CLINICAL STUDIES ON AUTOPHAGY-INDUCING NATURAL PRODUCTS ARE STRONGLY ENCOURAGED, ALSO TO HIGHLIGHT SOME FUNDAMENTAL ASPECTS, SUCH AS THE DOSE, THE DURATION, AND THE POSSIBLE SYNERGISTIC ACTION OF THESE COMPOUNDS WITH CONVENTIONAL THERAPY. 2019