1 5046 200 PHARMACOLOGICAL AND DIETARY ANTIOXIDANT THERAPIES FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE PROGRESSION AND EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE INTIMATELY ASSOCIATED WITH TOBACCO SMOKE/BIOMASS FUEL-INDUCED OXIDATIVE AND ALDEHYDE/CARBONYL STRESS. ALTERATIONS IN REDOX SIGNALING PROINFLAMMATORY KINASES AND TRANSCRIPTION FACTORS, STEROID RESISTANCE, UNFOLDED PROTEIN RESPONSE, MUCUS HYPERSECRETION, EXTRACELLULAR MATRIX REMODELING, AUTOPHAGY/APOPTOSIS, EPIGENETIC CHANGES, CELLULAR SENESCENCE/AGING, ENDOTHELIAL DYSFUNCTION, AUTOIMMUNITY, AND SKELETAL MUSCLE DYSFUNCTION ARE SOME OF THE PATHOLOGICAL HALLMARKS OF COPD. IN LIGHT OF THE ABOVE IT WOULD BE PRUDENT TO TARGET SYSTEMIC AND LOCAL OXIDATIVE STRESS WITH AGENTS THAT CAN MODULATE THE ANTIOXIDANTS/ REDOX SYSTEM OR BY BOOSTING THE ENDOGENOUS LEVELS OF ANTIOXIDANTS FOR THE TREATMENT AND MANAGEMENT OF COPD. IDENTIFICATION OF VARIOUS ANTIOXIDANT AGENTS, SUCH AS THIOL MOLECULES (GLUTATHIONE AND MUCOLYTIC DRUGS, SUCH AS N-ACETYL-L-CYSTEINE, N-ACYSTELYN, ERDOSTEINE, FUDOSTEINE, ERGOTHIONEINE, AND CARBOCYSTEINE LYSINE SALT), DIETARY NATURAL PRODUCT-DERIVED POLYPHENOLS AND OTHER COMPOUNDS (CURCUMIN, RESVERATROL, GREEN TEA CATECHINS, QUERCETIN SULFORAPHANE, LYCOPENE, ACAI, ALPHA-LIPOIC ACID, TOCOTRIENOLS, AND APOCYNIN) HAVE MADE IT POSSIBLE TO MODULATE VARIOUS BIOCHEMICAL ASPECTS OF COPD. VARIOUS RESEARCHES AND CLINICAL TRIALS HAVE REVEALED THAT THESE ANTIOXIDANTS CAN DETOXIFY FREE RADICALS AND OXIDANTS, CONTROL EXPRESSION OF REDOX AND GLUTATHIONE BIOSYNTHESIS GENES, CHROMATIN REMODELING, AND ULTIMATELY INFLAMMATORY GENE EXPRESSION. IN ADDITION, MODULATION OF CIGARETTE SMOKE-INDUCED OXIDATIVE STRESS AND RELATED CELLULAR CHANGES HAVE ALSO BEEN REPORTED TO BE EFFECTED BY SYNTHETIC MOLECULES. THIS INCLUDES SPECIFIC SPIN TRAPS LIKE ALPHA-PHENYL-N-TERT-BUTYL NITRONE, A CATALYTIC ANTIOXIDANT (ECSOD MIMETIC), PORPHYRINS (AEOL 10150 AND AEOL 10113), AND A SUPEROXIDE DISMUTASE MIMETIC M40419, LIPID PEROXIDATION AND PROTEIN CARBONYLATION BLOCKERS/INHIBITORS, SUCH AS EDARAVONE AND LAZAROIDS/TIRILAZAD, MYELOPEROXIDASE INHIBITORS, AS WELL AS SPECIALIZED PRO-RESOLVING MEDIATORS/INFLAMMATORY RESOLVING LIPID MEDIATORS, OMEGA-3 FATTY ACIDS, VITAMIN D, AND HYDROGEN SULFIDE. ACCORDING TO VARIOUS STUDIES IT APPEARS THAT THE ADMINISTRATION OF MULTIPLE ANTIOXIDANTS COULD BE A MORE EFFECTIVE MODE USED IN THE TREATMENT OF COPD. IN THIS REVIEW, VARIOUS PHARMACOLOGICAL AND DIETARY APPROACHES TO ENHANCE LUNG ANTIOXIDANT LEVELS AND BENEFICIAL EFFECTS OF ANTIOXIDANT THERAPEUTICS IN TREATING OR INTERVENING THE PROGRESSION OF COPD HAVE BEEN DISCUSSED. 2013 2 3152 39 GLUCOSE VARIABILITY: HOW DOES IT WORK? A GROWING BODY OF EVIDENCE POINTS TO THE ROLE OF GLUCOSE VARIABILITY (GV) IN THE DEVELOPMENT OF THE MICROVASCULAR AND MACROVASCULAR COMPLICATIONS OF DIABETES. IN THIS REVIEW, WE SUMMARIZE DATA ON GV-INDUCED BIOCHEMICAL, CELLULAR AND MOLECULAR EVENTS INVOLVED IN THE PATHOGENESIS OF DIABETIC COMPLICATIONS. CURRENT DATA INDICATE THAT THE DETERIORATING EFFECT OF GV ON TARGET ORGANS CAN BE REALIZED THROUGH OXIDATIVE STRESS, GLYCATION, CHRONIC LOW-GRADE INFLAMMATION, ENDOTHELIAL DYSFUNCTION, PLATELET ACTIVATION, IMPAIRED ANGIOGENESIS AND RENAL FIBROSIS. THE EFFECTS OF GV ON OXIDATIVE STRESS, INFLAMMATION, ENDOTHELIAL DYSFUNCTION AND HYPERCOAGULABILITY COULD BE AGGRAVATED BY HYPOGLYCEMIA, ASSOCIATED WITH HIGH GV. OSCILLATING HYPERGLYCEMIA CONTRIBUTES TO BETA CELL DYSFUNCTION, WHICH LEADS TO A FURTHER INCREASE IN GV AND COMPLETES THE VICIOUS CIRCLE. IN CELLS, THE GV-INDUCED CYTOTOXIC EFFECT INCLUDES MITOCHONDRIAL DYSFUNCTION, ENDOPLASMIC RETICULUM STRESS AND DISTURBANCES IN AUTOPHAGIC FLUX, WHICH ARE ACCOMPANIED BY REDUCED VIABILITY, ACTIVATION OF APOPTOSIS AND ABNORMALITIES IN CELL PROLIFERATION. THESE EFFECTS ARE REALIZED THROUGH THE UP- AND DOWN-REGULATION OF A LARGE NUMBER OF GENES AND THE ACTIVITY OF SIGNALING PATHWAYS SUCH AS PI3K/AKT, NF-KAPPAB, MAPK (ERK), JNK AND TGF-BETA/SMAD. EPIGENETIC MODIFICATIONS MEDIATE THE POSTPONED EFFECTS OF GLUCOSE FLUCTUATIONS. THE MULTIPLE DETERIORATIVE EFFECTS OF GV PROVIDE FURTHER SUPPORT FOR CONSIDERING IT AS A THERAPEUTIC TARGET IN DIABETES. 2021 3 5809 26 STRAWBERRY AND HUMAN HEALTH: EFFECTS BEYOND ANTIOXIDANT ACTIVITY. THE USEFULNESS OF A DIET RICH IN VEGETABLES AND FRUITS ON HUMAN HEALTH HAS BEEN WIDELY RECOGNIZED: A HIGH INTAKE OF ANTIOXIDANT AND BIOACTIVE COMPOUNDS MAY IN FACT PLAY A CRUCIAL ROLE IN THE PREVENTION OF SEVERAL DISEASES, SUCH AS CANCER, CARDIOVASCULAR, NEURODEGENERATIVE, AND OTHER CHRONIC PATHOLOGIES. THE STRAWBERRY (FRAGARIA X ANANASSA DUCH.) POSSESSES A REMARKABLE NUTRITIONAL COMPOSITION IN TERMS OF MICRONUTRIENTS, SUCH AS MINERALS, VITAMIN C, AND FOLATES, AND NON-NUTRIENT ELEMENTS, SUCH AS PHENOLIC COMPOUNDS, THAT ARE ESSENTIAL FOR HUMAN HEALTH. ALTHOUGH STRAWBERRY PHENOLICS ARE KNOWN MAINLY FOR THEIR ANTI-INFLAMMATORY AND ANTIOXIDANT ACTIONS, RECENT STUDIES HAVE DEMONSTRATED THAT THEIR BIOLOGICAL ACTIVITIES ALSO SPREAD TO OTHER PATHWAYS INVOLVED IN CELLULAR METABOLISM AND CELLULAR SURVIVAL. THIS PAPER HAS THE MAIN OBJECTIVE OF REVIEWING CURRENT INFORMATION ABOUT THE POTENTIAL MECHANISMS INVOLVED IN THE EFFECTS ELICITED BY STRAWBERRY POLYPHENOLS ON HUMAN HEALTH, DEVOTING SPECIAL ATTENTION TO THE LATEST FINDINGS. 2014 4 4968 32 PATHOLOGICAL MECHANISMS AND THERAPEUTIC OUTLOOKS FOR ARTHROFIBROSIS. ARTHROFIBROSIS IS A FIBROTIC JOINT DISORDER THAT BEGINS WITH AN INFLAMMATORY REACTION TO INSULTS SUCH AS INJURY, SURGERY AND INFECTION. EXCESSIVE EXTRACELLULAR MATRIX AND ADHESIONS CONTRACT POUCHES, BURSAE AND TENDONS, CAUSE PAIN AND PREVENT A NORMAL RANGE OF JOINT MOTION, WITH DEVASTATING CONSEQUENCES FOR PATIENT QUALITY OF LIFE. ARTHROFIBROSIS AFFECTS PEOPLE OF ALL AGES, WITH PUBLISHED RATES VARYING. THE RISK FACTORS AND BEST MANAGEMENT STRATEGIES ARE LARGELY UNKNOWN DUE TO A POOR UNDERSTANDING OF THE PATHOLOGY AND LACK OF DIAGNOSTIC BIOMARKERS. HOWEVER, CURRENT RESEARCH INTO THE PATHOGENESIS OF FIBROSIS IN ORGANS NOW INFORMS THE UNDERSTANDING OF ARTHROFIBROSIS. THE PROCESS BEGINS WHEN STRESS SIGNALS STIMULATE IMMUNE CELLS. THE RESULTING CASCADE OF CYTOKINES AND MEDIATORS DRIVES FIBROBLASTS TO DIFFERENTIATE INTO MYOFIBROBLASTS, WHICH SECRETE FIBRILLAR COLLAGENS AND TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA). POSITIVE FEEDBACK NETWORKS THEN DYSREGULATE PROCESSES THAT NORMALLY TERMINATE HEALING PROCESSES. WE PROPOSE TWO SUBTYPES OF ARTHROFIBROSIS OCCUR: ACTIVE ARTHROFIBROSIS AND RESIDUAL ARTHROFIBROSIS. IN THE LATTER THE FIBROGENIC PROCESSES HAVE RESOLVED BUT THE JOINT REMAINS STIFF. THE BEST THERAPEUTIC APPROACH FOR EACH SUBTYPE MAY DIFFER SIGNIFICANTLY. TREATMENT TYPICALLY INVOLVES SURGERY, HOWEVER, A PHARMACOLOGICAL APPROACH TO CORRECT DYSREGULATED CELL SIGNALLING COULD BE MORE EFFECTIVE. RECENT RESEARCH SHOWS THAT MYOFIBROBLASTS ARE CAPABLE OF REVERSING DIFFERENTIATION, AND UNDERSTANDING THE MECHANISMS OF PATHOGENESIS AND RESOLUTION WILL BE ESSENTIAL FOR THE DEVELOPMENT OF CELL-BASED TREATMENTS. THERAPIES WITH SIGNIFICANT PROMISE ARE CURRENTLY AVAILABLE, WITH MORE IN DEVELOPMENT, INCLUDING THOSE THAT INHIBIT TGF-BETA SIGNALLING AND EPIGENETIC MODIFICATIONS. THIS REVIEW FOCUSES ON PATHOGENESIS OF STERILE ARTHROFIBROSIS AND THERAPEUTIC TREATMENTS. 2019 5 2597 33 EPIGENETICS OF SUBCELLULAR STRUCTURE FUNCTIONING IN THE ORIGIN OF RISK OR RESILIENCE TO COMORBIDITY OF NEUROPSYCHIATRIC AND CARDIOMETABOLIC DISORDERS. MECHANISMS CONTROLLING MITOCHONDRIAL FUNCTION, PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM (ER) AND NUCLEAR PROCESSES SUCH AS TELOMERE LENGTH AND DNA REPAIR MAY BE SUBJECT TO EPIGENETIC CUES THAT RELATE THE GENOMIC EXPRESSION AND ENVIRONMENTAL EXPOSURES IN EARLY STAGES OF LIFE. THEY MAY ALSO BE INVOLVED IN THE COMORBID APPEARANCE OF CARDIOMETABOLIC (CMD) AND NEUROPSYCHIATRIC DISORDERS (NPD) DURING ADULTHOOD. MITOCHONDRIAL FUNCTION AND PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM ARE ASSOCIATED WITH OXIDATIVE STRESS AND ELEVATED INTRACELLULAR CALCIUM LEVELS AND MAY ALSO UNDERLIE THE VULNERABILITY FOR COMORBID CMD AND NPD. MITOCHONDRIA PROVIDE KEY METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+), ATP, ALPHA-KETOGLUTARATE AND ACETYL COENZYME A THAT ARE REQUIRED FOR MANY TRANSCRIPTIONAL AND EPIGENETIC PROCESSES. THEY ARE ALSO A SOURCE OF FREE RADICALS. ON THE OTHER HAND, EPIGENETIC MARKERS IN NUCLEAR DNA DETERMINE MITOCHONDRIAL BIOGENESIS. THE ER IS THE SUBCELLULAR ORGANELLE IN WHICH SECRETORY PROTEINS ARE FOLDED. MANY ENVIRONMENTAL FACTORS STOP THE ABILITY OF CELLS TO PROPERLY FOLD PROTEINS AND MODIFY POST-TRANSLATIONALLY SECRETORY AND TRANSMEMBRANE PROTEINS LEADING TO ENDOPLASMIC RETICULUM STRESS AND OXIDATIVE STRESS. ER FUNCTIONING MAY BE EPIGENETICALLY DETERMINED. CHRONIC ER STRESS IS EMERGING AS A KEY CONTRIBUTOR TO A GROWING LIST OF HUMAN DISEASES, INCLUDING CMD AND NPD. TELOMERE LOSS CAUSES CHROMOSOMAL FUSION, ACTIVATION OF THE CONTROL OF DNA DAMAGE-RESPONSES, UNSTABLE GENOME AND ALTERED STEM CELL FUNCTION, WHICH MAY UNDERLIE THE COMORBIDITY OF CMD AND NPD. THE LENGTH OF TELOMERES IS RELATED TO OXIDATIVE STRESS AND MAY BE EPIGENETICALLY PROGRAMMED. PATHWAYS INVOLVED IN DNA REPAIR MAY BE EPIGENETICALLY PROGRAMMED AND MAY CONTRIBUTE TO DISEASES. IN THIS PAPER, WE DESCRIBE SUBCELLULAR MECHANISMS THAT ARE DETERMINED BY EPIGENETIC MARKERS AND THEIR POSSIBLE RELATION TO THE DEVELOPMENT OF INCREASED SUSCEPTIBILITY TO DEVELOP CMD AND NPD. 2018 6 4414 38 MOLECULAR AND CELLULAR MECHANISMS OF PROPOLIS AND ITS POLYPHENOLIC COMPOUNDS AGAINST CANCER. IN RECENT YEARS, INTEREST IN NATURAL PRODUCTS SUCH AS ALTERNATIVE SOURCES OF PHARMACEUTICALS FOR NUMEROUS CHRONIC DISEASES, INCLUDING TUMORS, HAS BEEN RENEWED. PROPOLIS, A NATURAL PRODUCT COLLECTED BY HONEYBEES, AND POLYPHENOLIC/FLAVONOID PROPOLIS-RELATED COMPONENTS MODULATE ALL STEPS OF THE CANCER PROGRESSION PROCESS. ANTICANCER ACTIVITY OF PROPOLIS AND ITS COMPOUNDS RELIES ON VARIOUS MECHANISMS: CELL-CYCLE ARREST AND ATTENUATION OF CANCER CELLS PROLIFERATION, REDUCTION IN THE NUMBER OF CANCER STEM CELLS, INDUCTION OF APOPTOSIS, MODULATION OF ONCOGENE SIGNALING PATHWAYS, INHIBITION OF MATRIX METALLOPROTEINASES, PREVENTION OF METASTASIS, ANTI-ANGIOGENESIS, ANTI-INFLAMMATORY EFFECTS ACCOMPANIED BY THE MODULATION OF THE TUMOR MICROENVIRONMENT (BY MODIFYING MACROPHAGE ACTIVATION AND POLARIZATION), EPIGENETIC REGULATION, ANTIVIRAL AND BACTERICIDAL ACTIVITIES, MODULATION OF GUT MICROBIOTA, AND ATTENUATION OF CHEMOTHERAPY-INDUCED DELETERIOUS SIDE EFFECTS. INGREDIENTS FROM PROPOLIS ALSO "SENSITIZE" CANCER CELLS TO CHEMOTHERAPEUTIC AGENTS, LIKELY BY BLOCKING THE ACTIVATION OF THE TRANSCRIPTION FACTOR NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB). IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE RELATED TO THE THE EFFECTS OF FLAVONOIDS AND OTHER POLYPHENOLIC COMPOUNDS FROM PROPOLIS ON TUMOR GROWTH AND METASTASIZING ABILITY, AND DISCUSS POSSIBLE MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE MODULATION OF INFLAMMATORY PATHWAYS AND CELLULAR PROCESSES THAT AFFECT SURVIVAL, PROLIFERATION, INVASION, ANGIOGENESIS, AND METASTASIS OF THE TUMOR. 2022 7 6285 42 THE POTENTIAL OF LIPID-POLYMER NANOPARTICLES AS EPIGENETIC AND ROS CONTROL APPROACHES FOR COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A LUNG DISEASE CAUSED BY AN INFLAMMATORY RESPONSE TO VARIOUS INHALED TOXINS, ESPECIALLY CIGARETTE SMOKE. REACTIVE OXYGEN SPECIES (ROS) AND EPIGENETIC ABNORMALITY ARE INTIMATELY RELATED TO THE PATHOLOGY OF COPD, AND THE OVERPRODUCTION OF ROS RESULTS IN A DECREASE OF HISTONE DEACETYLASE 2 (HDAC2), LEADING TO GLUCOCORTICOID RESISTANCE. THEREFORE, A NOVEL TREATMENT THAT SIMULTANEOUSLY REDUCES ROS LEVEL AND GLUCOCORTICOID RESISTANCE IS URGENTLY NEEDED. IN THIS STUDY, WE DEVELOPED A CODELIVERY SYSTEM USING CORE-SHELL TYPE LIPID-POLYMER NANOPARTICLES (LPNS) COMPOSED OF A POLY(LACTIC ACID) (PLA) CORE ENCAPSULATING A POTENT ANTIOXIDANT MN-PORPHYRIN DIMER (MNPD) AND A CATIONIC LIPID (DOTAP) SHELL THAT BINDS HDAC2-ENCODING PLASMID DNA (PHDAC2), AS A NEW THERAPEUTIC APPROACH TOWARD COPD. THE TRANSFECTION OF PHDAC2 COMBINED WITH THE ELIMINATION OF ROS BY MNPD EXHIBITED A SIGNIFICANT ENHANCEMENT OF INTRACELLULAR HDAC2 EXPRESSION LEVELS, SUGGESTING THAT THE MULTI-ANTIOXIDATIVE ACTIVITY OF MNPD PLAYS A CRUCIAL ROLE IN THE EXPRESSION OF HDAC2. MOREOVER, TREATMENT WITH LPNS EFFICIENTLY AMELIORATED THE STEROID RESISTANCE IN COPD MODELS IN VITRO AS EVIDENCED BY THE LOWERED EXPRESSION LEVELS OF IL-8. RECOVERY FROM MITOCHONDRIAL DYSFUNCTION MAY BE THE MECHANISM UNDERLYING THE ACTION OF LPNS. THE PLA-MNPD/DOTAP/PHDAC2 SYSTEM PROPOSED OFFERS A NEW THERAPEUTIC APPROACH FOR COPD BASED ON THE SYNERGISM OF ROS ELIMINATION AND HDAC2 EXPRESSION. 2020 8 1898 30 ENDOTHELINS IN CARDIOVASCULAR BIOLOGY AND THERAPEUTICS. CARDIOVASCULAR DISEASE IS A MAJOR CONTRIBUTOR TO GLOBAL MORBIDITY AND MORTALITY AND IS THE COMMON END POINT OF MANY CHRONIC DISEASES. THE ENDOTHELINS COMPRISE THREE STRUCTURALLY SIMILAR PEPTIDES OF 21 AMINO ACIDS IN LENGTH. ENDOTHELIN 1 (ET-1) AND ET-2 ACTIVATE TWO G PROTEIN-COUPLED RECEPTORS - ENDOTHELIN RECEPTOR TYPE A (ET(A)) AND ENDOTHELIN RECEPTOR TYPE B (ET(B)) - WITH EQUAL AFFINITY, WHEREAS ET-3 HAS A LOWER AFFINITY FOR ET(A). ET-1 IS THE MOST POTENT VASOCONSTRICTOR IN THE HUMAN CARDIOVASCULAR SYSTEM AND HAS REMARKABLY LONG-LASTING ACTIONS. ET-1 CONTRIBUTES TO VASOCONSTRICTION, VASCULAR AND CARDIAC HYPERTROPHY, INFLAMMATION, AND TO THE DEVELOPMENT AND PROGRESSION OF CARDIOVASCULAR DISEASE. ENDOTHELIN RECEPTOR ANTAGONISTS HAVE REVOLUTIONIZED THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION. CLINICAL TRIALS CONTINUE TO EXPLORE NEW APPLICATIONS OF ENDOTHELIN RECEPTOR ANTAGONISTS, PARTICULARLY IN TREATMENT-RESISTANT HYPERTENSION, CHRONIC KIDNEY DISEASE AND PATIENTS RECEIVING ANTIANGIOGENIC THERAPIES. TRANSLATIONAL STUDIES HAVE IDENTIFIED IMPORTANT ROLES FOR THE ENDOTHELIN ISOFORMS AND NEW THERAPEUTIC TARGETS DURING DEVELOPMENT, IN FLUID-ELECTROLYTE HOMEOSTASIS, AND IN CARDIOVASCULAR AND NEURONAL FUNCTION. NOVEL PHARMACOLOGICAL STRATEGIES ARE EMERGING IN THE FORM OF SMALL-MOLECULE EPIGENETIC MODULATORS, BIOLOGICS (SUCH AS MONOCLONAL ANTIBODIES FOR ET(B)) AND POSSIBLY SIGNALLING PATHWAY-BIASED AGONISTS AND ANTAGONISTS. 2019 9 6642 35 UNRAVELING THE PATHOGENESIS OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE OVERLAP: FOCUSING ON EPIGENETIC MECHANISMS. ASTHMA AND COPD OVERLAP (ACO) IS CHARACTERIZED BY PATIENTS PRESENTING WITH PERSISTENT AIRFLOW LIMITATION AND FEATURES OF BOTH ASTHMA AND COPD. IT IS ASSOCIATED WITH A HIGHER FREQUENCY AND SEVERITY OF EXACERBATIONS, A FASTER LUNG FUNCTION DECLINE, AND A HIGHER HEALTHCARE COST. SYSTEMIC INFLAMMATION IN COPD AND ASTHMA IS DRIVEN BY TYPE 1 T HELPER (TH1) AND TH2 IMMUNE RESPONSES, RESPECTIVELY, BOTH OF WHICH MAY CONTRIBUTE TO AIRWAY REMODELING IN ACO. ACO-RELATED BIOMARKERS CAN BE CLASSIFIED INTO FOUR CATEGORIES: NEUTROPHIL-MEDIATED INFLAMMATION, TH2 CELL RESPONSES, ARACHIDONIC ACID-EICOSANOIDS PATHWAY, AND METABOLITES. GENE-ENVIRONMENT INTERACTIONS ARE KEY CONTRIBUTORS TO THE COMPLEXITY OF ACO AND ARE REGULATED BY EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNAS. THUS, THIS REVIEW FOCUSES ON THE LINK BETWEEN EPIGENETICS AND ACO, AND OUTLINES THE FOLLOWING: (I) INHERITING EPIGENOTYPES WITHOUT CHANGE WITH ENVIRONMENTAL STIMULI, OR EPIGENETIC CHANGES IN RESPONSE TO LONG-TERM EXPOSURE TO INHALED PARTICLES PLUS INTERMITTENT EXPOSURE TO SPECIFIC ALLERGENS; (II) EPIGENETIC MARKERS DISTINGUISHING ACO FROM COPD AND ASTHMA; (III) POTENTIAL EPIGENETIC DRUGS THAT CAN REVERSE OXIDATIVE STRESS, GLUCOCORTICOID INSENSITIVITY, AND CELL INJURY. IMPROVED UNDERSTANDING OF THE EPIGENETIC REGULATIONS HOLDS GREAT VALUE TO GIVE DEEPER INSIGHT INTO THE MECHANISMS, AND CLARIFY THEIR IMPLICATIONS FOR BIOMEDICAL RESEARCH IN ACO. 2022 10 5153 28 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION. 2019 11 4665 30 NEW INSIGHTS AND ADVANCES IN PATHOGENESIS AND TREATMENT OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE. VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE (VEO-IBD) IS CHARACTERIZED BY MULTIFACTORIAL CHRONIC RECURRENT INTESTINAL INFLAMMATION. COMPARED WITH ELDERLY PATIENTS, THOSE WITH VEO-IBD HAVE A MORE SERIOUS CONDITION, NOT RESPONSIVE TO CONVENTIONAL TREATMENTS, WITH A POOR PROGNOSIS. RECENT STUDIES FOUND THAT GENETIC AND IMMUNOLOGIC ABNORMALITIES ARE CLOSELY RELATED TO VEO-IBD. INTESTINAL IMMUNE HOMEOSTASIS MONOGENIC DEFECTS (IIHMDS) ARE CHANGED THROUGH VARIOUS MECHANISMS. RECENT STUDIES HAVE ALSO REVEALED THAT ABNORMALITIES IN GENES AND IMMUNE MOLECULAR MECHANISMS ARE CLOSELY RELATED TO VEO-IBD. IIHMDS CHANGE THROUGH VARIOUS MECHANISMS. EPIGENETIC FACTORS CAN MEDIATE THE INTERACTION BETWEEN THE ENVIRONMENT AND GENOME, AND GENETIC FACTORS AND IMMUNE MOLECULES MAY BE INVOLVED IN THE PATHOGENESIS OF THE ENVIRONMENT AND GUT MICROBIOTA. THESE DISCOVERIES WILL PROVIDE NEW DIRECTIONS AND IDEAS FOR THE TREATMENT OF VEO-IBD. 2022 12 3933 30 LIVER SINUSOIDAL ENDOTHELIAL CELLS ARE IMPLICATED IN MULTIPLE FIBROTIC MECHANISMS. CHRONIC LIVER DISEASES ARE ATTRIBUTED TO LIVER INJURY. DEVELOPMENT OF FIBROSIS FROM CHRONIC LIVER DISEASES IS A DYNAMIC PROCESS THAT INVOLVES MULTIPLE MOLECULAR AND CELLULAR PROCESSES. AS THE FIRST TO BE IMPACTED BY INJURY, LIVER SINUSOIDAL ENDOTHELIAL CELLS (LSECS) ARE INVOLVED IN THE PATHOGENESIS OF LIVER DISEASES CAUSED BY A VARIETY OF ETIOLOGIES. MOREOVER, CAPILLARIZATION OF LSECS HAS BEEN RECOGNIZED AS AN IMPORTANT EVENT IN THE DEVELOPMENT OF CHRONIC LIVER DISEASES AND FIBROSIS. STUDIES HAVE REPORTED THAT VARIOUS CYTOKINES (SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR, TRANSFORMING GROWTH FACTOR-BETA), AND PATHWAYS (SUCH AS HEDGEHOG, AND NOTCH), AS WELL AS EPIGENETIC AND METABOLIC FACTORS ARE INVOLVED IN THE DEVELOPMENT OF LSEC-MEDIATED LIVER FIBROSIS. THIS REVIEW DESCRIBES THE COMPLEXITY AND PLASTICITY OF LSECS IN FIBROTIC LIVER DISEASES FROM SEVERAL PERSPECTIVES, INCLUDING THE CROSS-TALK BETWEEN LSECS AND OTHER INTRA-HEPATIC CELLS. MOREOVER, IT SUMMARIZES THE MECHANISMS OF SEVERAL KINDS OF LSECS-TARGETING ANTI-FIBROSIS CHEMICALS, AND PROVIDES A THEORETICAL BASIS FOR FUTURE STUDIES. 2021 13 3899 29 LATE NEUROLOGICAL CONSEQUENCES OF ZIKA VIRUS INFECTION: RISK FACTORS AND PHARMACEUTICAL APPROACHES. ZIKA VIRUS (ZIKV) INFECTION WAS HISTORICALLY CONSIDERED A DISEASE WITH MILD SYMPTOMS AND NO MAJOR CONSEQUENCES TO HUMAN HEALTH. HOWEVER, SEVERAL LONG-TERM, LATE ONSET, AND CHRONIC NEUROLOGICAL COMPLICATIONS, BOTH IN CONGENITALLY-EXPOSED BABIES AND IN ADULT PATIENTS, HAVE BEEN REPORTED AFTER ZIKV INFECTION, ESPECIALLY AFTER THE 2015 EPIDEMICS IN THE AMERICAN CONTINENT. THE DEVELOPMENT OR SEVERITY OF THESE CONDITIONS CANNOT BE FULLY PREDICTED, BUT IT IS POSSIBLE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO DETERMINE ZIKV INFECTION OUTCOMES. THIS REINFORCES THE IMPORTANCE THAT INDIVIDUALS EXPOSED TO ZIKV ARE SUBMITTED TO LONG-TERM CLINICAL SURVEILLANCE AND HIGHLIGHTS THE URGENT NEED FOR THE DEVELOPMENT OF THERAPEUTIC APPROACHES TO REDUCE OR ELIMINATE THE NEUROLOGICAL BURDEN OF INFECTION. HERE, WE REVIEW THE EPIDEMIOLOGY OF ZIKV-ASSOCIATED NEUROLOGICAL COMPLICATIONS AND THE ROLE OF FACTORS THAT MAY INFLUENCE DISEASE OUTCOME. MOREOVER, WE DISCUSS EXPERIMENTAL AND CLINICAL EVIDENCE OF DRUGS THAT HAVE SHOWN PROMISING RESULTS IN VITRO OR IN VITRO AGAINST VIRAL REPLICATION AND AND/OR ZIKV-INDUCED NEUROTOXICITY. 2019 14 6584 35 TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 : OUR NEW PARTNER IN HUMAN ONCOLOGY? INFLAMMATION IS RECOGNIZED AS ONE OF THE HALLMARKS OF CANCER. INDEED, STRONG EVIDENCE INDICATES THAT CHRONIC INFLAMMATION PLAYS A MAJOR ROLE IN ONCOGENESIS, PROMOTING GENOME INSTABILITY, EPIGENETIC ALTERATIONS, PROLIFERATION AND DISSEMINATION OF CANCER CELLS. MONONUCLEAR PHAGOCYTES (MPS) HAVE BEEN IDENTIFIED AS KEY CONTRIBUTORS OF THE INFLAMMATORY INFILTRATE IN SEVERAL SOLID HUMAN NEOPLASIA, PROMOTING ANGIOGENESIS AND CANCER PROGRESSION. ONE OF THE MOST DESCRIBED AMPLIFIERS OF MPS PRO-INFLAMMATORY INNATE IMMUNE RESPONSE IS THE TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 (TREM-1). GROWING EVIDENCE SUGGESTS TREM-1 INVOLVEMENT IN ONCOGENESIS THROUGH CANCER RELATED INFLAMMATION AND THE SURROUNDING TUMOR MICROENVIRONMENT. IN HUMAN ONCOLOGY, HIGH LEVELS OF TREM-1 AND/OR ITS SOLUBLE FORM HAVE BEEN ASSOCIATED WITH POORER SURVIVAL DATA IN SEVERAL SOLID MALIGNANCIES, ESPECIALLY IN HEPATOCELLULAR CARCINOMA AND LUNG CANCER. TREM-1 SHOULD BE CONSIDERED AS A POTENTIAL BIOMARKER IN HUMAN ONCOLOGY AND COULD BE USED AS A NEW THERAPEUTIC TARGET OF INTEREST IN HUMAN ONCOLOGY (TREM-1 INHIBITORS, TREM-1 AGONISTS). MORE CLINICAL STUDIES ARE URGENTLY NEEDED TO CONFIRM TREM-1 (AND TREM FAMILY) ROLES IN THE PROGNOSIS AND THE TREATMENT OF HUMAN SOLID CANCERS. 2022 15 5392 48 REDOXISOME AND DIABETIC RETINOPATHY: PATHOPHYSIOLOGY AND THERAPEUTIC INTERVENTIONS. DIABETIC RETINOPATHY (DR) IS A CHRONIC MICROVASCULAR COMPLICATION OF DIABETES MELLITUS (DM). IT IS A WORLDWIDE GROWING EPIDEMIC DISEASE CONSIDERED TO BE THE LEADING CAUSE OF VISION-LOSS AND BLINDNESS IN PEOPLE WITH DM. REDOX REACTIONS OCCURRING AT THE EXTRA- AND INTRACELLULAR LEVELS ARE ESSENTIAL FOR THE MAINTENANCE OF CELLULAR HOMEOSTASIS. DYSREGULATION OF REDOX HOMEOSTASIS ARE IMPLICATED IN THE ONSET AND DEVELOPMENT OF DR. THIOREDOXIN1 (TRX1) AND THIOREDOXIN2 (TRX2) ARE CYTOPLASMIC AND MITOCHONDRIALLY LOCALIZED ANTIOXIDANT PROTEINS UBIQUITOUSLY EXPRESSED IN VARIOUS CELLS AND CONTROL CELLULAR REACTIVE OXYGEN SPECIES (ROS) BY REDUCING THE DISULFIDES INTO THIOL GROUPS. THIOREDOXIN-INTERACTING PROTEIN (TXNIP) BINDS TO TRX SYSTEM AND INHIBITS THE ACTIVE REDUCED FORM OF TRX THROUGH DISULFIDE EXCHANGE REACTION. RECENT STUDIES INDICATE THE ASSOCIATION OF TRX/TXNIP WITH REDOX SIGNAL TRANSDUCTION PATHWAYS INCLUDING ACTIVATION OF NOD-LIKE RECEPTOR PYRIN DOMAIN CONTAINING PROTEIN-3 (NLRP3) INFLAMMASOME, APOPTOSIS, AUTOPHAGY/MITOPHAGY, EPIGENETIC MODIFICATIONS IN A REDOX-DEPENDENT MANNER. THUS, IT IS IMPORTANT TO GAIN A MORE IN-DEPTH UNDERSTANDING ABOUT THE CELLULAR AND MOLECULAR MECHANISMS THAT LINKS REDOXISOME AND ER/MITOCHONDRIAL DYSFUNCTION TO DRIVE THE PROGRESSION OF DR. THE PURPOSE OF THIS REVIEW IS TO PROVIDE A MECHANISTIC UNDERSTANDING OF THE COMPLEX MOLECULAR MECHANISMS AND PATHOPHYSIOLOGICAL ROLES ASSOCIATED WITH REDOXISOME, THE TRX/TXNIP REDOX SIGNALING COMPLEX UNDER OXIDATIVE STRESS IN THE DEVELOPMENT OF DR. ALSO, THE MOLECULAR TARGETS OF FDA APPROVED DRUGS AND CLINICAL TRIALS IN ADDITION TO EFFECTIVE ANTIOXIDANT STRATEGIES FOR THE TREATMENT OF DIABETIC RETINOPATHY ARE REVIEWED. 2022 16 6398 32 THE ROLE OF VITAMIN D AND VDR IN CARCINOGENESIS: THROUGH EPIDEMIOLOGY AND BASIC SCIENCES. IN THE LAST TWO DECADES VITAMIN D (VD) RESEARCH HAS DEMONSTRATED NEW EXTRASKELETAL ACTIONS OF THIS PRE-HORMONE, SUGGESTING A PROTECTIVE ROLE OF THIS SECOSTEROID IN THE ONSET, PROGRESSION AND PROGNOSIS OF SEVERAL CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS CARDIOVASCULAR DISEASE, DIABETES MELLITUS OR CANCER. REGARDING CARCINOGENESIS, BOTH PRECLINICAL AND EPIDEMIOLOGICAL EVIDENCE AVAILABLE SHOW ONCOPROTECTIVE ACTIONS OF VD AND ITS RECEPTOR, THE VDR. HOWEVER, IN LATE NEOPLASTIC STAGES THE VD SYSTEM (VDS) SEEMS TO BE LESS FUNCTIONAL, WHICH APPEARS TO BE DUE TO AN EPIGENETIC SILENCING OF THE SYSTEM. IN PRECLINICAL EXPERIMENTAL STUDIES, VD PRESENTS ONCOPROTECTIVE ACTIONS THROUGH MODULATION OF INFLAMMATION, CELL PROLIFERATION, CELL DIFFERENTIATION, ANGIOGENESIS, INVASIVE AND METASTATIC POTENTIAL, APOPTOSIS, MIRNA EXPRESSION REGULATION AND MODULATION OF THE HEDGEHOG SIGNALLING PATHWAY. MOREOVER, EPIDEMIOLOGICAL EVIDENCE POINTS TOWARDS AN ONCOPROTECTIVE ROLE OF VITAMIN D AND VDR IN COLORECTAL CANCER. THIS ASSOCIATION IS MORE CONTROVERSIAL WITH BREAST, OVARIAN AND PROSTATE CANCERS, ALTHOUGH WITH A FEW ADVERSE EFFECTS. NONETHELESS, WE SHOULD CONSIDER OTHER FACTORS TO DETERMINE THE BENEFIT OF INCREASED SERUM CONCENTRATION OF VD. MUCH OF THE EPIDEMIOLOGICAL EVIDENCE IS STILL INCONCLUSIVE, AND WE WILL HAVE TO WAIT FOR NEW, BETTER-DESIGNED ONGOING RCTS AND THEIR RESULTS TO DISCERN THE REAL EFFECT OF VITAMIN D IN CANCER RISK REDUCTION AND THERAPY. THE OBJECTIVE OF THIS LITERATURE REVIEW IS TO OFFER AN UP-TO-DATE ANALYSIS OF THE ROLE OF THE VD AND VDR, IN THE ONSET, PROGRESSION AND PROGNOSIS OF ALL TYPES OF CANCER. WE FURTHER DISCUSS THE AVAILABLE LITERATURE AND SUGGEST NEW HYPOTHESES AND FUTURE CHALLENGES IN THE FIELD OF VD RESEARCH. 2017 17 2616 34 EPIGENOME MODULATION INDUCED BY KETOGENIC DIETS. KETOGENIC DIETS (KD) ARE DIETARY STRATEGIES LOW IN CARBOHYDRATES, NORMAL IN PROTEIN, AND HIGH, NORMAL, OR REDUCED IN FAT WITH OR WITHOUT (VERY LOW-CALORIES KETOGENIC DIET, VLCKD) A REDUCED CALORIC INTAKE. KDS HAVE BEEN SHOWN TO BE USEFUL IN THE TREATMENT OF OBESITY, METABOLIC DISEASES AND RELATED DISORDERS, NEUROLOGICAL DISEASES, AND VARIOUS PATHOLOGICAL CONDITIONS SUCH AS CANCER, NONALCOHOLIC LIVER DISEASE, AND CHRONIC PAIN. SEVERAL STUDIES HAVE INVESTIGATED THE INTRACELLULAR METABOLIC PATHWAYS THAT CONTRIBUTE TO THE BENEFICIAL EFFECTS OF THESE DIETS. ALTHOUGH EPIGENETIC CHANGES ARE AMONG THE MOST IMPORTANT DETERMINANTS OF AN ORGANISM'S ABILITY TO ADAPT TO ENVIRONMENTAL CHANGES, DATA ON THE EPIGENETIC CHANGES ASSOCIATED WITH THESE DIETARY PATHWAYS ARE STILL LIMITED. THIS REVIEW PROVIDES AN OVERVIEW OF THE MAJOR EPIGENETIC CHANGES ASSOCIATED WITH KDS. 2022 18 5374 30 RECENT ADVANCES IN UNDERSTANDING/MANAGEMENT OF PREMENSTRUAL DYSPHORIC DISORDER/PREMENSTRUAL SYNDROME. PREMENSTRUAL SYNDROME (PMS) AND PREMENSTRUAL DYSPHORIC DISORDER (PMDD) ARE COMMON DISORDERS OF THE LUTEAL PHASE OF THE MENSTRUAL CYCLE AND ARE CHARACTERIZED BY MODERATE TO SEVERE PHYSICAL, AFFECTIVE, OR BEHAVIORAL SYMPTOMS THAT IMPAIR DAILY ACTIVITIES AND QUALITY OF LIFE. PMS AND PMDD HAVE RECENTLY RAISED GREAT INTEREST IN THE RESEARCH COMMUNITY FOR THEIR CONSIDERABLE GLOBAL PREVALENCE. THE ETIOLOGY OF PMS/PMDD IS COMPLEX. OVARIAN REPRODUCTIVE STEROIDS (ESTRADIOL AND PROGESTERONE) ARE CONSIDERED PATHOGENETIC EFFECTORS, BUT THE KEY FEATURE SEEMS TO BE AN ALTERED SENSITIVITY OF THE GABAERGIC CENTRAL INHIBITORY SYSTEM TO ALLOPREGNANOLONE, A NEUROSTEROID DERIVED FROM PROGESTERONE PRODUCED AFTER OVULATION. ALSO, A REDUCED AVAILABILITY OF SEROTONIN SEEMS TO BE INVOLVED. NEW INSIGHTS POINT TO A ROLE FOR GENETIC AND EPIGENETIC MODIFICATIONS OF HORMONAL AND NEUROTRANSMITTER PATHWAYS, AND INFLAMMATION IS THE POTENTIAL LINK BETWEEN PERIPHERAL AND NEUROLOGICAL INTEGRATED RESPONSES TO STRESSORS. THUS, NEW THERAPEUTIC APPROACHES TO PMS/PMDD INCLUDE INHIBITION OF PROGESTERONE RECEPTORS IN THE BRAIN (I.E., WITH ULIPRISTAL ACETATE), REDUCED CONVERSION OF PROGESTERONE TO ITS METABOLITE ALLOPREGNANOLONE WITH DUTASTERIDE, AND POSSIBLE MODULATION OF THE ACTION OF ALLOPREGNANOLONE ON THE BRAIN GABAERGIC SYSTEM WITH SEPRANOLONE. FURTHER RESEARCH IS NEEDED TO BETTER UNDERSTAND THE INTERACTION BETWEEN PERIPHERAL INFLAMMATORY MOLECULES (CYTOKINES, INTERLEUKINS, C-REACTIVE PROTEIN, AND REACTIVE OXYGEN SPECIES) AND THE BRAIN NEUROTRANSMITTER SYSTEMS IN WOMEN WITH PMS/PMDD. IF CONFIRMED, NEUROINFLAMMATION COULD LEAD BOTH TO DEVELOP TARGETED ANTI-INFLAMMATORY THERAPIES AND TO DEFINE PREVENTION STRATEGIES FOR THE ASSOCIATED CHRONIC INFLAMMATORY RISK IN PMS/PMDD. FINALLY, THE OBSERVED ASSOCIATION BETWEEN PREMENSTRUAL DISORDERS AND PSYCHOLOGICAL DISEASES MAY GUIDE PROMPT AND ADEQUATE INTERVENTIONS TO ACHIEVE A BETTER QUALITY OF LIFE. 2022 19 4143 30 MECHANISMS OF SCARRING IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS. FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) PRESENTS WITH SCAR IN PARTS OF SOME GLOMERULI AND OFTEN PROGRESSES TO GLOBAL AND DIFFUSE GLOMERULOSCLEROSIS. PODOCYTE INJURY IS THE INITIAL TARGET IN PRIMARY FSGS, INDUCED BY A CIRCULATING FACTOR. SEVERAL GENE VARIANTS, FOR EXAMPLE, APOL1, ARE ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO FSGS. PRIMARY FSGS MAY BE DUE TO GENETIC MUTATION IN KEY PODOCYTE GENES. INCREASED WORK STRESS AFTER LOSS OF NEPHRONS, EPIGENETIC MECHANISMS, AND VARIOUS PROFIBROTIC PATHWAYS CAN CONTRIBUTE TO PROGRESSIVE SCLEROSIS, REGARDLESS OF THE INITIAL INJURY. THE PROGRESSION OF FSGS LESIONS ALSO INVOLVES CROSSTALK BETWEEN PODOCYTES AND OTHER KIDNEY CELLS, SUCH AS PARIETAL EPITHELIAL CELLS, GLOMERULAR ENDOTHELIAL CELLS, AND EVEN TUBULAR EPITHELIAL CELLS. NEW INSIGHTS RELATED TO THESE MECHANISMS COULD POTENTIALLY LEAD TO NEW THERAPEUTIC STRATEGIES TO PREVENT PROGRESSION OF FSGS. 2019 20 3762 40 INTEGRATING THE TUMOR-SUPPRESSIVE ACTIVITY OF MASPIN WITH P53 IN RETUNING THE EPITHELIAL HOMEOSTASIS: A WORKING HYPOTHESIS AND APPLICABLE PROSPECTS. EPITHELIAL MALIGNANT TRANSFORMATION AND TUMOROUS DEVELOPMENT WERE BELIEVED TO BE CLOSELY ASSOCIATED WITH THE LOSS OF ITS MICROENVIRONMENT INTEGRITY AND HOMEOSTASIS. THE TUMOR-SUPPRESSIVE MOLECULES MASPIN AND P53 WERE DEMONSTRATED TO PLAY A CRUCIAL ROLE IN BODY EPITHELIAL AND IMMUNE HOMEOSTASIS. DOWNREGULATION OF MASPIN AND MUTATION OF P53 WERE FREQUENTLY ASSOCIATED WITH MALIGNANT TRANSFORMATION AND POOR PROGNOSIS IN VARIOUS HUMAN CANCERS. IN THIS REVIEW, WE FOCUSED ON SUMMARIZING THE PROGRESS OF THE MOLECULAR NETWORK OF MASPIN IN STUDYING EPITHELIAL TUMOROUS DEVELOPMENT AND ITS RESPONSE TO CLINIC TREATMENT AND TRY TO CLARIFY THE UNDERLYING ANTITUMOR MECHANISM. NOTABLY, MASPIN EXPRESSION WAS REPORTED TO BE TRANSCRIPTIONALLY ACTIVATED BY P53, AND THE TRANSCRIPTIONAL ACTIVITY OF P53 WAS DEMONSTRATED TO BE ENHANCED BY ITS ACETYLATION THROUGH INHIBITION OF HDAC1. AS AN ENDOGENOUS INHIBITOR OF HDAC1, MASPIN POSSIBLY POTENTIATES THE TRANSCRIPTIONAL ACTIVITY OF P53 BY ACETYLATING THE P53 PROTEIN. HEREBY, IT COULD FORM A "SELF-PROPELLING" ANTITUMOR MECHANISM. THUS, WE SUMMARIZED THAT, UPON STIMULATION OF CELLULAR STRESS AND BY INTEGRATING WITH P53, THE AROUSED MASPIN PLAYED THE EPIGENETIC SURVEILLANT ROLE TO PREVENT THE EPITHELIAL DIGRESSIONAL PROCESS AND RETUNE THE EPITHELIAL HOMEOSTASIS, WHICH IS INVOLVED IN ACTIVATING HOST IMMUNE SURVEILLANCE, REGULATING THE INFLAMMATORY FACTORS, AND FINE-TUNING ITS ASSOCIATED CELL SIGNALING PATHWAYS. CONSEQUENTIALLY, IN A NORMAL PHYSIOLOGICAL CONDITION, ACTIVATION OF THE ABOVE "SELF-PROPELLING" ANTITUMOR MECHANISM OF MASPIN AND P53 COULD REDUCE CELLULAR STRESS (E.G., CHRONIC INFECTION/INFLAMMATION, OXIDATIVE STRESS, TRANSFORMATION) EFFECTIVELY AND ACHIEVE CANCER PREVENTION. MEANWHILE, DESIGNING A STRATEGY OF MIMICKING MASPIN'S EPIGENETIC REGULATION ACTIVITY WITH INTEGRATING P53 TUMOR-SUPPRESSIVE ACTIVITY COULD ENHANCE THE CHEMOTHERAPY EFFICACY THEORETICALLY IN A PATHOLOGICAL CONDITION OF CANCER. 2022