1 429 99 ANTI-INFLAMMATORY TOPICAL MEDICATION - NEW DEVELOPMENTS IN THE TREATMENT OF ATOPIC DERMATITIS. ATOPIC DERMATITIS IS A CHRONIC INFLAMMATORY DISEASE THAT ARISES FROM POLYGENIC DISPOSITION, A DYSFUNCTION OF THE PHYSICOCHEMICAL EPITHELIAL BARRIER, A CUTANEOUS DYSBIOSIS, AND A FAULTY NEUROSENSORY ACTIVITY AND SHOWS A HIGHLY INDIVIDUAL ACUITY DUE TO EPIGENETIC FACTORS. AN ESSENTIAL COMPONENT OF THERAPEUTIC MANAGEMENT IS THE APPLICATION OF ANTI-INFLAMMATORY TOPICAL MEDICATION. CURRENTLY, TOPICAL GLUCOCORTICOIDS AND TOPICAL CALCINEURIN INHIBITORS ARE ROUTINELY USED IN REACTIVE AND PROACTIVE THERAPY. IN RECENT YEARS, THE DEVELOPMENT OF MOLECULAR MEDICINE HAS IDENTIFIED SEVERAL NEW THERAPEUTIC TARGETS THAT HAVE ENABLED THE DEVELOPMENT OF INNOVATIVE THERAPEUTIC APPROACHES. IN ADDITION TO PHOSPHODIESTERASE-4 INHIBITORS AND ARYL HYDROCARBON RECEPTOR MODULATORS, IT IS MAINLY JANUS KINASE INHIBITORS WITH DIFFERENT SELECTIVITY THAT ARE EMERGING AS NEW EFFECTIVE AND SAFE OPTIONS FOR TOPICAL THERAPY. THE CURRENT DATA SUGGESTS THAT IN THE COMING MONTHS AND YEARS REPRESENTATIVES OF THE ABOVE-MENTIONED SUBSTANCE CLASSES WILL BE APPROVED FOR TOPICAL USE. 2021 2 1943 31 EPIDERMAL GROWTH FACTOR IN HEALING DIABETIC FOOT ULCERS: FROM GENE EXPRESSION TO TISSUE HEALING AND SYSTEMIC BIOMARKER CIRCULATION. LOWER-EXTREMITY DIABETIC ULCERS ARE RESPONSIBLE FOR 80% OF ANNUAL WORLDWIDE NONTRAUMATIC AMPUTATIONS. EPIDERMAL GROWTH FACTOR (EGF) REDUCTION IS ONE OF THE MOLECULAR PILLARS OF DIABETIC ULCER CHRONICITY, THUS EGF ADMINISTRATION MAY BE CONSIDERED A TYPE OF REPLACEMENT THERAPY. TOPICAL EGF AD-MINISTRATION TO IMPROVE AND SPEED WOUND HEALING BEGAN IN 1989 ON BURN PATIENTS AS PART OF AN ACUTE-HEALING THERAPY. FURTHER CLINICAL STUDIES BASED ON TOPICALLY ADMINISTERING EGF TO DIFFERENT CHRONIC WOUNDS RESULTED IN DISAPPOINTING OUT-COMES. AN ANALYSIS OF THE LITERATURE ON UNSUCCESSFUL CLINICAL TRIALS IDENTIFI ED A LACK OF KNOWLEDGE CONCERNING: (I) MOLECULAR AND CELLULAR FOUNDATIONS OF WOUND CHRONICITY AND (II) THE PHAR-MACODYNAMIC REQUISITES GOVERNING EGF INTERACTION WITH ITS RECEPTOR TO PROMOTE CELL RESPONSE. YET, EGF INTRA- AND PERILE-SIONAL INFI LTRATION WERE SHOWN TO CIRCUMVENT THE PHARMACODY-NAMIC LIMITATIONS OF TOPICAL APPLICATION. SINCE THE FI RST STUDIES, THE FOLLOWING DECADES OF BASIC AND CLINICAL RESEARCH ON EGF THERAPY FOR PROBLEM WOUNDS HAVE SHED LIGHT ON POTENTIAL USES OF GROWTH FACTORS IN REGENERATIVE MEDICINE. EGF'S MOLECULAR AND BIOCHEMICAL EFFECTS AT BOTH LOCAL AND SYSTEMIC LEVELS ARE DIVERSE: (1) DOWNREGULATION OF GENES ENCODING INFL AMMATION MEDIATORS AND INCREASED EXPRESSION OF GENES INVOLVED IN CELL PROLIFERATION, ANGIOGENESIS AND MATRIX SECRETION; (2) EGF IN-TERVENTION POSITIVELY IMPACTS BOTH MESENCHYMAL AND EPITHELIAL CELLS, REDUCING INFL AMMATION AND STIMULATING THE RECRUITMENT OF PRECURSOR CIRCULATING CELLS THAT PROMOTE THE FORMATION OF NEW BLOOD VESSELS; (3) AT THE SUBCELLULAR LEVEL, UPREGULATION OF THE EGF RECEPTOR WITH SUBSEQUENT INTRACELLULAR TRAFFI CKING, INCLUD-ING MITOCHONDRIAL ALLOCATION ALONG WITH RESTORED MORPHOLOGY OF MULTIPLE ORGANELLES; AND (4) LOCAL EGF INFI LTRATION RESULTING IN A SYSTEMIC, ORGANISMAL REPERCUSSION, THUS CONTRIBUTING TO ATTENUATION OF CIRCULATING INFL AMMATORY AND CATABOLIC REAC-TANTS, RESTORED REDUCTION-OXIDATION BALANCE, AND DECREASED TOXIC GLYCATION PRODUCTS AND SOLUBLE APOPTOGENIC EFFECTORS. IT IS LIKELY THAT EGF TREATMENT MAY REARRANGE CRITICAL EPIGENETIC DRIVERS OF DIABETIC METABOLIC MEMORY. KEYWORDS EPIDERMAL GROWTH FACTOR, DIABETES, DIABETES COMPLICATIONS, WOUND HEALING, DIABETIC FOOT, AMPUTATION, ULCER, CUBA. 2020 3 3730 25 INHIBITION OF THE COREST REPRESSOR COMPLEX PROMOTES WOUND RE-EPITHELIALIZATION VIA REGULATION OF KERATINOCYTE MIGRATION. WOUND HEALING IS A COMPLEX PROCESS INVOLVING PHASES OF HEMOSTASIS, INFLAMMATION, PROLIFERATION, AND REMODELING. THE REGENERATIVE PROCESS IN THE SKIN REQUIRES COORDINATION BETWEEN MANY REGULATORS INCLUDING SIGNALING MOLECULES, TRANSCRIPTION FACTORS AND THE EPIGENETIC MACHINERY. HERE WE SHOW THAT CHROMATIN REGULATORS HISTONE DEACETYLASE 1 (HDAC1) AND LYSINE-SPECIFIC HISTONE DEMETHYLASE 1 (LSD1), KEY COMPONENTS OF THE COREST REPRESSOR COMPLEX, ARE UPREGULATED IN THE REGENERATING EPIDERMIS DURING WOUND REPAIR. WE ALSO SHOW THAT CORIN, A SYNTHETIC DUAL INHIBITOR OF THE COREST COMPLEX AND HDAC1/LSD1 ACTIVITIES, SIGNIFICANTLY ACCELERATES WOUND CLOSURE THROUGH ENHANCED RE-EPITHELIALIZATION IN A MOUSE TAIL WOUND MODEL. ACETYLATED H3K9 EXPRESSION, A HISTONE MODIFICATION TARGETED BY HDAC1, IS INCREASED IN KERATINOCYTES AFTER TOPICAL TREATMENT WITH 100 NM AND 1 MUM OF CORIN. IN VITRO EXPERIMENTS DEMONSTRATE THAT CORIN PROMOTES MIGRATION AND INHIBITS PROLIFERATION OF HUMAN KERATINOCYTES. FURTHERMORE, EXPRESSION LEVELS OF GENES PROMOTING KERATINOCYTE MIGRATION, SUCH AS AREG, CD24, EPHB2, ITGAX, PTGS, SCT1, SERPINB2, SERPINE1, SLPI, SNAI2 AND TWIST INCREASED IN KERATINOCYTES TREATED WITH CORIN. THESE DATA DEMONSTRATE THAT DUAL INHIBITION OF CLASS I HDACS AND LSD1 BY CORIN, MAY SERVE AS A NEW APPROACH FOR PROMOTING WOUND RE-EPITHELIALIZATION AND PROVIDE A PLATFORM FOR FURTHER APPLICATIONS OF CORIN FOR THE TREATMENT OF CHRONIC WOUNDS. 2023 4 5087 32 PIMECROLIMUS FOR THE TREATMENT OF ATOPIC DERMATITIS IN INFANTS: AN ASIAN PERSPECTIVE. ATOPIC DERMATITIS (AD) IS A COMMON CHRONIC, MULTISYSTEM INFLAMMATORY SKIN DISEASE IN PEDIATRIC PATIENTS. THERE HAS BEEN AN INCREASE IN THE INCIDENCE OF AD IN THE PEDIATRIC POPULATION OF THE ASIA-PACIFIC REGION. STUDIES HAVE SHOWN THAT GENETIC, EPIGENETIC, ENVIRONMENTAL AND CULTURAL FACTORS MAY LEAD TO DIFFERENCES IN THE CLINICAL MANIFESTATION AND PREVALENCE OF AD BETWEEN RACES. EARLY TREATMENT OF AD IS NECESSARY TO PREVENT THE ATOPIC MARCH LEADING TO COMORBIDITIES SUCH AS ASTHMA AND ALLERGIC RHINITIS. TOPICAL CORTICOSTEROIDS (TCS) ARE USED AS FIRST-LINE THERAPY FOR THE TREATMENT OF AD, BUT THEIR LONG-TERM USAGE POSES A RISK TO THE PATIENT'S HEALTH. PIMECROLIMUS (1%) IS A TOPICAL CALCINEURIN INHIBITOR (TCI) THAT IS INDICATED FOR THE TREATMENT OF MILD TO MODERATE AD. PIMECROLIMUS HAS NO APPARENT INCREASE IN ADVERSE EVENTS COMPARED TO TCS, AND IT CAUSES LESS OF A BURNING SENSATION THAN TACROLIMUS. THE SAFETY AND EFFICACY OF PIMECROLIMUS HAS BEEN ESTABLISHED THROUGH VARIOUS CLINICAL TRIALS; YET, IN MANY ASIAN COUNTRIES, THE USE OF PIMECROLIMUS IN INFANTS IS STILL RESTRICTED DUE TO SAFETY CONCERNS. BASED ON THE AVAILABLE EVIDENCE, THE EXPERT PANEL RECOMMENDS PIMECROLIMUS IN INFANTS BETWEEN 3 MONTHS AND 2 YEARS OF AGE IN THE ASIAN POPULATION. 2023 5 2726 34 EXPERIMENTAL PHARMACOLOGICAL MANAGEMENT OF PSORIASIS. PSORIASIS IS A CHRONIC, RELAPSING, IMMUNE-MEDIATED SYSTEMIC DISEASE. ITS PATHOGENESIS IS COMPLEX AND NOT FULLY UNDERSTOOD YET. GENETIC AND EPIGENETIC FACTORS INTERACT WITH MOLECULAR PATHWAYS INVOLVING TNF-ALPHA, IL-23/IL-17 AXIS, AND PECULIAR CYTOKINES, AS IL-36 OR PHOSPHODIESTERASE 4. THIS REVIEW DISCUSSES THE MECHANISMS INVOLVED IN THE DEVELOPMENT OF THE DISEASE, AS WELL AS THE THERAPEUTIC OPTIONS PROPOSED FOLLOWING THE INVESTIGATION OF THE INFLAMMATORY PSORIATIC PATHWAYS. WE PERFORMED A COMPREHENSIVE SEARCH USING THE WORDS "PSORIASIS" AND THE NEWEST MOLECULES CURRENTLY UNDER INVESTIGATION AND APPROVAL. FROM THESE DATA, A NEW SCENARIO IN PSORIASIS IS OCCURRING TO PERSONALIZE THE THERAPIES - ESPECIALLY SYSTEMIC ONES AND THOSE USING SMALL MOLECULES - AND AVOID TOPICAL AND INJECTABLE DRUGS. WE REPORTED THE NEWEST THERAPEUTIC OPPORTUNITIES, INCLUDING THE INHIBITORS OF JANUS KINASE/TYROSINE KINASE 2, PHOSPHODIESTERASE-4 AND IL-36 RECEPTOR. TODAY, MORE THAN 20 MOLECULES ARE UNDER INVESTIGATION FOR THE TREATMENT OF CUTANEOUS PSORIASIS. MOST OF THEM ARE CONSTITUTED BY SMALL MOLECULES OR BIOLOGIC THERAPIES. THIS UNDERLINES HOW PSORIASIS NEEDS SYSTEMIC THERAPIES, DUE TO ITS COMPLEX PATHOGENESIS AND MULTISYSTEMIC INVOLVEMENT. 2021 6 5172 31 PREDICTING PAIN AFTER STANDARD PAIN THERAPY FOR KNEE OSTEOARTHRITIS - THE FIRST STEPS TOWARDS PERSONALIZED MECHANISTIC-BASED PAIN MEDICINE IN OSTEOARTHRITIS. OBJECTIVES: THE PREVALENCE OF OSTEOARTHRITIS (OA) IS RISING, AND PAIN IS THE HALLMARK SYMPTOM OF OA. PAIN IN OA IS COMPLICATED AND CAN BE INFLUENCED BY MULTIPLE JOINT-RELATED FACTORS AND FACTORS RELATED TO, E.G., PHYSIOLOGICAL, EPIGENETIC, AND PAIN SENSORY PROFILES. INCREASING EVIDENCE SUGGESTS THAT A SUBSET OF PATIENTS WITH OA ARE PAIN SENSITIVE. THIS CAN BE ASSESSED USING QUANTITATIVE SENSORY TESTING (QST). COMMON TREATMENTS OF OA ARE TOTAL KNEE ARTHROPLASTY (TKA) AND ADMINISTRATION OF 3-WEEKS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS), WHICH PROVIDE PAIN RELIEF TO MANY PATIENTS WITH OA. HOWEVER, APPROX. 20% OF PATIENTS EXPERIENCE CHRONIC POSTOPERATIVE PAIN AFTER TKA, WHEREAS NSAIDS PROVIDE AN AVERAGE PAIN RELIEF OF APPROX. 25%. THE CURRENT TOPICAL REVIEW FOCUSES ON THE EMERGING EVIDENCE LINKING PRETREATMENT QST TO THE TREATMENT RESPONSE OF TKA AND NSAID TREATMENTS. CONTENT: MEDLINE WAS SYSTEMATICALLY SEARCHED FOR ALL STUDIES FROM 2000 TO 2022 ON PRETREATMENT QST, TKA, AND NSAIDS. PRE-CLINICAL STUDIES, REVIEWS, AND META-ANALYSES WERE EXCLUDED. SUMMARY: CURRENTLY, 14 STUDIES ON TKA AND FOUR STUDIES ON NSAIDS HAVE BEEN PUBLISHED WITH THE AIM TO ATTEMPT PREDICTION OF THE TREATMENT RESPONSE. THE QST METHODOLOGIES IN THE STUDIES ARE INCONSISTENT, BUT 11/14 (79%) STUDIES ON TKA AND 4/4 (100%) STUDIES ON NSAIDS REPORT STATISTICALLY SIGNIFICANT ASSOCIATIONS BETWEEN PRETREATMENT QST AND CHRONIC POSTOPERATIVE PAIN AFTER TKA OR ANALGESIC EFFECT AFTER NSAID TREATMENT. THE STRENGTH OF THE ASSOCIATIONS REMAINS LOW-TO-MODERATE. THE MOST CONSISTENT PRETREATMENT QST PREDICTORS ARE PRESSURE PAIN THRESHOLDS, TEMPORAL SUMMATION OF PAIN, AND CONDITIONED PAIN MODULATION. OUTLOOK: THE USE OF QST AS PREDICTORS OF STANDARD OA TREATMENT IS INTERESTING, BUT THE PREDICTIVE STRENGTH REMAINS LOW-TO-MODERATE. A TRANSITION OF QST FROM A RESEARCH-BASED SETTING AND INTO THE CLINIC IS NOT ADVISED UNTIL THE PREDICTIVE STRENGTH HAS BEEN IMPROVED AND THE METHODOLOGY HAS BEEN STANDARDIZED. 2023 7 3838 29 IOX1 IMPEDES HOST INFLAMMATION IN IMIQUIMOD-TRIGGERED PSORIASIS. PSORIASIS IS A CHRONIC AUTOIMMUNE DISEASE WITH AN UNKNOWN ETIOLOGY AND HIGHLY LIMITED TREATMENT STRATEGIES. THE DRUGS CURRENTLY USED IN THE TREATMENT OF PSORIASIS ARE RARELY RECOMMENDED FOR LONG-TERM USE OWING TO THE SERIOUS SIDE EFFECTS. ALTHOUGH DIFFERENT TARGETS HAVE BEEN IDENTIFIED FOR CONTROLLING PSORIASIS, THE ROLE OF EPIGENETIC MODIFICATIONS AS THERAPEUTIC TARGETS IS YET TO BE ELUCIDATED. HERE, WE INVESTIGATED THE THERAPEUTIC POTENTIAL OF 8-HYDROXYQUINOLINE-5-CARBOXYLIC ACID (IOX1), A NOVEL DRUG WITH A GENETIC TARGET, IN PSORIASIS. THE DAILY TOPICAL ADMINISTRATION OF IOX1 IN A MOUSE MODEL OF IMIQUIMOD (IMQ)-INDUCED PSORIATIC INFLAMMATION REDUCED INFLAMMATORY REACTIONS IN THE SKIN AND LOWERED THE PASI SCORE. FURTHERMORE, INTRAPERITONEALLY INJECTED IOX1 REPRESSED THE INFLAMMATORY STATUS INDUCED BY IMQ IN PSORIATIC MICE BY REDUCING THE MRNA LEVELS OF PRO-INFLAMMATORY CYTOKINES, RESTORING SPLENOCYTE POPULATIONS, AND REGULATING MACROPHAGE POLARIZATION. OUR FINDINGS INDICATE THE REMEDIAL EFFECTS OF IOX1 ON DERMATITIS PSORIASIS AND THE POTENTIAL OF IOX1 AS A THERAPEUTIC COMPOUND IN PSORIASIS. 2021 8 6576 23 TREATMENT OF PRIMARY SJOGREN SYNDROME. PRIMARY SJOGREN SYNDROME (PSS) IS A PROGRESSIVE AUTOIMMUNE DISEASE CHARACTERIZED BY SICCA AND SYSTEMIC MANIFESTATIONS. IN THIS REVIEW, WE SUMMARIZE THE AVAILABLE DATA ON TOPICAL AND SYSTEMIC MEDICATIONS, ACCORDING TO CLINICAL SIGNS AND DISEASE ACTIVITY, AND WE DESCRIBE THE ONGOING STUDIES USING BIOLOGIC DRUGS IN THE TREATMENT OF PSS. EXPANDING KNOWLEDGE ABOUT THE EPIDEMIOLOGY, CLASSIFICATION CRITERIA, SYSTEMIC ACTIVITY SCORING (ESSDAI) AND PATIENT-REPORTED OUTCOMES (ESSPRI) IS DRIVING ACTIVE RESEARCH. TREATMENT DECISIONS ARE BASED ON THE EVALUATION OF SYMPTOMS AND EXTRAGLANDULAR MANIFESTATIONS. SYMPTOMATIC TREATMENT IS USUALLY APPROPRIATE, WHEREAS SYSTEMIC TREATMENT IS RESERVED FOR SYSTEMIC MANIFESTATIONS. SICCA IS MANAGED BY EDUCATION, ENVIRONMENT MODIFICATION, ELIMINATION OF CONTINGENT OFFENDING DRUGS, ARTIFICIAL TEARS, SECRETAGOGUES AND TREATMENTS FOR COMPLICATIONS. MILD SYSTEMIC SIGNS SUCH AS FATIGUE ARE TREATED BY EXERCISE. PAIN CAN REQUIRE SHORT-TERM MODERATE-DOSE GLUCOCORTICOID THERAPY AND, IN SOME CASES, DISEASE-MODIFYING DRUGS. SEVERE AND ACUTE SYSTEMIC MANIFESTATIONS INDICATE TREATMENT WITH GLUCOCORTICOIDS AND/OR IMMUNOSUPPRESSANT DRUGS. THE ROLE FOR BIOLOGIC AGENTS IS PROMISING, BUT NO DOUBLE-BLIND RANDOMIZED CONTROLLED TRIALS (RCTS) PROVING THE EFFICACY OF THESE DRUGS ARE AVAILABLE. TARGETS FOR NEW TREATMENTS DIRECTED AGAINST THE IMMUNOPATHOLOGICAL MECHANISMS OF PSS INCLUDE EPITHELIAL CELLS, T CELLS, B-CELL OVERACTIVITY, THE INTERFERON SIGNATURE, PROINFLAMMATORY CYTOKINES, ECTOPIC GERMINAL CENTRE FORMATION, CHEMOKINES INVOLVED IN LYMPHOID CELL HOMING, AND EPIGENETIC MODIFICATIONS. 2016 9 2976 34 GENETIC AND MOLECULAR BASIS OF DIABETIC FOOT ULCERS: CLINICAL REVIEW. DIABETIC FOOT ULCERS (DFUS) ARE MAJOR COMPLICATIONS ASSOCIATED WITH DIABETES AND OFTEN CORRELATE WITH PERIPHERAL NEUROPATHY, TRAUMA AND PERIPHERAL VASCULAR DISEASE. IT IS NECESSARY TO UNDERSTAND THE MOLECULAR AND GENETIC BASIS OF DIABETIC FOOT ULCERS IN ORDER TO TAILOR PATIENT CENTRED CARE TOWARDS PARTICULAR PATIENT GROUPS. THIS REVIEW AIMED TO EVALUATE WHETHER CURRENT LITERATURE WAS INDICATIVE OF AN UNDERLYING MOLECULAR AND GENETIC BASIS FOR DFUS AND TO DISCUSS CLINICAL APPLICATIONS. FROM A MOLECULAR PERSPECTIVE, WOUND HEALING IS A PROCESS THAT TRANSPIRES FOLLOWING BREACH OF THE SKIN BARRIER AND IS USUALLY MEDIATED BY GROWTH FACTORS AND CYTOKINES RELEASED BY SPECIALISED CELLS ACTIVATED BY THE IMMUNE RESPONSE, INCLUDING FIBROBLASTS, ENDOTHELIAL CELLS, PHAGOCYTES, PLATELETS AND KERATINOCYTES. GROWTH FACTORS AND CYTOKINES ARE FUNDAMENTAL IN THE ORGANISATION OF THE MOLECULAR PROCESSES INVOLVED IN MAKING CUTANEOUS WOUND HEALING POSSIBLE. THERE IS A SIGNIFICANT ROLE FOR SINGLE NUCLEOTIDE POLYMORPHISM (SNPS) IN THE FLUCTUATION OF THESE GROWTH FACTORS AND CYTOKINES IN DFUS. FURTHERMORE, RECENT EVIDENCE SUGGESTS A KEY ROLE FOR EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION FROM LONG STANDING HYPERGLYCEMIA AND NON-CODING RNAS IN THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT. GENETIC FACTORS AND ETHNICITY CAN ALSO PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF DIABETIC NEUROPATHY LEADING TO DFUS. CLINICALLY, INTERVENTIONS WHICH HAVE IMPROVED OUTCOMES FOR PEOPLE WITH DFUS OR THOSE AT RISK OF DFUS INCLUDE SOME SYSTEMIC THERAPEUTIC DRUG INTERVENTIONS WHICH IMPROVE MICROVASCULAR BLOOD FLOW, SURGICAL INTERVENTIONS, HUMAN GROWTH FACTORS, AND HYPERBARIC OXYGEN THERAPY, NEGATIVE PRESSURE WOUND THERAPY, SKIN REPLACEMENT OR SHOCKWAVE THERAPY AND THE USE OF TOPICAL TREATMENTS. FUTURE TREATMENT MODALITIES INCLUDING STEM CELL AND GENE THERAPIES ARE PROMISING IN THE THERAPEUTIC APPROACH TO PREVENT THE PROGRESSION OF CHRONIC DIABETIC COMPLICATIONS. 2016 10 631 35 BIOLOGICAL AND SYNTHETIC TARGET DMARDS IN PSORIATIC ARTHRITIS. PSORIATIC ARTHRITIS (PSA) IS A CHRONIC MULTI-FACETED IMMUNE-MEDIATED SYSTEMIC DISORDER, CHARACTERIZED BY ARTICULAR, CUTANEOUS, ENTHESIS, NAIL AND SPINE INVOLVEMENT. ARTICULAR MANIFESTATIONS OF PSA ARE PARTICULARLY COMMON AND HIGHLY DISABLING FOR PATIENTS, WHILE THE HETEROGENEOUS CLINICAL SUBSETS OF THE DISEASE ARE CHALLENGING FOR CLINICIANS. IN RECENT YEARS, RESEARCH HAS MADE MANY ADVANCES IN UNDERSTANDING THE PATHOGENESIS OF THE DISEASE FROM GENETIC, EPIGENETIC AND MOLECULAR POINTS OF VIEW. NEW DRUGS ARE NOW AVAILABLE FOR THE TREATMENT OF THIS CONDITION, AND, IN PARTICULAR, TNF-ALFA INHIBITORS, HISTORICALLY THE FIRST BIOLOGICALS APPROVED IN PSA, ARE NOW JUXTAPOSED BY NEW BIOLOGICAL DISEASE MODIFYING ANTI-RHEUMATIC DRUGS (BDMARDS) WITH DIFFERENT MODES OF ACTION. TARGETING IL-12/IL-23 P40 COMMON SUBUNIT WITH USTEKINUMAB, IL-17A WITH SECUKINUMAB AND IXEKIZUMAB, T CELLS CO-STIMULATION WITH ABATACEPT, IS NOW POSSIBLE, SAFE AND EFFECTIVE. MOREOVER, TARGETED SYNTHETIC MOLECULES WITH ORAL ADMINISTRATION ARE AVAILABLE, WITH THE POSSIBILITY TO INTERFERE WITH PHOSPHODIESTERASE-4 AND JAK/STAT PATHWAYS. INDEED, NEW DRUGS ARE UNDER DEVELOPMENT, WITH THE POSSIBILITY TO TARGET SELECTIVELY IL-17 RECEPTOR, IL-23, AND OTHER KEY MOLECULAR TARGETS IN THE PATHOGENESIS OF THIS CONDITION. IN THIS NARRATIVE REVIEW, WE PROVIDE AN UP-TO-DATE OVERVIEW OF THE CURRENT APPLICATION OF BIOLOGICAL AND TARGETED SYNTHETIC DMARDS IN THE FIELD OF PSA, WITH PARTICULAR REGARD TO THE CLINICAL SIGNIFICANCE OF THIS POSSIBILITY TO TARGET A HIGHER NUMBER OF DISTINCT IMMUNE-PATHWAYS. 2019 11 258 26 ADVANCES IN PATHOGENESIS AND NANOPARTICLES (NPS)-MEDIATED TREATMENT OF PSORIASIS. PSORIASIS IS A CHRONIC PAPULOSQUAMOUS SKIN DISEASE WITH AN AUTOIMMUNE PATHOGENIC TRAITS AND STRONG GENETIC PREDISPOSITION. IN THE PAST FEW DECADES, WITH THE RAPID DEVELOPMENT OF MOLECULAR BIOLOGY AND CELL BIOLOGY, THE INHERENT PATHOGENESIS OF PSORIASIS HAS BEEN GRADUALLY ELUCIDATED, IN WHICH CYTOKINE INFLAMMATORY LOOPS, CELL SIGNALING PATHWAYS, AND EPIGENETIC FACTORS SUCH AS MIRNAS HAVE BEEN DEMONSTRATED TO PLAY IMPORTANT ROLES IN REGULATING THE DEVELOPMENT AND PROGRESSION OF PSORIASIS. MORE IMPORTANTLY, UNDERSTANDING THE PATHOGENESIS OF PSORIASIS HAS PROMOTED THE DEVELOPMENT OF EFFECTIVE TREATMENT FOR PSORIASIS. IN THIS REVIEW, WE SYSTEMICALLY SUMMARIZED THE MOLECULAR MECHANISMS REGULATING THE DEVELOPMENT AND PROGRESSION PSORIASIS, INTRODUCED VARIOUS THERAPEUTICS USED FOR CLINICAL PSORIASIS THERAPY, AND HIGHLIGHTED THE RECENT ADVANCES IN NANOPARTICLES (NPS)-MEDIATED DRUG DELIVERY FOR PSORIASIS TREATMENT. 2022 12 4452 24 MOLECULAR MECHANISMS AND MANAGEMENT OF A CUTANEOUS INFLAMMATORY DISORDER: PSORIASIS. PSORIASIS IS A COMPLEX CHRONIC INFLAMMATORY CUTANEOUS DISORDER. TO DATE, ROBUST MOLECULAR MECHANISMS OF PSORIASIS HAVE BEEN REPORTED. AMONG DIVERSE ABERRANT IMMUNOPATHOGENETIC MECHANISMS, THE CURRENT MODEL EMPHASIZES THE ROLE OF TH1 AND THE IL-23/TH17 AXIS, SKIN-RESIDENT IMMUNE CELLS AND MAJOR SIGNAL TRANSDUCTION PATHWAYS INVOLVED IN PSORIASIS. THE MULTIPLE GENETIC RISK LOCI FOR PSORIASIS HAVE BEEN RAPIDLY REVEALED WITH THE ADVENT OF A NOVEL TECHNOLOGY. MOREOVER, IDENTIFYING EPIGENETIC MODIFICATIONS COULD BRIDGE THE GAP BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS IN PSORIASIS. THIS REVIEW WILL PROVIDE A BETTER UNDERSTANDING OF THE PATHOGENESIS OF PSORIASIS BY UNRAVELING THE COMPLICATED INTERPLAY AMONG IMMUNOLOGICAL ABNORMALITIES, GENETIC RISK FOCI, EPIGENETIC MODIFICATION AND ENVIRONMENTAL FACTORS OF PSORIASIS. WITH ADVANCES IN MOLECULAR BIOLOGY, DIVERSE NEW TARGETS ARE UNDER INVESTIGATION TO MANAGE PSORIASIS. THE RECENT ADVANCES IN TREATMENT MODALITIES FOR PSORIASIS BASED ON TARGETED MOLECULES ARE ALSO DISCUSSED. 2017 13 4685 24 NEW TARGETS AND STRATEGIES FOR RHEUMATOID ARTHRITIS: FROM SIGNAL TRANSDUCTION TO EPIGENETIC ASPECT. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE THAT CAN LEAD TO JOINT DAMAGE AND EVEN PERMANENT DISABILITY, SERIOUSLY AFFECTING PATIENTS' QUALITY OF LIFE. AT PRESENT, THE COMPLETE CURE FOR RA IS NOT ACHIEVABLE, ONLY TO RELIEVE THE SYMPTOMS TO REDUCE THE PAIN OF PATIENTS. FACTORS SUCH AS ENVIRONMENT, GENES, AND SEX CAN INDUCE RA. PRESENTLY, NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, DRMADS, AND GLUCOCORTICOIDS ARE COMMONLY USED IN TREATING RA. IN RECENT YEARS, SOME BIOLOGICAL AGENTS HAVE ALSO BEEN APPLIED IN CLINICAL PRACTICE, BUT MOST HAVE SIDE EFFECTS. THEREFORE, FINDING NEW MECHANISMS AND TARGETS FOR TREATING RA IS NECESSARY. THIS REVIEW SUMMARIZES SOME POTENTIAL TARGETS DISCOVERED FROM THE PERSPECTIVE OF EPIGENETICS AND RA MECHANISMS. 2023 14 5265 27 PROMISING THERAPEUTIC TARGETS FOR TREATMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A SYSTEMIC POLY-ARTICULAR CHRONIC AUTOIMMUNE JOINT DISEASE THAT MAINLY DAMAGES THE HANDS AND FEET, WHICH AFFECTS 0.5% TO 1.0% OF THE POPULATION WORLDWIDE. WITH THE SUSTAINED DEVELOPMENT OF DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS), SIGNIFICANT SUCCESS HAS BEEN ACHIEVED FOR PREVENTING AND RELIEVING DISEASE ACTIVITY IN RA PATIENTS. UNFORTUNATELY, SOME PATIENTS STILL SHOW LIMITED RESPONSE TO DMARDS, WHICH PUTS FORWARD NEW REQUIREMENTS FOR SPECIAL TARGETS AND NOVEL THERAPIES. UNDERSTANDING THE PATHOGENETIC ROLES OF THE VARIOUS MOLECULES IN RA COULD FACILITATE DISCOVERY OF POTENTIAL THERAPEUTIC TARGETS AND APPROACHES. IN THIS REVIEW, BOTH EXISTING AND EMERGING TARGETS, INCLUDING THE PROTEINS, SMALL MOLECULAR METABOLITES, AND EPIGENETIC REGULATORS RELATED TO RA, ARE DISCUSSED, WITH A FOCUS ON THE MECHANISMS THAT RESULT IN INFLAMMATION AND THE DEVELOPMENT OF NEW DRUGS FOR BLOCKING THE VARIOUS MODULATORS IN RA. 2021 15 1879 27 EMERGING ROLES OF NON-CODING RNAS IN PSORIASIS PATHOGENESIS. PSORIASIS IS A COMPLEX GENETIC SKIN DISORDER TYPICALLY MANIFESTED BY RED, SCALY, AND ITCHY PLAQUES MOST COMMONLY OVER THE SCALP, TRUNK, ELBOWS, AND KNEES. HISTOPATHOLOGICAL FEATURES INCLUDE THICKENING OF THE EPIDERMAL LAYER DUE TO HYPER-PROLIFERATION AND ABNORMAL DIFFERENTIATION OF EPIDERMAL KERATINOCYTES ALONG WITH INFILTRATION OF IMMUNE CELLS IN THE PSORIATIC SKIN. IT IS A CHRONIC INFLAMMATORY RELAPSING DISEASE, AND THERE IS CURRENTLY NO PERMANENT CURE FOR PSORIASIS. PROPER MEDICATIONS CAN REDUCE THE SEVERITY OF THE DISEASE AND IMPROVE THE QUALITY OF LIFE OF THE PATIENTS. WHILE THE GENETIC COMPONENTS OF PSORIASIS PATHOGENESIS ARE WELL EXPLORED, THE FULL UNDERSTANDING OF ITS EPIGENETIC COMPONENT REMAINS ELUSIVE. NON-CODING RNAS (NCRNAS) ARE DOCUMENTED TO REGULATE VARIOUS EPIGENETIC PROCESSES THAT LEAD TO THE PATHOGENESIS OF DIFFERENT DISEASES INCLUDING PSORIASIS. IN THIS REVIEW, WE HAVE DISCUSSED THE MOLECULAR INTERPLAY OF DIFFERENT NCRNAS IN PSORIASIS PATHOGENESIS. THE ROLES OF MICRORNAS (MIRNAS) IN PSORIASIS ARE PRETTY WELL STUDIED, WHEREAS THE ROLES OF LONG NONCODING RNAS (LNCRNAS) AND CIRCULAR RNAS (CIRCRNAS) ARE EMERGING. THIS REVIEW PROVIDES IDEAS COVERING SOME OF THE LATEST FINDINGS OF DIFFERENT MODES OF FUNCTIONS PLAYED BY THOSE DIFFERENT NCRNAS DOCUMENTED IN THE LITERATURE. AS AN EVER-EVOLVING TOPIC, SOME WORKS ARE STILL ONGOING AS WELL AS THERE ARE SEVERAL FIELDS THAT NEED RIGOROUS SCIENTIFIC VENTURES. WE HAVE PROPOSED THE AREAS WHICH CLAIM MORE EXPLORATIONS TO BETTER UNDERSTAND THE ROLES PLAYED BY THE NCRNAS IN PSORIASIS PATHOGENESIS. 2023 16 2238 28 EPIGENETIC MODULATION AS A THERAPEUTIC PROSPECT FOR TREATMENT OF AUTOIMMUNE RHEUMATIC DISEASES. SYSTEMIC INFLAMMATORY RHEUMATIC DISEASES ARE CONSIDERED AS AUTOIMMUNE DISEASES, MEANING THAT THE BALANCE BETWEEN RECOGNITION OF PATHOGENS AND AVOIDANCE OF SELF-ATTACK IS IMPAIRED AND THE IMMUNE SYSTEM ATTACKS AND DESTROYS ITS OWN HEALTHY TISSUE. TREATMENT WITH CONVENTIONAL DISEASE MODIFYING ANTIRHEUMATIC DRUGS (DMARDS) AND/OR NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) IS OFTEN ASSOCIATED WITH VARIOUS ADVERSE REACTIONS DUE TO UNSPECIFIC AND TOXIC PROPERTIES OF THOSE DRUGS. ALTHOUGH BIOLOGIC DRUGS HAVE LARGELY IMPROVED THE OUTCOME IN MANY PATIENTS, SUCH DRUGS STILL POSE SIGNIFICANT PROBLEMS AND FAIL TO PROVIDE A SOLUTION TO ALL PATIENTS. THEREFORE, DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND IMPROVEMENTS IN EARLY DIAGNOSIS OF RHEUMATIC DISEASES ARE BADLY NEEDED IN ORDER TO INCREASE PATIENT'S FUNCTIONING AND QUALITY OF LIFE. THE REVERSIBLE NATURE OF EPIGENETIC MECHANISMS OFFERS A NEW CLASS OF DRUGS THAT MODULATE THE IMMUNE SYSTEM AND INFLAMMATION. IN FACT, EPIGENETIC DRUGS ARE ALREADY IN USE IN SOME TYPES OF CANCER OR CARDIOVASCULAR DISEASES. THEREFORE, EPIGENETIC-BASED THERAPEUTICS THAT CONTROL AUTOIMMUNITY AND CHRONIC INFLAMMATORY PROCESS HAVE BROAD IMPLICATIONS FOR THE PATHOGENESIS, DIAGNOSIS, AND MANAGEMENT OF RHEUMATIC DISEASES. THIS REVIEW SUMMARISES THE LATEST INFORMATION ABOUT POTENTIAL THERAPEUTIC APPLICATION OF EPIGENETIC MODIFICATION IN TARGETING IMMUNE ABNORMALITIES AND INFLAMMATION OF RHEUMATIC DISEASES. 2016 17 5309 22 PSORIASIS PATHOGENESIS AND TREATMENT. RESEARCH ON PSORIASIS PATHOGENESIS HAS LARGELY INCREASED KNOWLEDGE ON SKIN BIOLOGY IN GENERAL. IN THE PAST 15 YEARS, BREAKTHROUGHS IN THE UNDERSTANDING OF THE PATHOGENESIS OF PSORIASIS HAVE BEEN TRANSLATED INTO TARGETED AND HIGHLY EFFECTIVE THERAPIES PROVIDING FUNDAMENTAL INSIGHTS INTO THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES WITH A DOMINANT IL-23/TH17 AXIS. THIS REVIEW DISCUSSES THE MECHANISMS INVOLVED IN THE INITIATION AND DEVELOPMENT OF THE DISEASE, AS WELL AS THE THERAPEUTIC OPTIONS THAT HAVE ARISEN FROM THE DISSECTION OF THE INFLAMMATORY PSORIATIC PATHWAYS. OUR DISCUSSION BEGINS BY ADDRESSING THE INFLAMMATORY PATHWAYS AND KEY CELL TYPES INITIATING AND PERPETUATING PSORIATIC INFLAMMATION. NEXT, WE DESCRIBE THE ROLE OF GENETICS, ASSOCIATED EPIGENETIC MECHANISMS, AND THE INTERACTION OF THE SKIN FLORA IN THE PATHOPHYSIOLOGY OF PSORIASIS. FINALLY, WE INCLUDE A COMPREHENSIVE REVIEW OF WELL-ESTABLISHED WIDELY AVAILABLE THERAPIES AND NOVEL TARGETED DRUGS. 2019 18 4756 42 NOVEL THERAPEUTIC TARGET(S) FOR PSORIATIC DISEASE. PSORIASIS AND PSORIATIC ARTHRITIS, TOGETHER KNOWN AS PSORIATIC DISEASE, IS HIGHLY PREVALENT CHRONIC RELAPSING INFLAMMATORY DISEASE AFFECTING SKIN, JOINTS OR BOTH AND IS ASSOCIATED WITH SEVERAL COMORBIDITIES SUCH AS CARDIOVASCULAR, METABOLIC, PSYCHIATRIC, RENAL DISEASE ETC. THE ETIOPATHOGENESIS OF PSORIASIS IS COMPLEX AND MAINLY DRIVEN BY ABERRANT IMMUNE RESPONSE OWING TO THE GENETIC SUSCEPTIBILITY AND VARIOUS ENVIRONMENTAL FACTORS SUCH AS TRAUMA, INFECTIONS AND DRUGS. RECENT ADVANCES IN UNDERSTANDING MOLECULAR AND CELLULAR PATHWAYS HAVE IDENTIFIED TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), INTERLEUKIN-17 (IL-17), IL-23, IL-22 AS MAJOR CONTRIBUTORS IN PSORIASIS PATHOGENESIS. ADVANCES IN THE KNOWLEDGE OF PATHOPHYSIOLOGY, THE INTERACTION OF AUTOINFLAMMATION AND CLINICAL PHENOTYPES HAVE LED TO THE DEVELOPMENT OF HIGHLY EFFECTIVE TARGETED THERAPEUTIC AGENTS WHICH INCLUDE TNF-ALPHA, IL-17, IL-23, IL-1 ALPHA/BETA OR IL-36 INHIBITORS OR RECEPTOR BLOCKERS, SMALL MOLECULE DRUGS LIKE PHOSPHODIESTERASE-4 INHIBITORS (APREMILAST), JANUS KINASE (JAK) INHIBITORS, RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR GAMMAT (RORGAMMAT) INHIBITORS. THESE NOVEL DRUGS HAVE PROMISED THE POTENTIAL OF IMPROVED DISEASE CONTROL. IN RECENT YEARS, THE TRANSITION FROM BIOLOGICS TO BIOSIMILARS ESPECIALLY WITH TNF-ALPHA INHIBITORS HAD SIGNIFICANT IMPACT ON DECREASING HEALTH CARE COST AND INCREASING THERAPEUTIC OPTIONS TO THE PATIENTS. HOWEVER, SELECTION OF RIGHT TREATMENT FOR AN INDIVIDUAL PATIENT STILL REMAINS CHALLENGING. MOREOVER, INTERPLAY BETWEEN DIFFERENT EPIGENETIC MECHANISMS SUCH AS THE DNA METHYLATION, CHROMATIN MODIFICATIONS AND NONCODING RNA REGULATION HAS RECENTLY BEEN STARTED TO BE DECIPHERED. ENZYMES INHIBITORS INVOLVED IN EPIGENETIC PATHWAYS SUCH AS DNA METHYLTRANSFERASES AND HISTONE DEACETYLASES DEMONSTRATED TO RESTORE NORMAL EPIGENETIC PATTERNS IN CLINICAL SETTINGS AND HAVE PROVIDED THE POTENTIAL AS NOVEL THERAPEUTIC TARGETS FOR PSORIASIS. IN THIS REVIEW, WE WILL DISCUSS NOVEL BIOLOGIC AGENTS AND NEWER THERAPEUTIC APPROACHES IN TREATMENT OF PSORIATIC DISEASE. 2022 19 2694 29 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 20 5880 24 SYNTHETIC RETINOIDS BEYOND CANCER THERAPY. WHILE THE USES OF RETINOIDS FOR CANCER TREATMENT CONTINUE TO EVOLVE, THIS REVIEW FOCUSES ON OTHER THERAPEUTIC AREAS IN WHICH RETINOIDS [RETINOL (VITAMIN A), ALL-TRANS RETINOIC ACID (RA), AND SYNTHETIC RETINOIC ACID RECEPTOR (RAR)ALPHA-, BETA-, AND GAMMA-SELECTIVE AGONISTS] ARE BEING USED AND ON PROMISING NEW RESEARCH THAT SUGGESTS ADDITIONAL USES FOR RETINOIDS FOR THE TREATMENT OF DISORDERS OF THE KIDNEYS, SKELETAL MUSCLES, HEART, PANCREAS, LIVER, NERVOUS SYSTEM, SKIN, AND OTHER ORGANS. THE MOST MATURE AREA, IN TERMS OF US FOOD AND DRUG ADMINISTRATION-APPROVED, RAR-SELECTIVE AGONISTS, IS FOR TREATMENT OF VARIOUS SKIN DISEASES. SYNTHETIC RETINOID AGONISTS HAVE MAJOR ADVANTAGES OVER ENDOGENOUS RAR AGONISTS SUCH AS RA. BECAUSE THEY ACT THROUGH A SPECIFIC RAR, SIDE EFFECTS MAY BE MINIMIZED, AND SYNTHETIC RETINOIDS OFTEN HAVE BETTER PHARMACEUTICAL PROPERTIES THAN DOES RA. BASED ON OUR INCREASING KNOWLEDGE OF THE MULTIPLE ROLES OF RETINOIDS IN DEVELOPMENT, EPIGENETIC REGULATION, AND TISSUE REPAIR, OTHER EXCITING THERAPEUTIC AREAS ARE EMERGING. 2022