ABSTRACT
In obesity, adipose tissue undergoes dynamic remodeling processes such as adipocyte hypertrophy, hypoxia, immune responses, and adipocyte death. However, whether and how invariant natural killer T (iNKT) cells contribute to adipose tissue remodeling are elusive. In this study, we demonstrate that iNKT cells remove unhealthy adipocytes and stimulate the differentiation of healthy adipocytes. In obese adipose tissue, iNKT cells were abundantly found nearby dead adipocytes. FasL-positive adipose iNKT cells exerted cytotoxic effects to eliminate hypertrophic and pro-inflammatory Fas-positive adipocytes. Furthermore, in vivo adipocyte-lineage tracing mice model showed that activation of iNKT cells by alpha-galactosylceramide promoted adipocyte turnover, eventually leading to potentiation of the insulin-dependent glucose uptake ability in adipose tissue. Collectively, our data propose a novel role of adipose iNKT cells in the regulation of adipocyte turnover in obesity.
Subject(s)
Adipocytes/cytology , Adipose Tissue/cytology , Adipose Tissue/immunology , Cell Death/physiology , Lymphocyte Activation/physiology , Natural Killer T-Cells/physiology , Obesity/physiopathology , 3T3 Cells , Adipocytes/immunology , Adipocytes/metabolism , Animals , Cell Proliferation , Fas Ligand Protein/metabolism , Mice , Mice, Inbred C57BL , fas Receptor/metabolismABSTRACT
Somatic mutations in the isocitrate dehydrogenase 2 gene (IDH2) contribute to the pathogenesis of acute myeloid leukaemia (AML) through the production of the oncometabolite 2-hydroxyglutarate (2HG)1-8. Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks the production of 2HG by IDH2 mutants9,10. In a phase I/II clinical trial, enasidenib inhibited the production of 2HG and induced clinical responses in relapsed or refractory IDH2-mutant AML11. Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG. We show that therapeutic resistance is associated with the emergence of second-site IDH2 mutations in trans, such that the resistance mutations occurred in the IDH2 allele without the neomorphic R140Q mutation. The in trans mutations occurred at glutamine 316 (Q316E) and isoleucine 319 (I319M), which are at the interface where enasidenib binds to the IDH2 dimer. The expression of either of these mutant disease alleles alone did not induce the production of 2HG; however, the expression of the Q316E or I319M mutation together with the R140Q mutation in trans allowed 2HG production that was resistant to inhibition by enasidenib. Biochemical studies predicted that resistance to allosteric IDH inhibitors could also occur via IDH dimer-interface mutations in cis, which was confirmed in a patient with acquired resistance to the IDH1 inhibitor ivosidenib (AG-120). Our observations uncover a mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production in the pathogenesis of IDH-mutant malignancies.
Subject(s)
Aminopyridines/pharmacology , Drug Resistance, Neoplasm/genetics , Isocitrate Dehydrogenase/antagonists & inhibitors , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/genetics , Mutant Proteins/genetics , Mutation , Protein Multimerization/genetics , Triazines/pharmacology , Alleles , Allosteric Site/drug effects , Allosteric Site/genetics , Aminopyridines/chemistry , Aminopyridines/therapeutic use , Animals , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Disease Progression , Drug Resistance, Neoplasm/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Female , Glutamine/genetics , Glutarates/blood , Glutarates/metabolism , HEK293 Cells , Humans , Isoleucine/genetics , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/drug therapy , Mice , Mice, Inbred C57BL , Models, Molecular , Mutant Proteins/antagonists & inhibitors , Triazines/chemistry , Triazines/therapeutic useABSTRACT
Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.
Subject(s)
Aminopyridines/therapeutic use , Antineoplastic Agents/therapeutic use , Glycine/analogs & derivatives , Leukemia, Myeloid, Acute/drug therapy , Pyridines/therapeutic use , Triazines/therapeutic use , Adult , Aged , Aminopyridines/adverse effects , Antineoplastic Agents/adverse effects , Female , Glycine/adverse effects , Glycine/therapeutic use , Humans , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Mutation/drug effects , Pyridines/adverse effects , Treatment Outcome , Triazines/adverse effects , Young AdultABSTRACT
Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.
Subject(s)
Glycine/analogs & derivatives , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Mutation/genetics , Pyridines/therapeutic use , Aged , Aged, 80 and over , Blood Transfusion , Female , Glycine/adverse effects , Glycine/therapeutic use , Humans , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Pyridines/adverse effects , Remission Induction , Survival Analysis , Translational Research, Biomedical , Treatment OutcomeABSTRACT
Although the long-term use of topical glucocorticoids (TGC) may induce skin atrophy including striae distensae (SD), patients with atopic dermatitis (AD) appear to have lesser degree of skin atrophy than those with psoriasis (PSO). Periostin, encoded by POSTN, is involved in tissue remodelling processes of chronic AD lesions. This study was designed to investigate the difference in the occurrence of skin atrophy in patients with AD or PSO when treated with TGC and to elucidate the association between skin atrophy and periostin. Big data analysis using Korean Health Claims Database was performed to determine the prevalence of SD in AD and PSO patients. Blood and skin eosinophils count and dermal fibrosis between AD and PSO patients were compared, and immunohistochemistry for periostin and mRNA sequencing in the dermis were performed. Animal experiments using AD and PSO murine model were conducted. Big data analysis revealed that patients with AD have significantly lesser degree of SD than patients with PSO. The ratio of the dermal fibrous tissues and eosinophil counts were significantly higher in AD patients. In AD skin, periostin was more widely distributed in the entire dermis and POSTN mRNAs were significantly upregulated. Dermal thickness and fibrosis were significantly higher in AD mice even after TGC treatment. A significant positive correlation was observed between dermal fibrosis and tissue eosinophil counts. Lesser skin atrophy in AD patients even after long-term TGC application could be resulted from skin fibrosis caused by increased tissue eosinophils and periostin deposition.
Subject(s)
Dermatitis, Atopic , Psoriasis , Animals , Atrophy , Dermatitis, Atopic/pathology , Fibrosis , Glucocorticoids/adverse effects , Humans , Mice , Psoriasis/pathology , Skin/pathologyABSTRACT
BACKGROUND: Repurposing is a drug development strategy receiving heightened attention after the Food and Drug Administration granted emergency use authorization of several repurposed drugs to treat Covid-19. There remain knowledge gaps on the root causes, facilitators and barriers for repurposing. METHOD: This systematic review used controlled vocabulary and free text terms to search ABI/Informa, Academic Search Premier, Business Source Complete, Cochrane Library, EconLit, Google Scholar, Ovid Embase, Ovid Medline, Pubmed, Scopus, and Web of Science Core Collection databases for the characteristics, reasons and example of companies deprioritizing development of promising drugs and barriers, facilitators and examples of successful re-purposing. RESULTS: We identified 11,814 articles, screened 5,976 for relevance, found 437 eligible for full text review, 115 of which were included in full analysis. Most articles (66%, 76/115) discussed why promising drugs are abandoned, with lack of efficacy or superiority to other therapies (n = 59), strategic business reasons (n = 35), safety problems (n = 28), research design decisions (n = 12), the complex nature of a studied disease or drug (n = 7) and regulatory bodies requiring more information (n = 2) among top reasons. Key barriers to repurposing include inadequate resources (n = 42), trial data access and transparency around abandoned compounds (n = 20) and expertise (n = 11). Additional barriers include uncertainty about the value of repurposing (n = 13), liability risks (n = 5) and intellectual property (IP) challenges (n = 26). Facilitators include the ability to form multi-partner collaborations (n = 38), access to compound databases and database screening tools (n = 32), regulatory modifications (n = 5) and tax incentives (n = 2). CONCLUSION: Promising drugs are commonly shelved due to insufficient efficacy or superiority to alternate therapies, poor market prospects, and industry consolidation. Inadequate resources and data access and challenges negotiating IP are key barriers to repurposing reaching its full potential as a core approach in drug development. Multi-partner collaborations and the availability and use of compound databases and tax incentives are key facilitators for repurposing. More research is needed on the current value of repurposing in drug development and how to better facilitate resources to support it, where valuable, especially financial, staffing for out-licensing shelved products, and legal expertise to negotiate IP agreements in multi-partner collaborations. TRIAL REGISTRATION: The protocol was registered on Open Science Framework ( https://osf.io/f634k/ ) as it was not eligible for registration on PROSPERO as the review did not focus on a health-related outcome.
Subject(s)
COVID-19 Drug Treatment , Drug Repositioning , Commerce , Humans , Motivation , Pharmaceutical Preparations , United StatesABSTRACT
Accumulating evidence suggests that subcutaneous and visceral adipose tissues are differentially associated with metabolic disorders. In obesity, subcutaneous adipose tissue is beneficial for metabolic homeostasis because of repressed inflammation. However, the underlying mechanism remains unclear. Here, we demonstrate that γ-aminobutyric acid (GABA) sensitivity is crucial in determining fat depot-selective adipose tissue macrophage (ATM) infiltration in obesity. In diet-induced obesity, GABA reduced monocyte migration in subcutaneous inguinal adipose tissue (IAT), but not in visceral epididymal adipose tissue (EAT). Pharmacological modulation of the GABAB receptor affected the levels of ATM infiltration and adipose tissue inflammation in IAT, but not in EAT, and GABA administration ameliorated systemic insulin resistance and enhanced insulin-dependent glucose uptake in IAT, accompanied by lower inflammatory responses. Intriguingly, compared with adipose-derived stem cells (ADSCs) from EAT, IAT-ADSCs played key roles in mediating GABA responses that repressed ATM infiltration in high-fat diet-fed mice. These data suggest that selective GABA responses in IAT contribute to fat depot-selective suppression of inflammatory responses and protection from insulin resistance in obesity.
Subject(s)
Adipose Tissue/metabolism , Inflammation/metabolism , Obesity/metabolism , Stem Cells/metabolism , Subcutaneous Tissue/metabolism , gamma-Aminobutyric Acid/metabolism , Adipocytes/metabolism , Adiposity/genetics , Animals , Diet, High-Fat/adverse effects , Female , Humans , Insulin/metabolism , Intra-Abdominal Fat/metabolism , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, TransgenicABSTRACT
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D-2HG, we generated transgenic mice with conditionally activated IDH2(R140Q) and IDH2(R172K) alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span, recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant up-regulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2(R140Q)-expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2(R140Q) in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.
Subject(s)
Cardiomyopathies/genetics , Glutarates/metabolism , Isocitrate Dehydrogenase/genetics , Mutation , Neurodegenerative Diseases/genetics , Animals , Cardiomyopathies/enzymology , Cardiomyopathies/pathology , Cell Line , Gene Expression Profiling , Gene Expression Regulation, Developmental , Heart/physiopathology , Humans , Isocitrate Dehydrogenase/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Neurodegenerative Diseases/enzymology , Neurodegenerative Diseases/pathologyABSTRACT
BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).
Subject(s)
Enzyme Inhibitors/administration & dosage , Glycine/analogs & derivatives , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/drug therapy , Pyridines/administration & dosage , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Cell Count , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Female , Follow-Up Studies , Glycine/administration & dosage , Glycine/adverse effects , Glycine/pharmacokinetics , Hemoglobins/analysis , Humans , Isocitrate Dehydrogenase/antagonists & inhibitors , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Mutation , Pyridines/adverse effects , Pyridines/pharmacokinetics , Recurrence , Remission Induction , Survival Rate , Young AdultABSTRACT
Background: IDH1 mutations occur in approximately 13% of intrahepatic cholangiocarcinomas (IHCCs). The oral, targeted, mutant IDH1 (mIDH1) inhibitor ivosidenib (AG-120) suppresses production of the oncometabolite D-2-hydroxyglutarate, promoting disease stabilization and improved progression-free survival (PFS) in mIDH1 IHCC. Materials & methods: Harnessing matched baseline and on-treatment biopsies, we investigate the potential mechanisms underlying ivosidenib's efficacy. Results: mIDH1 inhibition leads to decreased cytoplasm and expression of hepatocyte lineage markers in patients with prolonged PFS. These findings are accompanied by downregulation of biliary fate, cell cycle progression and AKT pathway activity. Conclusion: Ivosidenib stimulates a hepatocyte differentiation program in mIDH1 IHCC, a phenotype associated with clinical benefit. mIDH1 inhibition could be a paradigm for differentiation-based therapy in solid tumors. Clinical trial registration: NCT02073994 (ClinicalTrials.gov).
Subject(s)
Bile Duct Neoplasms/drug therapy , Cholangiocarcinoma/drug therapy , Glycine/analogs & derivatives , Isocitrate Dehydrogenase/genetics , Mutation , Pyridines/pharmacology , Antineoplastic Agents/administration & dosage , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/pathology , Cell Differentiation/drug effects , Cholangiocarcinoma/genetics , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/pathology , Clinical Trials, Phase I as Topic , Glycine/pharmacology , Humans , Isocitrate Dehydrogenase/antagonists & inhibitors , Neoplasm Grading , Proto-Oncogene Proteins c-akt/metabolism , Survival Rate , Treatment OutcomeABSTRACT
Inactive cortisone is converted into active cortisol by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). Excessive levels of active glucocorticoids could deteriorate skin barrier function; barrier impairment is also observed in aged skin. In this study, we aimed to determine whether permeability barrier impairment in the aged skin could be related to increased 11ß-HSD1 expression. Aged humans (n = 10) showed increased cortisol in the stratum corneum (SC) and oral epithelium, compared to young subjects (n = 10). 11ß-HSD1 expression (as assessed via immunohistochemical staining) was higher in the aged murine skin. Aged hairless mice (56-week-old, n = 5) manifested greater transepidermal water loss, lower SC hydration, and higher levels of serum inflammatory cytokines than the young mice (8-week-old, n = 5). Aged 11ß-HSD1 knockout mice (n = 11), 11ß-HSD1 inhibitor (INHI)-treated aged wild type (WT) mice (n = 5) and young WT mice (n = 10) exhibited reduced SC corticosterone level. Corneodesmosome density was low in WT aged mice (n = 5), but high in aged 11ß-HSD1 knockout and aged INHI-treated WT mice. Aged mice exhibited lower SC lipid levels; this effect was reversed by INHI treatment. Therefore, upregulation of 11ß-HSD1 in the aged skin increases the active-glucocorticoid levels; this suppresses SC lipid biosynthesis, leading to impaired epidermal permeability barrier.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , Epidermis/metabolism , Gene Expression Regulation , Skin Aging/physiology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Adult , Aged , Animals , Biomarkers , Cytokines/blood , Cytokines/metabolism , Female , Glucocorticoids/metabolism , Glucocorticoids/pharmacology , Humans , Inflammation Mediators/blood , Inflammation Mediators/metabolism , Male , Mice , Mice, Knockout , Middle Aged , Permeability , Young AdultABSTRACT
Lipid droplets are specialized cellular organelles that contain neutral lipid metabolites and play dynamic roles in energy homeostasis. Perilipin 1 (Plin1), one of the major lipid droplet-binding proteins, is highly expressed in adipocytes. In mice, Plin1 deficiency impairs peripheral insulin sensitivity, accompanied with reduced fat mass. However, the mechanisms underlying insulin resistance in lean Plin1 knockout (Plin1-/-) mice are largely unknown. The current study demonstrates that Plin1 deficiency promotes inflammatory responses and lipolysis in adipose tissue, resulting in insulin resistance. M1-type adipose tissue macrophages (ATMs) were higher in Plin1-/- than in Plin1+/+ mice on normal chow diet. Moreover, using lipidomics analysis, we discovered that Plin1-/- adipocytes promoted secretion of pro-inflammatory lipid metabolites such as prostaglandins, which potentiated monocyte migration. In lean Plin1-/- mice, insulin resistance was relieved by macrophage depletion with clodronate, implying that elevated pro-inflammatory ATMs might be attributable for insulin resistance under Plin1 deficiency. Together, these data suggest that Plin1 is required to restrain fat loss and pro-inflammatory responses in adipose tissue by reducing futile lipolysis to maintain metabolic homeostasis.
Subject(s)
Adipose Tissue/pathology , Inflammation/etiology , Lipid Metabolism , Perilipin-1/deficiency , Adipocytes/metabolism , Animals , Insulin Resistance , Lipolysis , Macrophages/pathology , Mice , Mice, KnockoutABSTRACT
Treatment of male androgenetic alopecia with 5α-reductase inhibitors is efficacious. However, the risk of adverse sexual effects remains controversial. This systematic review and meta-analysis investigated the risk of adverse sexual effects due to treatment of androgenetic alopecia in male patients with finasteride, 1 mg/day, or dutasteride, 0.5 mg/day. Fifteen randomized double-blinded placebo-controlled trials (4,495 subjects) were meta-analysed. Use of 5α-reductase inhibitors carried a 1.57-fold risk of sexual dysfunction (95% confidence interval (95% CI) 1.19-2.08). The relative risk was 1.66 (95% CI 1.20-2.30) for finasteride and 1.37 (95% CI 0.81-2.32) for dutasteride. Both drugs were associated with an increased risk, although the increase was not statistically significant for dutasteride. As studies into dutasteride were limited, further trials are required. It is important that physicians are aware of, and assess, the possibility of sexual dysfunction in patients treated with 5α-reductase inhibitors.
Subject(s)
5-alpha Reductase Inhibitors/adverse effects , Alopecia/drug therapy , Dutasteride/adverse effects , Finasteride/adverse effects , Sexual Dysfunction, Physiological/chemically induced , 5-alpha Reductase Inhibitors/administration & dosage , Administration, Oral , Dutasteride/administration & dosage , Ejaculation/drug effects , Erectile Dysfunction/chemically induced , Erectile Dysfunction/physiopathology , Finasteride/administration & dosage , Humans , Libido/drug effects , Male , Randomized Controlled Trials as Topic , Risk Assessment , Risk Factors , Sexual Behavior/drug effects , Sexual Dysfunction, Physiological/diagnosis , Sexual Dysfunction, Physiological/physiopathologyABSTRACT
BACKGROUND: Contact immunotherapy with diphenylcyclopropenone (DPCP) is presently considered the treatment of choice for extensive alopecia areata. However, a major concern with contact immunotherapy is that it causes various adverse effects (AEs) that contribute to discontinuation of treatment. OBJECTIVE: We investigated whether a modified DPCP treatment protocol can promote hair regrowth with fewer AEs. METHODS: All patients were sensitized with 0.1% DPCP and began treatment with 0.01% DPCP. Thereafter, the DPCP concentration was slowly increased according to the treatment response and AEs. This was a retrospective review of DPCP treatment with modified protocols in 159 patients with alopecia areata. RESULTS: Of the 159 patients, 46 (28.9%) showed a complete response and 59 (37.1%) showed a partial response. No patients had AEs after sensitization. During the treatment, only 3 patients (1.9%) showed severe AEs, and 55 showed moderate AEs; however, all were well controlled with antihistamines alone or antihistamines and medium-potency topical steroids. There was no association between treatment response and AEs. LIMITATIONS: Sample size, subject composition, and the retrospective study design represent potential limitations. CONCLUSION: A modified DPCP treatment protocol with subclinical sensitization could induce a favorable therapeutic response and result in fewer AEs.
Subject(s)
Alopecia Areata/therapy , Cyclopropanes/administration & dosage , Dermatologic Agents/administration & dosage , Immunotherapy/methods , Adolescent , Adult , Aged , Cyclopropanes/adverse effects , Dermatologic Agents/adverse effects , Female , Hair/growth & development , Humans , Immunotherapy/adverse effects , Male , Middle Aged , Recurrence , Retrospective Studies , Risk Factors , Treatment Outcome , Young AdultABSTRACT
The in vitro generation of cell-based three dimensional (3D) nerve tissue is an attractive subject to improve graft survival and integration into host tissue for neural tissue regeneration or to model biological events in stem cell differentiation. Although 3D organotypic culture strategies are well established for 3D nerve tissue formation of pluripotent stem cells to study underlying biology in nerve development, cell-based nerve tissues have not been developed using human postnatal stem cells with therapeutic potential. Here, we established a culture strategy for the generation of in vitro cell-based 3D nerve tissue from postnatal stem cells from apical papilla (SCAPs) of teeth, which originate from neural crest-derived ectomesenchyme cells. A stem cell population capable of differentiating into neural cell lineages was generated during the ex vivo expansion of SCAPs in the presence of EGF and bFGF, and SCAPs differentiated into neural cells, showing neural cell lineage-related molecular and gene expression profiles, morphological changes and electrophysical property under neural-inductive culture conditions. Moreover, we showed the first evidence that 3D cell-based nerve-like tissue with axons and myelin structures could be generated from SCAPs via 3D organotypic culture using an integrated bioprocess composed of polyethylene glycol (PEG) microwell-mediated cell spheroid formation and subsequent dynamic culture in a high aspect ratio vessel (HARV) bioreactor. In conclusion, the culture strategy in our study provides a novel approach to develop in vitro engineered nerve tissue using SCAPs and a foundation to study biological events in the neural differentiation of postnatal stem cells. Biotechnol. Bioeng. 2017;114: 903-914. © 2016 Wiley Periodicals, Inc.
Subject(s)
Bioreactors , Dental Papilla/cytology , Nerve Tissue/cytology , Stem Cells/cytology , Stem Cells/physiology , Tissue Engineering/methods , Adolescent , Cell Differentiation , Child , Humans , Molar/cytology , Spheroids, Cellular/cytologyABSTRACT
UNLABELLED: Sterol regulatory element binding protein1c (SREBP1c) is a key transcription factor for de novo lipogenesis during the postprandial state. During nutritional deprivation, hepatic SREBP1c is rapidly suppressed by fasting signals to prevent lipogenic pathways. However, the molecular mechanisms that control SREBP1c turnover in response to fasting status are not thoroughly understood. To elucidate which factors are involved in the inactivation of SREBP1c, we attempted to identify SREBP1c-interacting proteins by mass spectrometry analysis. Since we observed that ring finger protein20 (RNF20) ubiquitin ligase was identified as one of SREBP1c-interacting proteins, we hypothesized that fasting signaling would promote SREBP1c degradation in an RNF20-dependent manner. In this work, we demonstrate that RNF20 physically interacts with SREBP1c, leading to degradation of SREBP1c via ubiquitination. In accordance with these findings, RNF20 represses the transcriptional activity of SREBP1c and turns off the expression of lipogenic genes that are targets of SREBP1c. In contrast, knockdown of RNF20 stimulates the expression of SREBP1c and lipogenic genes and induces lipogenic activity in primary hepatocytes. Furthermore, activation of protein kinase A (PKA) with glucagon or forskolin enhances the expression of RNF20 and potentiates the ubiquitination of SREBP1c via RNF20. In wild-type and db/db mice, adenoviral overexpression of RNF20 markedly suppresses FASN promoter activity and reduces the level of hepatic triglycerides, accompanied by a decrease in the hepatic lipogenic program. Here, we reveal that RNF20-induced SREBP1c ubiquitination down-regulates hepatic lipogenic activity upon PKA activation. CONCLUSION: RNF20 acts as a negative regulator of hepatic fatty acid metabolism through degradation of SREBP1c upon PKA activation. Knowledge regarding this process enhances our understanding of how SREBP1c is able to turn off hepatic lipid metabolism during nutritional deprivation.
Subject(s)
Cyclic AMP-Dependent Protein Kinases/physiology , Lipid Metabolism/physiology , Liver/chemistry , Liver/metabolism , Sterol Regulatory Element Binding Protein 1/metabolism , Ubiquitin-Protein Ligases/physiology , Animals , COS Cells , Chlorocebus aethiops , Fatty Liver/metabolism , Gene Expression Regulation , HeLa Cells , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Nutritional Status , Protein Stability , Sterol Regulatory Element Binding Protein 1/antagonists & inhibitorsSubject(s)
Hypoxia-Inducible Factor 1/metabolism , Hypoxia/metabolism , Metabolic Diseases , Obesity/metabolism , Adipose Tissue/immunology , Drug Discovery , Humans , Inflammation/immunology , Metabolic Diseases/etiology , Metabolic Diseases/immunology , Metabolic Diseases/therapy , Molecular Targeted Therapy , Obesity/complicationsABSTRACT
UNLABELLED: Recent evidence suggests that obese animals exhibit increased endoplasmic reticulum (ER) stress in the liver and adipose tissue. Although ER stress is closely associated with lipid homeostasis, it is largely unknown how ER stress contributes to hepatic steatosis. In this study, we demonstrate that the induction of ER stress stimulates hepatic steatosis through increased expression of the hepatic very low-density lipoprotein receptor (VLDLR). Among the unfolded protein response sensors, the protein kinase RNA-like ER kinase-activating transcription factor 4 signaling pathway was required for hepatic VLDLR up-regulation. In primary hepatocytes, ER stress-dependent VLDLR expression induced intracellular triglyceride accumulation in the presence of very low-density lipoprotein. Moreover, ER stress-dependent hepatic steatosis was diminished in the livers of VLDLR-deficient and apolipoprotein E-deficient mice compared with wild-type mice. In addition, the VLDLR-deficient mice exhibited decreased hepatic steatosis upon high-fat diet feeding. CONCLUSION: These data suggest that ER stress-dependent expression of hepatic VLDLR leads to hepatic steatosis by increasing lipoprotein delivery to the liver, which might be a novel mechanism explaining ER stress-induced hepatic steatosis.
Subject(s)
Endoplasmic Reticulum Stress/physiology , Fatty Liver/physiopathology , Receptors, LDL/physiology , Up-Regulation/physiology , Activating Transcription Factor 4/metabolism , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Disease Models, Animal , Fatty Liver/metabolism , Lipoproteins/metabolism , Liver/metabolism , Mice , Mice, Knockout , Receptors, LDL/deficiency , Receptors, LDL/genetics , Triglycerides/metabolismABSTRACT
The long-term association between mRNA-based coronavirus disease 2019 (COVID-19) vaccination and the development of autoimmune connective tissue diseases (AI-CTDs) remains unclear. In this nationwide, population-based cohort study involving 9,258,803 individuals, we aim to determine whether the incidence of AI-CTDs is associated with mRNA vaccination. The study spans over 1 year of observation and further analyses the risk of AI-CTDs by stratifying demographics and vaccination profiles and treating booster vaccination as time-varying covariate. We report that the risk of developing most AI-CTDs did not increase following mRNA vaccination, except for systemic lupus erythematosus with a 1.16-fold risk in vaccinated individuals relative to controls. Comparable results were reported in the stratified analyses for age, sex, mRNA vaccine type, and prior history of non-mRNA vaccination. However, a booster vaccination was associated with an increased risk of some AI-CTDs including alopecia areata, psoriasis, and rheumatoid arthritis. Overall, we conclude that mRNA-based vaccinations are not associated with an increased risk of most AI-CTDs, although further research is needed regarding its potential association with certain conditions.