Astrocyte-induced Cdk5 expedites breast cancer brain metastasis by suppressing MHC-I expression to evade immune recognition.

Brain metastases (BrMs) evade the immune response to develop in the brain, yet the mechanisms of BrM immune evasion remains unclear. This study shows that brain astrocytes induce the overexpression of neuronal-specific cyclin-dependent kinase 5 (Cdk5) in breast cancer-derived BrMs, which facilitates BrM outgrowth in mice. Cdk5-overexpressing BrMs exhibit reduced expression and function of the class I major histocompatibility complex (MHC-I) and antigen-presentation pathway, which are restored by inhibiting Cdk5 genetically or pharmacologically, as evidenced by single-cell RNA sequencing and functional studies. Mechanistically, Cdk5 suppresses MHC-I expression on the cancer cell membrane through the Irf2bp1-Stat1-importin α-Nlrc5 pathway, enabling BrMs to avoid recognition by T cells. Treatment with roscovitine-a clinically applicable Cdk5 inhibitor-alone or combined with immune checkpoint inhibitors, significantly reduces BrM burden and increases tumour-infiltrating functional CD8+ lymphocytes in mice. Thus, astrocyte-induced Cdk5 overexpression endorses BrM immune evasion, whereas therapeutically targeting Cdk5 markedly improves the efficacy of immune checkpoint inhibitors and inhibits BrM growth.

A Silent Threat: Deep Vein Thrombosis in Early-Stage Parkinson's Disease.

Introduction: The primary clinical manifestation of venous thrombosis is discomfort in the lower extremities. Some early Parkinson's disease (PD) patients feel discomfort in the lower limbs. Venous thrombosis can risk lives by causing pulmonary embolism. This study examines the incidence of DVT in early PD patients and its correlation with different clinical and lab features. Methods: A cross-sectional study was conducted on 117 patients with early-stage PD. Ultrasonography was employed to detect the presence of DVT. Factors such as age, gender, body mass index, lifestyle habits (smoking and drinking), medical history (hypertension, diabetes, atrial fibrillation, and tumor), and other lab tests linked to thrombosis were analyzed. Results: In 117 patients, 11 (9.4%) had DVT, while 106 (90.6%) did not. There were no significant differences in gender, BMI, habits, medical history, or other thrombosis-related tests between both groups. However, DVT patients were older with higher d-dimer levels. They also showed an increased right substantia nigra ultrasound echo area, higher HY grades, higher UPDRS 3 scores, less improvement in UPDRS 3 scores and levodopa response. Discussion: The primary risk factors for lower extremity venous thrombosis were found to be age, d-dimer levels, and low-dose levodopa. Therefore, for elderly patients with early-stage PD, it is crucial to conduct d-dimer and lower extremity vascular ultrasound tests. The prevention of venous thrombosis in the lower extremities of early PD patients is of utmost importance.

BATF is a major driver of NK cell epigenetic reprogramming and dysfunction in AML.

Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvß-integrin/TGF-ß/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as HAVCR2, LAG3, TIGIT, and CTLA4. BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-ß pathway or BATF.

Luspatercept enhances hemoglobin levels in a Chinese boy with congenital sideroblastic anemia: A case report.

BACKGROUND: Congenital sideroblastic anemia (CSA) is a rare and heterogeneous group of genetic disorders. Conventional treatment include pyridoxine (vitamin B6) and allogeneic hematopoietic stem cell transplantation (allo-HSCT), and can alleviate anemia in the majority of cases. Nevertheless, some CSA cases remain unresponsive to pyridoxine or are unable to undergo allo-HSCT. Novel management approaches is necessary to be developed. To explore the response of luspatercept in treating congenital sideroblastic anemia. CASE SUMMARY: We share our experience in luspatercept in a 4-year-old male patient with CSA. Luspatercept was administered subcutaneously at doses of 1.0 mg/kg/dose to 1.25 mg/kg/dose every 3 wk, three consecutive doses, evaluating the hematological response. Luspatercept leading to a significant improvement in the patient's anemia. The median hemoglobin during the overall treatment with three doses of luspatercept was 90 (75-101) g/L, the median absolute reticulocyte count was 0.0593 (0.0277-0.1030) × 1012/L, the median serum ferritin was 304.3 (234.4-399) ng/mL, and the median lifespan of mature red blood cells was 80 (57-92) days. Notably, no adverse reactions, such as headaches, dizziness, vomiting, joint pain, or back pain, were observed during the treatment period. CONCLUSION: We believe that luspatercept might emerge as a viable therapeutic option for the maintenance treatment of CSA or as a bridging treatment option before hematopoietic stem cell transplantation.

Cell State of Origin Impacts Development of Distinct Endometriosis-Related Ovarian Carcinoma Histotypes.

Clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are ovarian carcinoma histotypes, which are both thought to arise from ectopic endometrial (or endometrial-like) cells through an endometriosis intermediate. How the same cell type of origin gives rise to two morphologically and biologically different histotypes has been perplexing, particularly given that recurrent genetic mutations are common to both and present in nonmalignant precursors. We used RNA transcription analysis to show that the expression profiles of CCOC and ENOC resemble those of normal endometrium at secretory and proliferative phases of the menstrual cycle, respectively. DNA methylation at the promoter of the estrogen receptor (ER) gene (ESR1) was enriched in CCOC, which could potentially lock the cells in the secretory state. Compared with normal secretory-type endometrium, CCOC was further defined by increased expression of cysteine and glutathione synthesis pathway genes and downregulation of the iron antiporter, suggesting iron addiction and highlighting ferroptosis as a potential therapeutic target. Overall, these findings suggest that while CCOC and ENOC arise from the same cell type, these histotypes likely originate from different cell states. This "cell state of origin" model may help to explain the presence of histologic and molecular cancer subtypes arising in other organs. SIGNIFICANCE: Two cancer histotypes diverge from a common cell of origin epigenetically locked in different cell states, highlighting the importance of considering cell state to better understand the cell of origin of cancer.

Single-cell chromatin accessibility profiling of acute myeloid leukemia reveals heterogeneous lineage composition upon therapy-resistance.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy resistance. Here we leverage single-cell chromatin accessibility profiling of 22 AML bone marrow aspirates from eight patients at time of therapy resistance and following subsequent therapy to characterize their lineage landscape. Our findings reveal a complex lineage architecture of therapy-resistant AML cells that are primed for stem and progenitor lineages and spanning quiescent, activated and late stem cell/progenitor states. Remarkably, therapy-resistant AML cells are also composed of cells primed for differentiated myeloid, erythroid and even lymphoid lineages. The heterogeneous lineage composition persists following subsequent therapy, with early progenitor-driven features marking unfavorable prognosis in The Cancer Genome Atlas AML cohort. Pseudotime analysis further confirms the vast degree of heterogeneity driven by the dynamic changes in chromatin accessibility. Our findings suggest that therapy-resistant AML cells are characterized not only by stem and progenitor states, but also by a continuum of differentiated cellular lineages. The heterogeneity in lineages likely contributes to their therapy resistance by harboring different degrees of lineage-specific susceptibilities to therapy.

IL-8 Produced Via Bidirectional Communication Between Prostate Cancer and M2 Macrophages as a Potential Diagnostic and Prognostic Biomarker.

PURPOSE: Owing to the mortality associated with metastatic prostate cancer and the shortcomings of the current parameters in predicting the disease prognosis, we require the identification of viable biomarkers, which would help in the diagnosis and prognosis of the disease. We aimed to determine whether the interleukin-8 level in the tumor microenvironment could serve as a potential clinical diagnostic marker and prognostic factor for prostate cancer. METHODS: The migration assay of prostate cancer cells was performed in an in vitro co-culture model. Cell lines PC3 and DU145 were divided into two groups and co-cultured with M0 and M2 macrophages, respectively. We used reverse transcription-quantitative polymerase chain reaction to detect M2 macrophage marker expression levels. Immunohistochemistry analyses of tissue microarrays were performed to analyze the correlation between the increased expression of interleukin-8 and the prognosis of prostate cancer. A retrospective analysis based on 142 residual serum specimens was performed to analyze the level of interleukin-8. RESULTS: We observed that M2 macrophages promoted the migration of prostate cancer cells and significantly increased the concentrations of interleukin-8 in the co-culture supernatants. We observed increased expression of CD163 and interleukin-8 in prostate cancer tissues. Furthermore, the levels of interleukin-8 in the serum of prostate cancer patients were higher than those in healthy controls. Untreated patients had higher levels of interleukin-8, which could be a predictor of a higher metastasis rate. CONCLUSION: These results suggest that interleukin-8 produced via bidirectional communication between prostate cancer cells and M2 macrophages is a putative biomarker for prostate cancer diagnosis and treatment.

Development and validation of early death risk score model for emergency status prediction in very severe aplastic anemia.

This study developed and validated the Early Death Risk Score Model for early identification of emergency patients with very severe aplastic anemia (VSAA). All 377 patients with VSAA receiving first-line immunosuppressive therapy (IST) were categorized into training (n=252) and validation (n=125) cohorts. In the training cohort, age >24 years, absolute neutrophil count ≤0.015×109/L, serum ferritin >900ng/mL and times of fever before IST >1 time were significantly associated with early death. Covariates were assigned scores and categorized as: low (score 0-4), medium (score 5-7) and high (score ≥8) risk. Early death rate was significantly different between risk groups and the validation cohort results were consistent with those of the training cohort. The area under the receiver operating characteristic curve for the model was 0.835 (0.734,0.936) in the training cohort and 0.862 (0.730,0.994) in the validation cohort. The calibration plots showed high agreement, and decision curve analysis showed good benefit in clinical applications. The VSAA Early Death Risk Score Model can help with early identification of emergency VSAA and optimize treatment strategies. Emergency VSAA with high risk is associated with high early death rate, and alternative donor hematopoietic stem cell transplantation could be a better treatment than IST even without HLA-matching.

Enzalutamide-induced signatures revealed by epigenetic plasticity using single-cell multi-omics sequencing in prostate cancer.

Prostate cancer is morphologically and molecularly heterogeneous, which poses obstacles for early diagnosis and treatment. Advancements in understanding the heterogeneity of prostate cancer will help navigate through these challenges and ultimately benefit patients. In this study, we integrated single-cell sequencing for transposase-accessible chromatin and whole transcriptome in prostate cancer cell lines, aiming to decode the epigenetic plasticity upon enzalutamide (ENZ) treatment. By comparing the cell populations representing early-treatment response or resistance to the initial tumor cells, we identified seven signature gene sets; they present consistent trends of chromatin closing co-occurred with down-regulated genes during early response and chromatin opening with up-regulated genes upon maintaining drug resistance. In the molecular signatures, we found genes ZNF337, MAPK15, and ESRRG are favorable in progression-free prognosis during early response, while genes CCDC150, CCDC18, and POC1A marked poor prognosis underpinning the pre-existing drug resistance in The Cancer Genome Atlas prostate adenocarcinoma cohort. Ultimately, drug-target analyses nominated combinatory drug candidates to either enhance early-treatment response or potentially overcome ENZ resistance. Together, our integrative, single-cell multi-omics approach in pre-clinical models is effective in identifying informative signatures from complex molecular events, illustrating diverse drug responses in prostate cancer, and invoking novel combinatory drug strategies to inform clinical decision making.

Hetrombopag plus porcine ATG and cyclosporine for the treatment of aplastic anaemia: early outcomes of a prospective pilot study.

Hetrombopag, a small molecular thrombopoietin-receptor agonist, has shown encouraging efficiency in immunosuppressive therapy refractory or relapsed severe aplastic anaemia. To investigate the response rate of hetrombopag combined with IST as first-line treatment, we designed a prospective pilot study including 32 patients with SAA treated with anti-human T lymphocyte porcine immunoglobulin (p-ATG), cyclosporine, and hetrombopag. In addition, 96 patients with SAA treated with p-ATG and cyclosporine alone were matched as controls. In total, 21.9% of patients treated with hetrombopag achieved complete response (CR) at 3 months, while 5.2% of patients achieved CR in the control group (P = 0.005). At 6 months, the CR rates were 34.4% in the hetrombopag group and 14.6% in the control group (P = 0.015). The overall response rates at 6 months were 68.7% and 50.0% in the hetrombopag and control groups, respectively. The median time to haematologic response was 56 days and 77 days, and to CR was 96 days and 214 days in the hetrombopag and control groups, respectively. In conclusion, adding hetrombopag to IST as first-line treatment resulted in faster and better haematologic response in SAA.

Investigating cellular heterogeneity at the single-cell level by the flexible and mobile extrachromosomal circular DNA.

Extrachromosomal circular DNA (eccDNA) is a special class of DNA derived from linear chromosomes. It coexists independently with linear chromosomes in the nucleus. eccDNA has been identified in multiple organisms, including Homo sapiens, and has been shown to play important roles relevant to tumor progression and drug resistance. To date, computational tools developed for eccDNA detection are only applicable to bulk tissue. Investigating eccDNA at the single-cell level using a computational approach will elucidate the heterogeneous and cell-type-specific landscape of eccDNA within cellular context. Here, we performed the first eccDNA analysis at the single-cell level using data generated by single-cell Assay for Transposase-Accessible Chromatin with sequencing (scATAC-seq) in adult and pediatric glioblastoma (GBM) samples. Glioblastoma multiforme (GBM) is an aggressive tumor of the central nervous system with a poor prognosis. Our analysis provides an overview of cellular origins, genomic distribution, as well as the differential regulations between linear and circular genome under disease- and cell-type-specific conditions across the open chromatin regions in GBM. We focused on some eccDNA elements that are potential mobile enhancers acting in a trans-regulation manner. In summary, this pilot study revealed novel eccDNA features in the cellular context of brain tumor, supporting the strong need for eccDNA investigation at the single-cell level.

PKR induces TGF-ß and limits oncolytic immune therapy.

BACKGROUND: Mammalian cells have developed multiple intracellular mechanisms to defend against viral infections. These include RNA-activated protein kinase (PKR), cyclic GMP-AMP synthase and stimulation of interferon genes (cGAS-STING) and toll-like receptor-myeloid differentiation primary response 88 (TLR-MyD88). Among these, we identified that PKR presents the most formidable barrier to oncolytic herpes simplex virus (oHSV) replication in vitro. METHODS: To elucidate the impact of PKR on host responses to oncolytic therapy, we generated a novel oncolytic virus (oHSV-shPKR) which disables tumor intrinsic PKR signaling in infected tumor cells. RESULTS: As anticipated, oHSV-shPKR resulted in suppression of innate antiviral immunity and improves virus spread and tumor cell lysis both in vitro and in vivo. Single cell RNA sequencing combined with cell-cell communication analysis uncovered a strong correlation between PKR activation and transforming growth factor beta (TGF-ß) immune suppressive signaling in both human and preclinical models. Using a murine PKR targeting oHSV, we found that in immune-competent mice this virus could rewire the tumor immune microenvironment to increase the activation of antigen presentation and enhance tumor antigen-specific CD8 T cell expansion and activity. Further, a single intratumoral injection of oHSV-shPKR significantly improved the survival of mice bearing orthotopic glioblastoma. To our knowledge, this is the first report to identify dual and opposing roles of PKR wherein PKR activates antivirus innate immunity and induces TGF-ß signaling to inhibit antitumor adaptive immune responses. CONCLUSIONS: Thus, PKR represents the Achilles heel of oHSV therapy, restricting both viral replication and antitumor immunity, and an oncolytic virus that can target this pathway significantly improves response to virotherapy.

Long-term outcomes of aplastic anemia with cytogenetic abnormalities at diagnosis.

OBJECTIVES: To elucidate the clinical characteristics of AA patients with cytogenetic abnormalities. METHODS: We retrospectively screened 30 patients (30/1206, 2.5%) with cytogenetic abnormalities from 1206 patients with severe and very severe AA who received immunosuppressive therapy (IST) during the years 2012-2019. RESULTS: The most common abnormalities were trisomy 8 (+8, 10/30, 33.3%) and loss of Y (-Y, 8/30, 26.7%). The abnormal clones disappeared 6 months after IST in 14 patients and sustained in 12 patients. Patients with sustained abnormal clones had a lower hematologic response at 6 months after IST than the disappeared (33.3% vs. 64.3%, p = .116). The hematologic response after IST, 5-year overall survival, 5-year event-free survival, myelodysplastic syndrome or acute myeloid leukemia transformation in AA patients with cytogenetic abnormalities were not statistically different from those in normal cytogenetic patients. CONCLUSION: For AA patients with chromosome abnormalities but ineligible for hematopoietic stem cell transplant, IST is effective and appropriate as first-line treatment.

Chromosome-specific retention of cancer-associated DNA hypermethylation following pharmacological inhibition of DNMT1.

The DNA methylation status of the X-chromosome in cancer cells is often overlooked because of computational difficulties. Most of the CpG islands on the X-chromosome are mono-allelically methylated in normal female cells and only present as a single copy in male cells. We treated two colorectal cancer cell lines from a male (HCT116) and a female (RKO) with increasing doses of a DNA methyltransferase 1 (DNMT1)-specific inhibitor (GSK3685032/GSK5032) over several months to remove as much non-essential CpG methylation as possible. Profiling of the remaining DNA methylome revealed an unexpected, enriched retention of DNA methylation on the X-chromosome. Strikingly, the identified retained X-chromosome DNA methylation patterns accurately predicted de novo DNA hypermethylation in colon cancer patient methylomes in the TCGA COAD/READ cohort. These results suggest that a re-examination of tumors for X-linked DNA methylation changes may enable greater understanding of the importance of epigenetic silencing of cancer related genes.

The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1.

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. Importantly, cancer patients with low plasma histamine levels had a more than tripled objective response rate to anti-PD-1 treatment compared with patients with high plasma histamine. Altogether, pre-existing allergy or high histamine levels in cancer patients can dampen immunotherapy responses and warrant prospectively exploring antihistamines as adjuvant agents for combinatorial immunotherapy.

Cell-Type-Specific Profibrotic Scores across Multi-Organ Systems Predict Cancer Prognosis.

Fibrosis is a major cause of mortality. Key profibrotic mechanisms are common pathways involved in tumorigenesis. Characterizing the profibrotic phenotype will help reveal the underlying mechanisms of early development and progression of a variety of human diseases, such as fibrosis and cancer. Fibroblasts have been center stage in response to various stimuli, such as viral infections. However, a comprehensive catalog of cell types involved in this process is currently lacking. Here, we deployed single-cell transcriptomic data across multi-organ systems (i.e., heart, kidney, liver, and lung) to identify novel profibrotic cell populations based on ECM pathway activity at single-cell resolution. In addition to fibroblasts, we also reported that epithelial, endothelial, myeloid, natural killer T, and secretory cells, as well as proximal convoluted tubule cells of the nephron, were significantly actively involved. Cell-type-specific gene signatures were enriched in viral infection pathways, enhanced glycolysis, and carcinogenesis, among others; they were validated using independent datasets in this study. By projecting the signatures into bulk TCGA tumor samples, we could predict prognosis in the patients using profibrotic scores. Our profibrotic cellular phenotype is useful for identifying new mechanisms and potential drug targets at the cell-type level for a wide range of diseases involved in ECM pathway activation.

Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.

[Relationship between Changes of Lymphocyte Subsets and Early Hematologic Response in Immunosuppressive Therapy of Severe Aplastic Anemia Patients].

OBJECTIVE: To explore the relationship between the change of lymphocyte subsets before and after immunosuppressive therapy (IST) with disease severity of severe aplastic anemia (SAA) and hematologic response to IST. METHODS: The clinical data of 94 patients with SAA/VSAA treated by r-ATG and CsA in our hospital from December 2009 to October 2011 was analyzed retrospectively. Among them, 26 patients who had sequential data of lymphocyte subsets and cytokines before and after treatment were enrolled. The relationship between lymphocyte subsets, cytokine level before IST and disease severity, as well as the relationship between changes if lymphocyte subsets, changes of cytokine and the HR after IST for 6 months was analyzed. RESULTS: There were no statistical differences in the ratio and absolute count of lymphocyte, the ratio and absolute count of each lymphocyte subsets, including CD3+T cells, CD3+CD4+T cells, CD3+CD8+T cells, CD3-CD16+1CD56+NK cells, and CD19+B cells, and the level of cytokines, such as IL-1, IL-2, IL-4, IL-6 and TNF-α before IST between SAA and VSAA groups. Also, there were no statistical difference in the levels of above-motional parameter at 3 and 6 months after IST. The ratio and absolute count of Lym, absolute count of CD3+T cells, absolute count of B cells and IL-2 level in response group after IST for 3 and 6 months was significant lower than those before IST. However, only ratio of Lym showed significant decrease after IST for 3 and 6 months in non-response group. After IST for 3 months, the absolute count of CD3+T and CD4+T cells in response group was significant higher than those in non-response group. CONCLUSION: The hematopoietic recovery and early hematologic remission may be affected by the intensity of immune suppression reflected from the changes of lymphocyte subsets and the immune reconstruction reflected from the recovery of lymphocyte subsets. The immune reconstruction is most significant within 3 months after IST.

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants. METHODS: Primary astrocytes were isolated and cultured using neurobasal-based serum-free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α, and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses, and the underlying mechanisms were analyzed. RESULTS: All the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1ß (IL-1ß). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1ß but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity. CONCLUSIONS: The study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.