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International Journal of Molecular... Jan 2024A hypercaloric fatty diet predisposes an individual to metabolic syndrome and cardiovascular complications. Sirtuin1 (SIRT1) belongs to the class III histone deacetylase...
A hypercaloric fatty diet predisposes an individual to metabolic syndrome and cardiovascular complications. Sirtuin1 (SIRT1) belongs to the class III histone deacetylase family and sustains anabolism, mitochondrial biogenesis, and fat distribution. Epididymal white adipose tissue (eWAT) is involved in inflammation, whilst interscapular brown adipose tissue (iBAT) drives metabolism in obese rodents. Melatonin, a pineal indoleamine, acting as a SIRT1 modulator, may alleviate cardiometabolic damage. In the present study, we morphologically characterized the heart, eWAT, and iBAT in male heterozygous SIRT1 mice (HET mice) on a high-fat diet (60%E lard) versus a standard rodent diet (8.5% E fat) and drinking melatonin (10 mg/kg) for 16 weeks. Wild-type (WT) male C57Bl6/J mice were similarly fed for comparison. Cardiomyocyte fibrosis and endoplasmic reticulum (ER) stress response worsened in HET mice on a high-fat diet vs. other groups. Lipid peroxidation, ER, and mitochondrial stress were assessed by 4 hydroxy-2-nonenal (4HNE), glucose-regulated protein78 (GRP78), CCAA/enhancer-binding protein homologous protein (CHOP), heat shock protein 60 (HSP60), and mitofusin2 immunostainings. Ultrastructural analysis indicated the prevalence of atypical inter-myofibrillar mitochondria with short, misaligned cristae in HET mice on a lard diet despite melatonin supplementation. Abnormal eWAT adipocytes, crown-like inflammatory structures, tumor necrosis factor alpha (TNFα), and iBAT whitening characterized HET mice on a hypercaloric fatty diet and were maintained after melatonin supply. All these data suggest that melatonin's mechanism of action is strictly linked to full SIRT1 expression, which is required for the exhibition of effective antioxidant and anti-inflammatory properties.
Topics: Male; Animals; Mice; Diet, High-Fat; Melatonin; Sirtuin 1; Cardiovascular Diseases; Dietary Supplements
PubMed: 38255934
DOI: 10.3390/ijms25020860 -
Journal of Neuro-oncology Jan 2024To provide a treatment-focused review and develop basic treatment guidelines for patients diagnosed with pineal anlage tumor (PAT).
PURPOSE
To provide a treatment-focused review and develop basic treatment guidelines for patients diagnosed with pineal anlage tumor (PAT).
METHODS
Prospectively collected data of three patients with pineal anlage tumor from Germany was combined with clinical details and treatment information from 17 published cases.
RESULTS
Overall, 20 cases of PAT were identified (3 not previously reported German cases, 17 cases from published reports). Age at diagnosis ranged from 0.3 to 35.0 (median: 3.2 ± 7.8) years. All but three cases were diagnosed before the age of three years. For three cases, metastatic disease at initial staging was described. All patients underwent tumor surgery (gross-total resection: 9, subtotal resection/biopsy: 9, extent of resection unknown: 2). 15/20 patients were alive at last follow-up. Median follow-up for 10/15 surviving patients with available follow-up and treatment data was 2.4 years (0.3-6.5). Relapse was reported for 3 patients within 0.8 years after diagnosis. Five patients died, 3 after relapse and 2 from early postoperative complications. Two-year-progression-free- and -overall survival were 65.2 ± 12.7% and 49.2 ± 18.2%, respectively. All 4 patients who received intensive chemotherapy including high-dose chemotherapy combined with radiotherapy (2 focal, 2 craniospinal [CSI]) had no recurrence. Focal radiotherapy- and CSI-free survival rates in 13 evaluable patients were 46.2% (6/13) and 61.5% (8/13), respectively.
CONCLUSION
PAT is an aggressive disease mostly affecting young children. Therefore, adjuvant therapy using intensive chemotherapy and considering radiotherapy appears to comprise an appropriate treatment strategy. Reporting further cases is crucial to evaluate distinct treatment strategies.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Young Adult; Brain Neoplasms; Neoplasm Recurrence, Local; Pineal Gland; Pinealoma; Recurrence; Supratentorial Neoplasms; Treatment Outcome
PubMed: 38253790
DOI: 10.1007/s11060-023-04547-5 -
Acta Neuropathologica Communications Jan 2024Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at...
Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at extramedullary sites, and primarily involve the skin and soft tissue of middle-aged adults. ES may be concomitant with or secondary to myeloid neoplasms (mostly acute myeloid leukemia (AML)) or in isolated cases (de novo) without infiltration of the bone marrow by blasts. ES share cytogenetic and molecular abnormalities with AML, including RUNX1T1 fusions. Some of these alterations seem to be correlated with particular sites of involvement. Herein, we report an isolated erythroblastic sarcoma with NFIA::RUNX1T1 located in the central nervous system (CNS) of a 3-year-old boy. Recently, two pediatric cases of CNS MS with complete molecular characterization have been documented. Like the current case, they concerned infants (2 and 3 years-old) presenting a brain tumor (pineal involvement) with leptomeningeal dissemination. Both cases also harbored a NFIA::RUNX1T3 fusion. ES constitutes a diagnostic challenge for neuropathologists because it does not express differentiation markers such as CD45, and may express CD99 which could be confused with CNS Ewing sarcoma. CD43 is the earliest pan-hematopoietic marker and CD45 is not expressed by erythroid lineage cells. E-cadherin (also a marker of erythroid precursors) and CD117 (expressed on the surface of erythroid lineage cells) constitute other immunhistochemical hallmarks of ES. The prognosis of patients with ES is similar to that of other patients with AML but de novo forms seem to have a poorer prognosis, like the current case. To conclude, pediatric ES with NFIA::RUNX1T1/3 fusions seem to have a tropism for the CNS and thus constitute a potential pitfall for neuropathologists. Due to the absence of circulating blasts and a DNA-methylation signature, the diagnosis must currently be made by highlighting the translocation and expression of erythroid markers.
Topics: Child, Preschool; Humans; Infant; Male; Middle Aged; Bone Marrow; Central Nervous System Neoplasms; Leukemia, Myeloid, Acute; NFI Transcription Factors; RUNX1 Translocation Partner 1 Protein; Sarcoma; Sarcoma, Myeloid
PubMed: 38243303
DOI: 10.1186/s40478-023-01708-5 -
Heliyon Jan 2024Epidemiological as well as experimental studies have established that the pineal hormone melatonin has inhibitory effects on different types of cancers. Several...
Epidemiological as well as experimental studies have established that the pineal hormone melatonin has inhibitory effects on different types of cancers. Several mechanisms have been proposed for the anticancer activities of melatonin, but the fundamental molecular pathways still require clarity. We developed a mouse model of breast cancer using Ehrlich's ascites carcinoma (injected in the 4th mammary fat pad of female Swiss albino mice) and investigated the possibility of targeting the autophagy-inflammation-EMT colloquy to restrict breast tumor progression using melatonin as intervention. Contrary to its conventional antioxidant role, melatonin was shown to augment intracellular ROS and initiate ROS-dependent apoptosis in our system, by modulating the p53/JNK & NF-κB/pJNK expressions/interactions. Melatonin-induced ROS promoted SIRT1 activity. Interplay between SIRT1 and NF-κB/p65 is known to play a pivotal role in regulating the crosstalk between autophagy and inflammation. Persistent inflammation in the tumor microenvironment and subsequent activation of the IL-6/STAT3/NF-κB feedback loop promoted EMT and suppression of autophagy through activation of PI3K/Akt/mTOR signaling pathway. Melatonin disrupted NF-κB/SIRT1 interactions blocking IL-6/STAT3/NF-κB pathway. This led to reversal of pro-inflammatory bias in the breast tumor microenvironment and augmented autophagic responses. The interactions between p62/Twist1, NF-κB/Beclin1 and NF-κB/Slug were altered by melatonin to strike a balance between autophagy, inflammation and EMT, leading to tumor regression. This study provides critical insights into how melatonin could be utilized in treating breast cancer via inhibition of the PI3K/Akt/mTOR signaling and differential modulation of SIRT1 and NF-κB proteins, leading to the establishment of apoptotic and autophagic fates in breast cancer cells.
PubMed: 38226217
DOI: 10.1016/j.heliyon.2023.e23870 -
Journal of Translational Medicine Jan 2024Chimeric antigen receptor CAR-T cell therapies have ushered in a new era of treatment for specific blood cancers, offering unparalleled efficacy in cases of treatment...
BACKGROUND
Chimeric antigen receptor CAR-T cell therapies have ushered in a new era of treatment for specific blood cancers, offering unparalleled efficacy in cases of treatment resistance or relapse. However, the emergence of cytokine release syndrome (CRS) as a side effect poses a challenge to the widespread application of CAR-T cell therapies. Melatonin, a natural hormone produced by the pineal gland known for its antioxidant and anti-inflammatory properties, has been explored for its potential immunomodulatory effects. Despite this, its specific role in mitigating CAR-T cell-induced CRS remains poorly understood.
METHODS
In this study, our aim was to investigate the potential of melatonin as an immunomodulatory agent in the context of CD19-targeting CAR-T cell therapy and its impact on associated side effects. Using a mouse model, we evaluated the effects of melatonin on CAR-T cell-induced CRS and overall survival. Additionally, we assessed whether melatonin administration had any detrimental effects on the antitumor efficacy and persistence of CD19 CAR-T cells.
RESULTS
Our findings demonstrate that melatonin effectively mitigated the severity of CAR-T cell-induced CRS in the mouse model, leading to improved overall survival outcomes. Remarkably, melatonin administration did not compromise the antitumor effectiveness or persistence of CD19 CAR-T cells, indicating its compatibility with therapeutic goals. These results suggest melatonin's potential as an immunomodulatory compound to alleviate CRS without compromising the therapeutic benefits of CAR-T cell therapy.
CONCLUSION
The study's outcomes shed light on melatonin's promise as a valuable addition to the existing treatment protocols for CAR-T cell therapies. By attenuating CAR-T cell-induced CRS while preserving the therapeutic impact of CAR-T cells, melatonin offers a potential strategy for optimizing and refining the safety and efficacy profile of CAR-T cell therapy. This research contributes to the evolving understanding of how to harness immunomodulatory agents to enhance the clinical application of innovative cancer treatments.
Topics: Antigens, CD19; Cell- and Tissue-Based Therapy; Cytokine Release Syndrome; Immunologic Factors; Immunotherapy, Adoptive; Melatonin; Neoplasm Recurrence, Local; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Animals; Mice
PubMed: 38221609
DOI: 10.1186/s12967-023-04779-z -
International Journal of Surgery... Mar 2024
Topics: Humans; Retrospective Studies; Pinealoma; Brain Neoplasms; Pineal Gland; Neurosurgical Procedures
PubMed: 38215266
DOI: 10.1097/JS9.0000000000001038 -
World Neurosurgery Apr 2024Pineal region tumors are challenging lesions in terms of surgical accessibility and removal. The complexity is compounded by the infrequency and heterogeneity of pineal...
Pineal region tumors are challenging lesions in terms of surgical accessibility and removal. The complexity is compounded by the infrequency and heterogeneity of pineal neoplasms. In Video 1, we present the case of a 39-year-old woman who presented with progressive headaches and vision impairment. She underwent microsurgical resection for a pineal parenchymal tumor of intermediate differentiation. We discuss the rationale, risks, and benefits of treatment for this patient, as well as provide a detailed overview of the alternative approaches that may be considered. Additionally, we discuss the unique anatomic considerations for each approach and include a virtual reality-compatible 3-dimensional fly-through to highlight the relationship between the tumor and relevant venous anatomy. The patient tolerated the procedure well with excellent neurologic outcome, and her follow-up imaging showed no evidence of tumor recurrence.
Topics: Humans; Female; Adult; Pinealoma; Pineal Gland; Brain Neoplasms; Neoplasm Recurrence, Local; Veins
PubMed: 38211811
DOI: 10.1016/j.wneu.2024.01.015 -
Cureus Dec 2023Pineal parenchymal tumors of intermediate differentiation (PPTIDs) account for a significant proportion of pineal tumors and are classified as grade II/III according to...
Pineal parenchymal tumors of intermediate differentiation (PPTIDs) account for a significant proportion of pineal tumors and are classified as grade II/III according to the WHO classification. The management of PPTIDs remains controversial because of limited reported cases and the absence of standardized treatment guidelines. We present a case of an eight-year-old male child who presented with vomiting and a sudden squint of the eyes. Imaging revealed a well-defined heterogeneous enhancing lesion in the pineal region with acute hydrocephalus. The patient underwent surgical resection, and the tumor was diagnosed as PPTID. Local recurrence occurred 10 months later, requiring a second surgical intervention and adjuvant radiation therapy. A follow-up showed a regression of the tumor and improvement in symptoms. A literature review of reported PPTID cases revealed variability in clinical presentation, treatment approaches, and outcomes. Headaches were the most common symptom, and surgical resection was the primary treatment modality. Adjuvant therapies such as radiation therapy and chemotherapy were utilized in some cases. Tumor recurrence was observed in several instances, underscoring the need for long-term follow-up. In conclusion, PPTIDs are rare brain tumors with challenging diagnosis and management. Surgical resection remains the mainstay of treatment; however, the optimal approach is uncertain. Standardized reporting and larger studies are necessary to establish guidelines for the management of PPTIDs and improve long-term outcomes.
PubMed: 38192964
DOI: 10.7759/cureus.50139 -
Oncology Research 2023Melatonin is a versatile indolamine synthesized and secreted by the pineal gland in response to the photoperiodic information received by the retinohypothalamic...
Melatonin is a versatile indolamine synthesized and secreted by the pineal gland in response to the photoperiodic information received by the retinohypothalamic signaling pathway. Melatonin has many benefits, such as organizing circadian rhythms and acting as a powerful hormone. We aimed to show the antitumor effects of melatonin in both and models through the mammalian target of rapamycin (mTOR) signaling pathway and the Argyrophilic Nucleolar Regulatory Region (AgNOR), using the Microcomputed Tomography (Micro CT). Ehrlich ascites carcinoma (EAC) cells were administered into the mice by subcutaneous injection. Animals with solid tumors were injected intraperitoneally with 50 and 100 mg/kg melatonin for 14 days. Volumetric measurements for the taken tumors were made with micro-CT imaging, immunohistochemistry (IHC), real-time polymerase chain reaction (PCR) and AgNOR. Statistically, the tumor tissue volume in the Tumor+100 mg/kg melatonin group was significantly lower than that in the other groups in the data obtained from micro-CT images. In the IHC analysis, the groups treated with Tumor+100 mg/kg melatonin were compared when the mTOR signaling pathway and factor 8 (F8) expression were compared with the control group. It was determined that there was a significant decrease ( < 0.05). Significant differences were found in the total AgNOR area/nuclear area (TAA/NA) ratio in the treatment groups ( < 0.05). Furthermore, there were significant differences between the amount of mTOR mRNA for the phosphatidylinositol 3-kinase (PI3K), AKT Serine/Threonine Kinase (PKB/AKT) genes ( < 0.05). Cell apoptosis was evaluated with Annexin V in an study with different doses of melatonin; It was observed that 100 µg/mL melatonin dose caused an increase in the apoptotic cell death. In this study, we have reported anti-tumor effects of melatonin in cell culture studies as well as in mice models. Comprehensive characterization of the melatonin-mediated cancer inhibitory effects will be valuable in advancing our fundamental molecular understanding and translatability of pre-clinical findings to earlier phases of clinical trials.
Topics: Humans; Animals; Mice; Melatonin; X-Ray Microtomography; Ascites; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Carcinoma; TOR Serine-Threonine Kinases; Mammals
PubMed: 38188676
DOI: 10.32604/or.2023.042350