Protective Effects of Dietary Vitamin D, Turmeric Powder, and Their Combination against Gasoline Intoxication in Rats.

The inhalation of gasoline vapors (GV) is associated with developing various pathologies. Particularly, oil refinery and gas station workers are at a greater risk of developing lung cancer, kidney cancer, bladder cancer, and hematological disorders, including acute myeloid leukemia. Therefore, preventing the harmful effects of GV and alleviating their consequences appear to be important and timely issues.

Roles of Glutathione and AP-1 in the Enhancement of Vitamin D-Induced Differentiation by Activators of the Nrf2 Signaling Pathway in Acute Myeloid Leukemia Cells.

Active vitamin D derivatives (VDDs)-1α,25-dihydroxyvitamin D/D and their synthetic analogs-are well-known inducers of cell maturation with the potential for differentiation therapy of acute myeloid leukemia (AML). However, their dose-limiting calcemic activity is a significant obstacle to using VDDs as an anticancer treatment. We have shown that different activators of the NF-E2-related factor-2/Antioxidant Response Element (Nrf2/ARE) signaling pathway, such as the phenolic antioxidant carnosic acid (CA) or the multiple sclerosis drug monomethyl fumarate (MMF), synergistically enhance the antileukemic effects of various VDDs applied at low concentrations in vitro and in vivo.

Projection of Expression Profiles to Transcription Factor Activity Space Provides Added Information.

Acute myeloid leukemia (AML) is an aggressive type of leukemia, characterized by the accumulation of highly proliferative blasts with a disrupted myeloid differentiation program. Current treatments are ineffective for most patients, partly due to the genetic heterogeneity of AML. This is driven by genetically distinct leukemia stem cells, resulting in relapse even after most of the tumor cells are destroyed.

Novel pyrrolidine-aminophenyl-1,4-naphthoquinones: structure-related mechanisms of leukemia cell death.

Novel derivatives of aminophenyl-1,4-naphthoquinones, in which a pyrrolidine group was added to the naphthoquinone ring, were synthesized and investigated for the mechanisms of leukemic cell killing. The novel compounds, TW-85 and TW-96, differ in the functional (methyl or hydroxyl) group at the para-position of the aminophenyl moiety. TW-85 and TW-96 were found to induce concentration- and time-dependent apoptotic and/or necrotic cell death in human U937 promonocytic leukemia cells but only TW-96 could also kill K562 chronic myeloid leukemia cells and CCRF-CEM lymphoblastic leukemia cells.

Single-cell DNA sequencing identifies risk-associated clonal complexity and evolutionary trajectories in childhood medulloblastoma development.

We reconstructed the natural history and temporal evolution of the most common childhood brain malignancy, medulloblastoma, by single-cell whole-genome sequencing (sc-WGS) of tumours representing its major molecular sub-classes and clinical risk groups. Favourable-risk disease sub-types assessed (MB and infant desmoplastic/nodular MB) typically comprised a single clone with no evidence of further evolution. In contrast, highest risk sub-classes (MYC-amplified MB and TP53-mutated MB) were most clonally diverse and displayed gradual evolutionary trajectories.

Cytotoxicity of Thioalkaloid-Enriched Extract and Purified 6,6'-Dihydroxythiobinupharidine in Acute Myeloid Leukemia Cells: The Role of Oxidative Stress and Intracellular Calcium.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by uncontrolled proliferation of immature myeloid progenitors. Here, we report the in vitro antileukemic effects of the sesquiterpene thioalkaloid-enriched fraction of the leaf extract (NUP) and a purified thioalkaloid 6,6'-dihydroxythiobinupharidine (DTBN). Treatment with 0.

Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells.

Plant phenolic compounds have shown the ability to cooperate with one another at low doses in producing enhanced anticancer effects. This may overcome the limitations (e.g.

Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells.

Anticancer activities of plant polyphenols have been demonstrated in various models of neoplasia. However, evidence obtained in numerous in vitro studies indicates that proliferation arrest and/or killing of cancer cells require quite high micromolar concentrations of polyphenols that are difficult to reach in vivo and can also be (geno)toxic to at least some types of normal cells. The ability of certain polyphenols to synergize with one another at low concentrations can be used as a promising strategy to effectively treat human malignancies.

Inter and intra-tumoral heterogeneity as a platform for personalized therapies in medulloblastoma.

Medulloblastoma is the most common malignant CNS tumor of childhood, affecting ~350 patients/year in the USA. In 2020, most children are cured of their disease, however, survivors are left with life-long late-effects as a consequence of intensive surgery, and application of chemo- and radio-therapy to the developing brain. A major contributor to improvements in patient survival has been the development of risk-stratified treatments derived from a better understanding of the prognostic value of disease biomarkers.

Carnosic acid increases sorafenib-induced inhibition of ERK1/2 and STAT3 signaling which contributes to reduced cell proliferation and survival of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) has increasing worldwide incidence but when unresectable lacks curative options. Treatment with a kinase inhibitor Sorafenib (Sf), while initially effective, results in only short increases in patient survival, thus there is a need for improved treatment regimens. Numerous treatment regimens have been explored wherein Sf is combined with other agents, such as non-toxic botanicals like Curcumin or Silibinin.

The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes.

Aims: Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalized, risk-adapted therapies.

Methods: We characterized the iMB molecular landscape, including second-generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387).

Plasma 25-Hydroxyvitamin D Levels and VDR Gene Expression in Peripheral Blood Mononuclear Cells of Leukemia Patients and Healthy Subjects in Central Kazakhstan.

Low blood levels of the vitamin D metabolite 25-hydroxyvitamin D [25(OH)D] have been associated with an increased risk and poorer outcomes of various cancers, including hematological malignancies. The Central Kazakhstan area has a relatively high incidence rate of leukemia. However, the relationship between vitamin D status and leukemia or other types of cancer in Kazakhstan has not yet been addressed.

Differentiation agents increase the potential AraC therapy of AML by reactivating cell death pathways without enhancing ROS generation.

Acute myeloid leukemia (AML) has a poor prognosis and requires new approaches for treatment. We have reported that a combination of vitamin D-based cell differentiation agents (doxercalciferol/carnosic acid [D2/CA]) added following the cytotoxic drug arabinocytosine (AraC) increases AML cell death (CD), a model for improved therapy of this disease. Because AraC-induced CD is known to involve reactive oxygen species (ROS) generation, here we investigated if the modulation of cellular REDOX status plays a role in the enhancement of cell death (ECD) by D2/CA.

Synergistic Cytotoxicity of Methyl 4-Hydroxycinnamate and Carnosic Acid to Acute Myeloid Leukemia Cells Calcium-Dependent Apoptosis Induction.

Acute myeloid leukemia (AML) is a malignant hematopoietic disease with poor prognosis for most patients. Conventional chemotherapy has been the standard treatment approach for AML in the past 40 years with limited success. Although, several targeted drugs were recently approved, their long-term impact on survival of patients with AML is yet to be determined.

Dimethyl fumarate and vitamin D derivatives cooperatively enhance VDR and Nrf2 signaling in differentiating AML cells in vitro and inhibit leukemia progression in a xenograft mouse model.

Acute myeloid leukemia (AML) is one of the deadliest hematological malignancies without effective treatment for most patients. Vitamin D derivatives (VDDs) - active metabolites 1α,25-dihydroxyvitamin D (1,25D2) and 1α,25-dihydroxyvitamin D (1,25D3) and their analogs - are differentiation-inducing agents which have potential for the therapy of AML. However, calcemic toxicity of VDDs limits their clinical use at doses effective against cancer cells in vivo.

Participation of vitamin D-upregulated protein 1 (TXNIP)-ASK1-JNK1 signalosome in the enhancement of AML cell death by a post-cytotoxic differentiation regimen.

Standard therapy for Acute Myeloid Leukemia (AML) is rarely curative, and several suggested improvements have had little success so far. We have reported that in an in vitro model of a potential therapeutic regimen for AML, the activity of cytarabine (AraC) is enhanced by a sequential treatment with a combination of the vitamin D2 analog Doxercalciferol (D2) and the plant-derived antioxidant carnosic acid (CA). Importantly, the enhancement occurred selectively in patient-derived AML blasts, but not in the normal bone marrow cells.

Cardiolipin mediates curcumin interactions with mitochondrial membranes.

Curcumin, the main molecular ingredient of the turmeric spice, has been reported to exhibit therapeutic properties for varied diseases and pathological conditions. While curcumin appears to trigger multiple signaling pathways, the precise mechanisms accounting for its therapeutic activity have not been deciphered. Here we show that curcumin exhibits significant interactions with cardiolipin (CL), a lipid exclusively residing in the mitochondrial membrane.

Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib: The TRAC Randomized Clinical Trial.

Importance: There are no medical interventions for the orphan disease CYLD cutaneous syndrome (CCS). Transcriptomic profiling of CCS skin tumors previously highlighted tropomyosin receptor kinases (TRKs) as candidate therapeutic targets.

Objective: To investigate if topical targeting of TRK with an existing topical TRK inhibitor, pegcantratinib, 0.

Transcriptomic profiling of human skin biopsies in the clinical trial setting: A protocol for high quality RNA extraction from skin tumours.

Transcriptomic profiling of skin disease using next generation sequencing allows for detailed information on aspects of RNA biology including gene expression, non-coding regulatory elements and gene splicing. The application of RNA sequencing to human skin disease and cancer is often hampered by degraded RNA. Here we describe a protocol that allows for consistently intact RNA to be extracted from snap frozen skin biopsy samples, which has been validated in a clinical trial setting.

A composition of medicinal plants with an enhanced ability to suppress microsomal lipid peroxidation and a protective activity against carbon tetrachloride-induced hepatotoxicity.

Treatment of liver injury induced by various toxicants represents a serious clinical challenge. Here, we utilized the ability of natural agents to inhibit microsomal lipid peroxidation (LPO) as the in-vitro screening paradigm for selecting efficacious tissue-protective combinations of cooperatively acting medicinal plants. Based on screening of 70 water-ethanol extracts obtained from different parts of 65 plants we prepared a highly active phytocomposition (PC-1) containing oregano (Origanum vulgare), wild thyme (Thymus serpyllum) and coltsfoot (Tussilago farfara) aerial parts, valerian (Valeriana officinalis) leaves and little-leaf linden (Tilia cordata) flowers.

Development and validation of LC-MS/MS with in-source collision-induced dissociation for the quantification of pegcantratinib in human skin tumors.

Aim: Pegcantratinib is a mini-PEGylated K252a derivative, under clinical evaluation as an anticancer agent acting through inhibition of the tropomyosin receptor kinase. A method for quantifying pegcantratinib in skin tumor biopsies of patients was required to determine tumor drug penetration.

Methods & Results: A sensitive and PEGylated molecule specific HPLC-MS/MS method coupled with in-source collision-induced dissociation was developed.

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior.

The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown.

Binding site density enables paralog-specific activity of SLM2 and Sam68 proteins in Neurexin2 AS4 splicing control.

SLM2 and Sam68 are splicing regulator paralogs that usually overlap in function, yet only SLM2 and not Sam68 controls the Neurexin2 AS4 exon important for brain function. Herein we find that SLM2 and Sam68 similarly bind to Neurexin2 pre-mRNA, both within the mouse cortex and in vitro. Protein domain-swap experiments identify a region including the STAR domain that differentiates SLM2 and Sam68 activity in splicing target selection, and confirm that this is not established via the variant amino acids involved in RNA contact.