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Marine Natural Products, Multitarget Therapy and Repurposed Agents in Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial disease characterized by the presence of amyloid plaques, neurofibrillary tangles, and nerve cell death that affects, mainly, older people. After decades of investigation, the search for an efficacious treatment for AD remains and several strategies can be and are being employed in this journey. In this review, four of the most promising strategies, alongside with its most promising agents under investigation or development are highlighted. Marine natural products (MNP) are a source of unique chemical structures with useful biological activities for

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… However, it is metabolized in vivo to generate the hydroxylated metabolite 4-OH-GTS-21, formed by O -demethylation. These metabolites showed better efficacies than GTS-21 on α7 receptors in mammalian species but they possess poor penetration into the brain probably due to their high polarity. …

Leveraging Dietary Interventions to Benefit Patients with Hematologic Malignancies and Clonal Hematopoiesis.

Diet is a modifiable factor that influences multiple pathways relevant to hematologic malignancy, including systemic inflammation, immune cell activity, gut microbiota composition, and cancer cell metabolism. Translation of preclinical findings into clinical practice for hematologic malignancies remains nascent, although momentum is building to evaluate dietary interventions as a component of supportive and disease-modifying care. This review examines the mechanistic rationale for dietary interventions across the spectrum of clonal hematologic disorders and synthesizes current clinical evidenc

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… include DNA methyltransferase 3A ( DNMT3A ), which catalyzes de novo methylation of cytosine at CpG sites, and ten eleven translocation 2 ( TET2 ), an Fe(II)- and 2-oxoglutarate-dependent methylcytosine dioxygenase that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine and thereby initiates active DNA demethylation …

Цель METTL3/m6A/SOCS3 перепрограммирует макрофажную поляризацию, связанную с опухолью, с тем чтобы повысить эффективность анти-PD-1-терапии в множестве миеломы.

ИССЛЕДОВАНИЯ: В ходе этого исследования были изучены функции иммуномодулятора подавителя цитокина, сигнализирующего 3 (SOCS3) в макрофаге поляризации и активации цитотоксичных Т-клеток в микроопухоли (TME) множественной миэломы (MM). МЕТОДЫ: Выражение SOCS3 оценивалось в клинических образцах MM и здоровом контроле. Для разъяснения воздействия SOCS3 на злокачественное развитие клеток MM и поляризацию макрофага были разработаны анализы эффективности и потери функций, а также система кокультуры MM-камер. В рамках механистических исследований основное внимание было уделено модуляции SOCS3 при помо

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… Yu T, Yao L, Yin H, Teng Y, Hong M, Wu Q (2022) ALKBH5 Promotes Multiple Myeloma Tumorigenicity through inducing m6A-demethylation of SAV1 mRNA and myeloma stem cell phenotype. Int J Biol Sci 18:2235–2248. 10.7150/ijbs.64943 33. …

Management and Clinical Outcomes of Scleredema Diabeticorum: A Scoping Review.

Background/objectivesThe objective of this scoping review was to systematically map the available evidence for the management of scleredema diabeticorum (SD) to summarize the documented clinical outcomes with the aim to inform clinical practice and identify research gaps.MethodsWe conducted a scoping review identifying studies published in English from January 2005 to July 2025 through a comprehensive search of Scopus, MEDLINE, and the Cochrane Library. Eligible studies included randomized controlled trials, observational studies, case series, and case reports on treatment interventions and cl

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… In addition to its classical antifolate activity, MTX exerts multiple non-dihydrofolate reductase-mediated effects, including modulation of oxidative stress, induction of cellular differentiation, epigenetic regulation via DNA and protein demethylation, histone acetylation, and suppression of proinflammatory …

RVd и CyBord терапии ремоделируют созревание клеток B и изменяют иммунную и клональную архитектуру в множестве миеломы.

Множественная миелома (ММ) характеризуется неоднородностью плазменных клеток (ПХ) и изменениями в дифференциации В-клеток и иммунной регламентации. Хотя линалидомид/бортезомиб/дексатон (RV) и циклофосфамид/бортезомиб/дексамасон (CyBorD) являются клинически эффективными, их точное воздействие на созревание ПК/B-клеток остается неясным. МЕТОДЫ: Мы провели профилирование КИТОФ на образцах костного мозга из RVd (n = 47) и пациентов MM, проходящих лечение CyBorD (n = 15), каждый по сравнению с неочищенной когортой (n = 43). Внутри каждого терапевтического рукава ответные устройства (RV, n = 35; CyB

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… /AKT and MAPK signaling to promote malignant plasma cell survival; CD117⁺ cells may reflect favorable marrow profiles, but CD117⁺CD56⁻ phenotypes are associated with aggressive, drug-resistant disease. 45 MMSET, a histone methyltransferase overexpressed in t(4;14) MM (15% of cases), catalyzes H3K36 demethylation …

XPO1 inhibitor selinexor enhances the apoptotic effect of azacitidine in T-cell lymphoma with TET2/RHOA mutations via JAK3/STAT3 axis.

BACKGROUND: Peripheral T-cell lymphoma (PTCL) is a highly heterogeneous group of lymphoid malignancies with diverse pathological and molecular features. Patients harboring TET2 and RHOA double mutations exhibit poor response to anthracycline-based chemotherapy and unfavorable prognosis. Azacitidine, a hypomethylating agent, is frequently used in combination with anthracycline-based regimens in PTCL. However, resistance remains a significant challenge. This study aims to explore novel targeted therapies to overcome therapeutic resistance in TET2/RHOA-mutated PTCL patients. METHODS: A systemati

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… This change was likely due to azacitidine-induced demethylation, which enhances SOCS1 transcription, as supported by subsequent qPCR experiments. …

The Impact of Iron on Cancer-Related Immune Functions in Oncology: Molecular Mechanisms and Clinical Evidence.

Iron metabolism plays a dual role in cancer, serving as an essential nutrient for cellular functions and a potential catalyst for tumor growth and immune evasion. Here, we cover the complex interplay between iron levels within the serum or in the microenvironment and cancer therapy, focusing on how iron deficiency and overload can impact immune function, tumor progression, and treatment efficacy. On the one hand, we highlight iron deficiency as a factor of primary immune responses and its adverse effects on anti-cancer immunotherapy efficacy. On the other hand, we also stress the impact of iro

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… Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses. Nat. Commun. 2019;10:2935. doi: 10.1038/s41467-019-11002-5. 65. Bailey S.R., Nelson M.H., Himes R.A., Li Z., Mehrotra S., Paulos C.M. Th17 Cells in Cancer: The Ultimate Identity Crisis. …

The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies.

Toll-like receptors (TLR) belong to the pattern recognition receptors (PRR). TLR7 and the closely correlated TLR8 affiliate with toll-like receptors family, are located in endosomes. They recognize single-stranded ribonucleic acid (RNA) molecules and synthetic deoxyribonucleic acid (DNA)/RNA analogs-oligoribonucleotides. TLRs are primarily expressed in hematopoietic cells. There is compiling evidence implying that TLRs also direct the formation of blood cellular components and make a contribution to the pathogenesis of certain hematopoietic malignancies. The latest research shows a positive ef

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… Conjugation of TLR7 Agonist Combined with Demethylation Treatment Improves Whole-Cell Tumor Vaccine Potency in Acute Myeloid Leukemia. Int. J. Med. Sci. 2020;17:2346–2356. doi: 10.7150/ijms.49983. 142. Zhu F., Khatri I., Spaner D., Gorczynski R.M. An autologous tumor vaccine for CLL. Leuk. …

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential.

Brain cancers are the leading cause of cancer-related deaths in children. Biological changes in these tumors likely include epigenetic deregulation during embryonal development of the nervous system. Histone acetylation is one of the most widely investigated epigenetic processes, and histone deacetylase inhibitors (HDACis) are increasingly important candidate treatments in many cancer types. Here, we review advances in our understanding of how HDACis display antitumor effects in experimental models of specific pediatric brain tumor types, i.e., medulloblastoma (MB), ependymoma (EPN), pediatric

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… Enrichment of 5-carboxylcytosine (5caC) and increased TET1 expression, which are involved in active DNA demethylation, are epigenetic hallmarks of EPN and SHH MB ( Ramsawhook et al., 2017 ). …

From Bench to Bedside and Beyond: Therapeutic Scenario in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous group of clonal disorders characterized by abnormal proliferation of undifferentiated myeloid progenitors, impaired hematopoiesis, and variable response to therapy. To date, only about 30% of adult patients with AML become long-term survivors and relapse and/or disease refractoriness are the major cause of treatment failure. Thus, this is an urgent unmet clinical need and new drugs are envisaged in order to ameliorate disease survival outcomes. Here, we review the latest therapeutic approaches (investigational and approved agents) for AML treatme

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… Figure 2 Epigenetic drugs influence main post-translational modifications of the nucleosomal histones including deacetylation of lysine residues (HDACi), methylation (HMAs), reduction of H3K79 methylation (DOT1Li) and H3K27 (EZH2i), demethylation of lysine residues (LSD1i) and bromodomain, and extra-terminal …

Targeting Metabolic Reprogramming in Acute Myeloid Leukemia.

The cancer metabolic reprogramming allows the maintenance of tumor proliferation, expansion and survival by altering key bioenergetics, biosynthetic and redox functions to meet the higher demands of tumor cells. In addition, several metabolites are also needed to perform signaling functions that further promote tumor growth and progression. These metabolic alterations have been exploited in different cancers, including acute myeloid leukemia, as novel therapeutic strategies both in preclinical models and clinical trials. Here, we review the complexity of acute myeloid leukemia (AML) metabolism

Metabolic Alterations in Cancer Cells and the Emerging Role of Oncometabolites as Drivers of Neoplastic Change.

The mitochondrion is an important organelle and provides energy for a plethora of intracellular reactions. Metabolic dysregulation has dire consequences for the cell, and alteration in metabolism has been identified in multiple disease states-cancer being one. Otto Warburg demonstrated that cancer cells, in the presence of oxygen, undergo glycolysis by reprogramming their metabolism-termed "aerobic glycolysis". Alterations in metabolism enable cancer cells to gain a growth advantage by obtaining precursors for macromolecule biosynthesis, such as nucleic acids and lipids. To date, several molec

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… IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483:474–478. doi: 10.1038/nature10860. 97. Koivunen P., Lee S., Duncan C.G., Lopez G., Lu G., Ramkissoon S., Losman J.A., Joensuu P., Bergmann U., Gross S., et al. …

Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue.

In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre-clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so-called 'master modulators' of tumors, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs, etc., the results indicate clinically relevant communicative reprogram

Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are a diverse group of chronic hematological disorders that involve unregulated clonal proliferation of white blood cells. Sevearl of them are associated with mutations in receptor tyrosine kinases or cytokine receptor associated tyrosine kinases rendering them independent of cytokine-mediated regulation. Classically they have been broadly divided into BCR-ABL1 fusion + ve (Ph + ve) or -ve (Ph-ve) MPNs. Identification of BCR-ABL1 tyrosine kinase as a driver of chronic myeloid leukemia (CML) and successful application of small molecule inhibitors of the tyrosi

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… The information presented is current as of 24 th January 2015 Compounds | Target/mechanism | National Clinical Trial Identifier | Phase | Condition | Status Decitabine | Anti-metabolite chemotherapeutic, DNA demethylation | NCT02076191 | I/II | Accelerated or blast phase MPN | Recruiting Azacitidine …

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021).

PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin-proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article "PROTACs:

Gene regulation by non-Coding RNAs in infertility: a mechanistic review.

Infertility is a significant global health issue affecting millions of couples, with noncoding RNAs (ncRNAs) emerging as pivotal regulators in reproductive biology. This review explores the roles of various ncRNAs, including microRNAs (miRNAs), small interfering RNAs (siRNAs), long noncoding RNAs (lncRNAs), PIWI-interacting RNAs (piRNAs), and circular RNAs (circRNAs) in male and female infertility. These ncRNAs modulate critical processes such as spermatogenesis, oogenesis, follicular development, and embryo implantation through mechanisms like post-transcriptional regulation, chromatin remode

Integrated Engineering of CAR-T Cells for Solid Tumours.

Chimeric antigen receptor (CAR) T-cell therapy has achieved durable efficacy in hematologic malignancies but encounters persistent obstacles in solid tumours, including antigen heterogeneity, a suppressive tumour microenvironment (TME), and intrinsic T-cell dysfunction. This review examines the transition from single-axis engineering to an integrated framework that addresses these hurdles in sequence. We delineate how next-generation CAR-T cells are designed for precise spatiotemporal activation through logic-gated and pharmacologically regulatable receptors, while being reinforced by metaboli

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… mitochondrial dysfunction and stemness loss | Elderly patients with T‐cell senescence | [ 48 ] P4HA1‐targeted T cells | Reversal of P4HA1‐mediated TCA cycle disruption | Enhanced precursor CD8 + T‐cell expansion | Solid tumours with dysfunctional TILs | [ 59 ] Vitamin C‐primed CAR‐T | TET2‐mediated DNA demethylation … Vitamin C (ascorbate) facilitated TET2‐mediated DNA demethylation during manufacturing, inhibiting exhaustion programs and promoting memory phenotypes with enhanced in vivo expansion [ 141 ]. …

Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy.

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children. Despite this, very little improvement in survival rates has been achieved over the past few decades. This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years. In the past 20 years, research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell prolife

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… IDH mutations in AML IDH1 and IDH2 mutations can be found in up to 20% of AML patients and are one of the more frequently occurring mutations in cytogenetically normal AML patients. 47 IDH enzymes are key regulators in cellular metabolism and are also important for adaptation to hypoxia, histone demethylation …

Reprogramming of nitrogen metabolism in tumors: mechanisms and therapeutic implications.

Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dynamic balance to meet the body's demand for synthesis of biological macromolecules such as proteins and nucleic acids. However, in the process of tumor development, the nitrogen metabolism of tumor cells is reprogrammed to meet the demand of rapid proliferation, showing significantly different metabolic characteristics from normal cells. Key enzymes in the tumor microenvironment affect nitrogen meta

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… Bott AJ, Peng IC, Fan Y, Faubert B, Zhao L, Li J, Neidler S, Sun Y, Jaber N, Krokowski D, Lu W, Pan JA, Powers S, Rabinowitz J, Hatzoglou M, Murphy DJ, Jones R, Wu S, Girnun G, Zong WX (2015) Oncogenic myc induces expression of glutamine synthetase through promoter demethylation. …

Overcoming resistance to immune checkpoint inhibitor therapy in acute myeloid leukemia.

Acute myeloid leukemia (AML) is characterized by molecular, immunological, and clinical heterogeneity and this has been reflected with changing paradigms in the treatment landscape of AML in recent years. Despite high remission rates with conventional chemotherapy regimens, most patients eventually relapse and have disappointing outcomes in the relapsed setting, with estimated 5-year overall survival rates ranging from 10-15%. Immune checkpoint inhibitors (ICIs) restrain T-cell suppressive signals delivered through cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death p

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… Clinical studies indicate that azacytidine (AZA) can induce PD-1 promoter demethylation, leading to increased PD-1 expression and poorer outcomes in the absence of immune checkpoint blockade (121). …