Despite improved overall prognosis, the treatment of high-risk acute lymphoblastic leukemia (ALL) remains challenging due to the toxicity of intensive polychemotherapy and the limited efficacy of antibody-targeted therapies beyond cluster of differentiation 20 and 22 (CD20 and CD22). ALL is driven not only by genetic alterations but also by profound epigenetic dysregulation, including promoter hypermethylation that also silences surface receptor genes. This epigenetic repression can reduce the efficacy of targeted immunotherapies and contribute to relapse. Epigenetic reprogramming with DNA demethylating agents (e.g., decitabine) has the potential to restore the expression of key B cell receptors such as CD19 or CD20, as well as other therapeutically relevant target antigens on the cell surface, thus enhancing the susceptibility of leukemia cells to antibody-based therapies. In addition to new generations of bispecific antibodies and advanced CAR-T cell constructs, novel antibody-drug conjugates (ADCs) are increasingly coming into focus. The sequential application of DNA methylation inhibitors followed by ADC or inhibitor treatment represents an innovative approach that simultaneously restores tumor suppressor function, enhances leukemia immunogenicity, and expands the therapeutic window of receptor-targeted therapies. We investigated the hypothesis that several hypermethylated genes encoding cell surface proteins accessible to immunotherapy exist in acute lymphoblastic leukemia (ALL). Our review provides a comprehensive analysis of hypermethylated cell surface markers for ALL and the underlying epigenetic reprogramming after demethylation. We propose that the integration of epigenetic therapies into existing immuno-oncology treatment regimens could substantially improve treatment efficacy and open new avenues to overcome resistance mechanisms in ALL.

Neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s disease (AD) are driven by complex, multifactorial mechanisms in which oxidative stress (OS) and neuroinflammation (NI) play central, mutually reinforcing roles. Their interaction is mediated through key signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nuclear factor erythroid 2–related factor 2–Kelch-like ECH-associated protein 1 (Nrf2-Keap1), and the mitogen-activated protein kinase (MAPK) pathway, as well as mitochondrial dysfunction, microglial activation, and dysregulated redox homeostasis. Increasing attention has been directed toward understanding how Food and Drug Administration (FDA)-approved neuroprotective agents influence these interconnected processes. Drugs such as riluzole, edaravone, memantine, and acetylcholinesterase inhibitors exhibit diverse effects on glutamate excitotoxicity, free radical production, inflammatory cytokine release, and microglial reactivity, yet their modest clinical efficacy highlights the limitations of single-target approaches. This review synthesizes current evidence on the mechanistic relationship between OS and NI in ALS and AD and evaluates how existing therapeutics modulate these pathways, emphasizing the need for multitarget strategies to achieve meaningful disease-modifying outcomes.

Protein arginine deiminases (PADs) are key enzymes in the development of rheumatoid arthritis (RA), catalyzing the conversion of arginine to citrulline in a process called citrullination. This post-translational modification is crucial to RA pathogenesis as it creates neo-antigens that trigger the production of anti-citrullinated protein antibodies (ACPAs). These ACPAs are highly specific to RA and often appear before clinical symptoms, making them valuable biomarkers for diagnosis and prognosis. Beyond ACPA production, PADs, particularly PAD4, play a vital role in forming neutrophil extracellular traps (NETs). NETs contribute to inflammation and joint damage, further highlighting the importance of PAD activity in the disease. The dysregulation of PADs is not limited to joint inflammation but also contributes to systemic complications of RA, such as cardiovascular and pulmonary disorders like interstitial lung disease (ILD). Citrullination of proteins in various tissues may contribute to these complications by generating autoantigens or disrupting tissue structures. Targeting PADs with small-molecule inhibitors or monoclonal antibodies shows promise in preclinical studies, with compounds like Cl-amidine and isozyme-selective inhibitors like GSK199 demonstrating efficacy in animal models. However, challenges remain in drug development, including limited isozyme specificity, off-target effects, and the complexity of citrullination networks, which hinder clinical translation. Overcoming these obstacles will require a multidisciplinary approach to optimize drug design and validate PADs as effective therapeutic targets for improving RA management and mitigating its systemic effects. The purpose of this review is to summarize the current understanding of the multifaceted roles of PADs in RA, from pathogenesis and systemic complications to the status and challenges of therapeutic development.

Objectives: Plant-derived bioactive molecules are increasingly recognized as valuable therapeutic resources for managing diverse pathological conditions, particularly those involving vascular inflammation. This study aimed to determine whether veratramine (VRT), a naturally occurring steroidal alkaloid found in Veratrum species of the Liliaceae family, attenuates LPS-induced vascular and pulmonary inflammation by upregulating heme oxygenase-1 (HO-1) and modulating the Nrf2, nuclear factor (NF)-κB, and signal transducer and activator of transcription (STAT1) signaling pathways. Methods: The study assessed the modulatory effects of VRT on HO-1, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in LPS-activated human umbilical vein endothelial cells (HUVECs), as well as on iNOS, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) expression in LPS-treated mice. The VRT doses (0.06–0.6 mg/kg) in mice were chosen to approximate peripheral concentrations of 2–20 μM, corresponding to the non-cytotoxic, anti-inflammatory range in HUVECs, based on calculations using mouse blood volume and body weight, and no overt acute toxicity was observed at these doses in this model. Results: Treatment with VRT enhanced HO-1 induction, inhibited NF-κB activation, diminished COX-2/PGE2 and iNOS/NO production, and attenuated STAT1 phosphorylation. In addition, VRT promoted nuclear translocation of Nrf2 and its binding to antioxidant response elements (AREs), thereby suppressing IL-1β expression in HUVECs. The VRT-mediated inhibition of iNOS/NO was abolished by HO-1 silencing through RNA interference. In vivo, VRT markedly reduced iNOS expression in lung tissue and lowered TNF-α levels in bronchoalveolar lavage fluid. Conclusion: Altogether, these findings demonstrate that VRT exhibits substantial anti-inflammatory potential and may serve as a promising candidate for managing inflammation-related vascular disorders.

Background: Although transforming growth factor-β (TGF-β) drives hepatic stellate cell activation and fibrogenesis, the mechanisms by which 12-O-tetradecanoylphorbol-13-acetate (TPA) modulates these processes in TGF-β1-activated hepatic stellate cells remain to be determined. Therefore, we investigated whether TPA alleviates fibrosis in TGF-β1-treated hepatic stellate cells and regulates both canonical and non-canonical pathways. Further, we assessed whether inhibitors of these pathways similarly affect proliferation and fibrosis in LX-2 cells. Methods: LX-2 hepatic stellate cells were used as the experimental model. Cells were treated with TPA, TGF-β, or TGF-β plus TPA, and Yes-associated protein (YAP) and protein kinase B (PKB; AKT) phosphorylation, as well as YAP intracellular localization, were assessed. PKC-δ involvement was examined using the pan-PKC inhibitor Go 6983, and the roles of YAP and AKT in TGF-β1-activated LX-2 cells were evaluated using verteporfin and AKTI-1/2, respectively. Results: TPA significantly increased YAP phosphorylation and reduced its nuclear translocation, resulting in decreased LX-2 cell proliferation and fibronectin (FN1) production. Although TPA also inhibited AKT phosphorylation, FN1 expression was primarily regulated by YAP inhibition. Notably, proliferation in TGF-β1-treated LX-2 cells was suppressed only upon co-administration of both inhibitors. Our results suggest that coordinated regulation of YAP and AKT activity is essential for controlling fibroblast proliferation and ECM production. Conclusions: These findings suggest that in TGF-β-activated hepatic stellate cells, YAP simultaneously controls proliferation and fibrosis, and AKT regulates only proliferation. Therefore, TPA, which regulates both YAP and AKT activity, may be a promising therapeutic candidate for liver fibrosis treatment by simultaneously controlling proliferation and fibrosis in hepatic stellate cells.

Objective: Neural stem cells (NSCs) are essential for replenishing nerve cells, providing neuroprotection, and repairing damaged brain function, while mitophagy is critical for maintaining NSCs’ homeostasis. The study investigated whether pyruvate kinase M2 (PKM2) regulates NSCs’ proliferation and differentiation by modulating mitophagy. Method: This study established a model of excessive autophagy in neural stem cell mitochondria induced by cobalt chloride (CoCl2) and used plasmid transfection technology to knock down PKM2 expression, examining its effects on NSCs proliferation and differentiation. Additionally, potential mechanisms were explored by overexpressing phosphatase and tensin homolog-induced putative kinase 1 (PINK1) and adding the mitophagy inducer carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Result: Treatment with CoCl2 significantly inhibited the proliferation of NSCs and their differentiation into neurons, induced excessive mitophagy, and activated the PKM2/PINK1/Parkin pathway. Knockdown of PKM2 markedly enhanced cell viability, promoted NSCs’ proliferation, and neuronal differentiation. Mechanistically, PKM2 knockdown not only decreased the protein levels of PINK1, Parkin, p-Parkin, Beclin1, and LC3 II/I but also increased p62 expression, thereby mitigating excessive mitophagy. Overexpression of PINK1 attenuated the inhibitory effect of PKM2 knockdown on CoCl2-induced mitophagy in NSCs. Moreover, PKM2 knockdown significantly reversed the detrimental effects of CCCP on mitochondrial function, cell survival, and neuronal differentiation, further confirming that PKM2 promotes NSC proliferation and neuronal differentiation by inhibiting mitophagy. Conclusion: Knocking down PKM2 could inhibit PINK1/Parkin-mediated excessive mitophagy, thereby promoting NSCs proliferation and neuronal differentiation.

The paradigm of cancer treatment has been reshaped by chimeric antigen receptor (CAR) αβ T cell therapy, yet its full potential remains constrained by fundamental limitations. While conventional CAR αβ T cells have achieved notable success in hematological malignancies, their broader application is hindered by the high cost and delays of autologous manufacturing, as well as the critical risk of graft-vs-host disease (GvHD). In addition, their efficacy against solid tumors is often compromised by the immunosuppressive tumor microenvironment (TME). As a promising solution, γδ T cells are being developed as an alternative CAR platform. Their intrinsic ability to recognize transformed cells in a major histocompatibility complex (MHC)-independent manner minimizes the risk of GvHD and supports the creation of safe, effective allogeneic therapies. Building on this unique biology, the therapeutic efficacy of CAR γδ T cells is being enhanced through advanced engineering strategies. Key innovations include “armoring” technologies, such as cytokine secretion, checkpoint blockade, and metabolic rewiring, to overcome local immunosuppression and improve persistence, as well as the use of induced pluripotent stem cells (iPSCs) to generate standardized products from a renewable and consistent source. This expanding technological toolbox is also enabling novel applications beyond oncology. For example, chimeric autoantibody receptor (CAAR) constructs built on γδ T cells integrate both classical and emerging insights into CAR γδ T cell therapy, highlighting innovations that are driving the field toward safer, more versatile, and longer-lasting treatments for cancer and autoimmunity. In light of these advancements, this review provides an overview of the current understanding of γδ T cell biology and highlights emerging engineering strategies that enhance the efficacy and durability of CAR γδ T cells across oncologic and autoimmune contexts.

Objectives: Neutrophil extracellular traps (NETs) have emerged as critical effectors in immune defense but also as potential drivers of tissue damage in chronic inflammatory diseases. Their role in periodontitis, a highly prevalent condition characterized by dysregulated host–microbe interactions, remains incompletely defined. This systematic review aimed to synthesize, for the first time, ex vivo human evidence on the presence, activity, and clinical significance of NETs in periodontitis. Methods: A comprehensive search of Medline, Web of Science, and Scopus was conducted up to August 2025. Eligible studies included ex vivo human investigations assessing NETs or NET markers in gingival tissues, gingival crevicular fluid, saliva, blood, or biofilms from patients with periodontitis. Study selection, data extraction, and risk-of-bias assessment were conducted in duplicate, and the protocol was registered in PROSPERO (CRD420251109174). Results: Seventeen studies met the inclusion criteria. NET markers such as citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and neutrophil elastase were consistently elevated in periodontitis samples compared with controls. Several studies reported a reduction in NET levels or improved NET degradation following periodontal therapy. NETs were also implicated in biofilm stability and in systemic associations with rheumatoid arthritis and chronic kidney disease. However, heterogeneity in methodologies, small sample sizes, and inconsistent marker use limited comparability across studies. Conclusions: Ex vivo evidence indicates that aberrant NET formation and impaired clearance contribute to periodontal inflammation and tissue destruction. Nonetheless, methodological variability and risk of bias constrain definitive conclusions. Standardization of detection methods, consensus on marker panels, and exploration of neutrophil subsets and systemic confounders are essential to establish NETs as reliable biomarkers and therapeutic targets in periodontitis.

Ischemic stroke is one of the major causes of long-term disability and mortality worldwide. It results from an interruption in the cerebral blood flow, triggering a cascade of detrimental events like oxidative stress, mitochondrial dysfunction, neuroinflammation, excitotoxicity, and apoptosis, causing neuronal injury and cellular death. Melatonin, a pleiotropic indoleamine produced by the pineal gland, has multifaceted neuroprotective effects on stroke pathophysiology. Interestingly, the serum melatonin levels are associated with peroxidation and antioxidant status, along with mortality score in patients with severe middle cerebral artery infarction. Melatonin exhibits strong antioxidant, anti-inflammatory, and anti-apoptotic properties and preserves mitochondrial function and homeostasis. Several preclinical studies have shown that melatonin administration conserves blood-brain barrier integrity, reduces infarct size, and edema. These mechanisms contribute to minimizing tissue damage and improving the neurological outcomes following ischemic events. Therefore, the present review evaluates evidence from experimental studies furthered with limited clinical investigations and explores the mechanistic pathways of melatonin functions to establish its therapeutic potential in stroke management.

Background: The efficient transdermal delivery of biologically active molecules remains a major challenge because of the structural barrier of the stratum corneum, which limits the penetration of large or hydrophilic molecules. Low-molecular-weight protamine (LMWP) has a structure similar to that of the HIV TAT protein-derived peptide and is a representative cell-penetrating peptide (CPP) used to increase cell permeability. However, protamine has been reported to have many toxicities and side effects. Objectives: We developed human-derived low-molecular-weight protamine (hLMWP), which is based on fish-derived LMWP but designed using human protein sequences to improve safety and functionality. As it is derived from human proteins, it may reduce side effects and immune rejection during long-term or repeated administration. Additionally, we confirmed in our preliminary study that hLMWP enhances permeability compared to LMWP. In this study, we evaluated physiological activities and skin cell penetration of hLMWP conjugates to assess the potential applications of hLMWP. Methods: cDNA sequences for hLMWP-EGF (His) and hLMWP-SOD-1 (His) were synthesized by connecting hLMWP (RSRRRRRRSCQTRRR) to the N-terminus of Epidermal growth factor (EGF) and Superoxide dismutase 1 (SOD-1), respectively, with a 6 His-tag added to the C-terminus. The constructs were cloned into a pET-41b(+) expression vector and expressed in E. coli BL21-CodonPlus (DE3)-RIL cells. Expressed proteins were purified using a nickel column and eluted with imidazole buffer. Protein purity was confirmed by SDS-PAGE, and concentrations were quantified using a BCA assay. To evaluate the functional properties of these hLMWP-protein conjugates, a series of in vitro assays were conducted using keratinocyte and macrophage cell lines. These included assessments of permeability, proliferation, wound healing, and anti-inflammatory activity. Results: The results demonstrated that hLMWP-EGF and hLMWP-SOD-1 exhibited superior biological activities, including increased cell proliferation, wound healing, and anti-inflammatory effects, compared to EGF and SOD-1. Moreover, hLMWP-EGF and hLMWP-SOD-1 significantly enhanced the skin permeability of both EGF and SOD-1, as shown by Franz diffusion cell assay and immunofluorescence analysis. Conclusion: Our findings demonstrate that hLMWP significantly enhances skin permeability and biological activity of functional proteins such as EGF and SOD-1 while maintaining safety. This suggests its potential for application in transdermal drug delivery, regenerative medicine, and cosmeceutical formulations.