Archives of Pharmacal Research最新文献

Gastrointestinal cancers (GICs) remain a major global health burden due to their aggressive nature, therapeutic resistance, and immunosuppressive tumor microenvironment (TME). Histone lactylation, a novel epigenetic modification driven by tumor-derived lactate, has emerged as a key mediator linking metabolic reprogramming to gene expression and immune regulation. In GICs, aberrant lactylation contributes to M2 macrophage polarization, increased PD-L1 expression, and diminished cytotoxic immune cell infiltration, all of which are associated with poor prognosis and resistance to immunotherapy. Targeting histone lactylation-related enzymes—such as p300, SIRT2, and LDHA—or interfering with lactate metabolism offers promising avenues to reshape the TME and enhance responses to immune checkpoint blockade. This review highlights the mechanistic underpinnings and immunological consequences of histone lactylation in GICs and discusses emerging therapeutic strategies that leverage this epigenetic axis to improve cancer immunotherapy outcomes.

Atopic dermatitis (AD) is an inflammatory skin disease that produces a variety of inflammatory cytokines and chemokines. Chitinase-3-like protein 1 (CHI3L1, YKL-40) significantly contributes to AD-associated inflammatory response and is highly expressed in patients with AD. Therefore, this study elucidated the effects and potential mechanisms of human YKL-40 antibody on AD-affected skin. The anti-AD like inflammatory effects and inhibition of exosome release effectors of human YKL-40 antibody were evaluated. Since exosomes have been closely related to AD inflammation and cytokine production, we detected exosome release in in vitro reconstituted human skin (RHS) models and HaCaT cells. Cytokine expression was analyzed using enzyme-linked immunosorbent assay (ELISA) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, related signaling pathways were evaluated using Western blotting and immunofluorescence staining. Human YKL-40 antibody significantly inhibited epidermal hyperplasia commonly induced by AD in the RHS model. In addition, this antibody effectively reduced the secretion of AD-associated inflammatory cytokines. Furthermore, it inhibited the expression of CD63, a marker for exosomes, and the phosphorylation of JAK3/STAT6, which are primarily involved in signaling pathways for AD and exosome release. This study provides strong evidence supporting the potential therapeutic efficacy of human YKL-40 antibody in the treatment of AD. It offers a new therapeutic approach for patients with incurable inflammatory skin diseases.

Bacoside A (BCA), a triterpenoid saponin isolated from Bacopa monnieri, exhibits diverse pharmacological properties, including neuroprotective, hepatoprotective, anti-stress, anti-inflammatory, and anti-ulcer effects. In the present study, BCA demonstrates pronounced anticancer activity against K562 chronic myelogenous leukemia (CML) cells by modulating autophagy-apoptosis dynamics. BCA induces dose- and time-dependent cytotoxicity in K562 cells while sparing normal human peripheral blood mononuclear cells (hPBMCs) and Vero cells, indicating therapeutic selectivity. Mechanistically, BCA elicits a biphasic cellular response characterized by autophagy induction at 24 h, followed by caspase-dependent apoptosis at 48 h. Autophagy activation was confirmed by the formation of Monodansylcadaverine-positive autophagic vacuoles, upregulation of Beclin-1 and LC3-II, and increased LC3 puncta in EGFP-LC3-transfected K562 cells. Notably, BCA treatment led to persistent accumulation of p62/SQSTM1 despite functional autophagic flux. Co-immunoprecipitation analysis revealed p62/SQSTM1–LC3-II interactions, while siRNA-mediated silencing of p62/SQSTM1 attenuated LC3-II accumulation, implicating p62/SQSTM1 as a positive modulator of autophagy. Moreover, p62/SQSTM1 facilitated apoptosis progression by interacting with and activating caspase-8, thereby bridging autophagy and apoptosis. Pharmacological inhibition of autophagy using 3-methyladenine abrogated both autophagic and apoptotic responses, establishing autophagy as a prerequisite for BCA-induced cell death. BCA promoted ERK1/2 activation and concomitant suppression of mTOR pathway via dephosphorylation of mTOR and 4E-BP1. Inhibition of ERK1/2 using PD98059 reversed mTOR dephosphorylation and autophagy induction, whereas mTOR overexpression restored ERK1/2 phosphorylation to basal levels. Collectively, these findings delineate BCA as a novel autophagy-inducing agent in CML, exerting cytotoxic effects via ERK1/2-mTOR signaling and p62/SQSTM1-mediated autophagy-apoptosis crosstalk.

c-Jun N-terminal kinases (JNKs), a subfamily of mitogen-activated protein kinases (MAPKs), are key mediators of cellular responses to environmental stress, inflammation, and apoptotic signals. The three isoforms—JNK1, JNK2, and JNK3 exhibit both overlapping and isoform-specific functions. While JNK1 and JNK2 are broadly expressed across tissues and regulate immune signaling, cell proliferation, and apoptosis, JNK3 expression is largely restricted to the brain, heart, and testis, where it plays a crucial role in neuronal function and survival. Subtle structural variations among the isoforms, particularly within the ATP-binding pocket and activation loop, provide a basis for the developing isoform-selective inhibitors to improve therapeutic precision. JNK3 has been increasingly recognized for its involvement in the pathogenesis of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, through mechanisms involving neuroinflammation, oxidative stress, and neuronal apoptosis. Given the limited efficacy of current therapies, which remain largely symptomatic and do not modify disease progression, covalent inhibitors of JNK3 represent a compelling alternative due to their potential for high selectivity and sustained target engagement. In parallel, JNK signaling contributes to fibrosis, with JNK1 serving as the predominant isoform driving profibrotic pathways such as fibroblast activation and extracellular matrix (ECM) deposition. Current antifibrotic agents provide only partial benefit and lack specificity for downstream effectors like JNK1. PROteolysis TArgeting Chimeras (PROTACs), which induce selective protein degradation via the ubiquitin–proteasome system, represent a promising modality to overcome these limitations. Selective degradation of JNK1 could provide a novel therapeutic avenue for fibrotic diseases. This review highlights therapeutic efforts to date and discusses how emerging approaches—particularly covalent JNK3 inhibitors for neurodegeneration and PROTACs for JNK1 in fibrosis—may advance future treatment paradigms.

Enhancers are crucial cis-regulatory DNA elements that regulate gene transcription by interacting with promoters, often over long genomic distances. Unlike promoters, their activity is independent of orientation or proximity to the gene. Active enhancers are transcribed into non-coding enhancer RNAs (eRNAs), which help stabilize enhancer-promoter loops, recruit transcription machinery, and shape the chromatin architecture. These eRNAs are regulated post-transcriptionally, through modifications such as the N6-methyladenosine (m⁶A) modification, which enhances their stability, facilitates interactions with nuclear reader proteins, and supports transcriptional condensate formation, thereby boosting enhancer activity. Super-enhancers, clusters of strong enhancers marked by high levels of modified H3 histone protein, acetylated at lysine 27, generate abundant eRNAs and are key drivers of gene expression in development and cancer. This review offers a comprehensive overview of the structure and function of enhancers and super-enhancers, highlights their regulatory roles, and examines the emerging contribution of m⁶A RNA modification in enhancer-mediated transcription during carcinogenesis. Additionally, we discuss experimental approaches for studying enhancer activity and explore potential therapeutic strategies targeting enhancer-associated pathways in cancer. By integrating recent advances in enhancer research, we aim to shed light on the intricate molecular choreography that orchestrates gene expression and its dysregulation in cancer.

NRF2 is a redox-sensitive transcription factor that activates the expression of phase II detoxifying and antioxidant enzymes. In addition to maintaining redox homeostasis, NRF2 regulates various other processes, including metabolism, stem cell renewal, mitochondrial function, and proteostasis. NRF2 is considered a tumor suppressor because its activation by chemopreventive phytochemicals contributes to the detoxification of oxidants and electrophiles in normal cells. However, aberrant NRF2 activation occurs in cancer due to mutations in the KEAP1/NRF2 pathway, and it contributes to the generation of a tumor microenvironment that favors the proliferation, survival, and chemoresistance of cancer cells. In this review, we present the regulatory mechanisms of NRF2 and discuss how NRF2 activation contributes to chemoresistance. We also explain therapeutic strategies that exploit the vulnerabilities of NRF2-addicted cancer cells, providing NRF2 small-molecule inhibitors along with their mechanisms of action.

Alzheimer’s disease (AD) is characterized by progressive cognitive decline, amyloid plaque accumulation, synaptic dysfunction, and neuroinflammation. This study reports the therapeutic potential of (S)-4-amino-5,5-difluoro-N′-methyl-N′-phenylpentanehydrazide hydrochloride (RA-058HM), a novel compound, in ameliorating these pathological features of AD in the 5xFAD mouse model. RA-058HM was administered orally for 8 weeks, and its multi-target effects – including relief from neuroinflammation, normalization of synaptic transmission, reduction of amyloidogenesis (plaque and soluble oligomers, as well as BACE1 levels), and rescue of cognitive function—were evaluated. To our knowledge, RA-058HM is the first compound to demonstrate simultaneous modulation of these key pathways in the 5xFAD model, highlighting its potential as a comprehensive disease-modifying therapy for AD. Behavioural tests revealed marked improvements in spatial and recognition memory in RA-058HM-treated 5xFAD mice, suggesting a reversal of cognitive deficits. At the molecular level, RA-058HM treatment reduced amyloidogenesis, as evidenced by decreased levels of amyloid precursor protein (APP) and β-secretase (BACE1) in the hippocampus, accompanied by reduced plaque formation, as detected by Thioflavin-S staining. Furthermore, synaptic transmission was restored to near-normal levels in RA-058HM-treated neurons, indicating that RA-058HM effectively rescues synaptic deficits without altering synaptic protein levels of PSD95 and synaptophysin. In addition, treatment of RA-058HM downregulated hippocampal levels of the NLRP3 inflammasome, TNF-α, and GFAP, suggesting a decrease in neuroinflammatory signaling and a modulation of glial activity. Restoration of mitochondrial motility in hippocampal neurons further suggests that RA-058HM may improve cellular energy dynamics. Collectively, these findings indicate that RA-058HM has multifaceted effects on AD pathology, targeting amyloid accumulation, synaptic transmission, neuroinflammation, and mitochondrial function. This study highlights RA-058HM as a promising candidate for AD therapy and underscores the potential of multi-targeted approaches in addressing the complex mechanisms underlying AD progression.

Ginger (Zingiber officinale) rhizome has been widely used in traditional medicine for centuries to promote good health and well-being, treating conditions such as diarrhea, stomach discomfort, nausea, cholera, asthma, and respiratory diseases. Gingerol and shogaol are essential bioactive phenolic compounds abundantly found in fresh and dried ginger and have been extensively studied using modern technology to evaluate their therapeutic effects. These phenolic compounds demonstrate a wide range of properties, including antioxidant, anti-inflammatory, antidiabetic, and anticancer effects, which operate through various mechanisms. Furthermore, researchers have utilized the chemical structures of gingerol and shogaol as templates to develop novel, safer, and more effective drugs for treating multiple illnesses. This review article focuses on previous literature assessing the potential efficacy of these compounds as therapies based on their antioxidant, anti-inflammatory, antidiabetic, anticancer, and neuroprotective properties.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons due to oxidative stress and inflammation. Targeting inflammation and oxidative stress offers a promising means of slowing PD progression. Taurine, a naturally occurring amino sulfonic acid, has demonstrated potent antioxidant properties, thereby preventing cell death. While taurine has been studied for its potential to restrain the progression of Alzheimer’s disease and mitigate microglial activation, its impact on astrocyte activation in PD models remains underexplored. Here, we found that taurine significantly reduces astroglial activation in MPP⁺-induced primary astrocytes by inhibiting the NF-κB pathway. Additionally, in vivo experiments in MPTP-induced PD models using male C57BL/6 mice showed that taurine improved motor function, protected against dopaminergic neuronal loss, and reduced glial activation in the striatum and substantia nigra. These findings highlight that the anti-inflammatory effects of taurine involve the inhibition of astroglial activation, suggesting that taurine has therapeutic potential in PD.

By continuously activating silent gene cluster of the marine-derived Streptomyces strain OUCMDZ-5511 under high salt stress, three new iodinated 9H-carbazole derivatives (1–3) and a novel oxazole-fused chlorinated 9H-carbazole derivative (4), along with five previously reported analogues (5–9), were obtained from the cultures grown with 7.5% potassium iodide (KI). The structures of these previously undocumented compounds were elucidated as 4-iodo-3-methoxy-9H-carbazole (1), 4-iodo-3-methoxy-9H-carbazole-6-ol (2), 4-iodo-3-methoxy-9H-carbazole-8-ol (3), and 10-chloro-9-methoxy-6H-oxazolo[5,4-c]carbazole (4), using MS and NMR spectroscopic techniques. Notably, compound 3 demonstrated a more potent anti-inflammatory effect than the positive control in a CuSO₄-induced inflammation zebrafish model, likely by modulating the Myd88/NF-κB signaling pathway to exert its anti-inflammatory activity.