Archives of Pharmacal Research最新文献

Cancer remains a critical global health issue, presenting multifaceted challenges in both prevention and treatment. It is characterized by uncontrolled cell proliferation, primarily driven by the dysregulation of cyclin-dependent kinases (CDKs). CDKs are the key regulators of phosphorylation, capable of phosphorylating various proteins at serine and threonine residues, thereby initiating essential cellular processes such as cell division, differentiation, and programmed cell death. Due to their significant role in cell cycle regulation, CDKs have emerged as attractive drug targets for anticancer drug design and development. Although several conventional CDK inhibitors have demonstrated efficacy, their associated toxicities and the development of resistance underscore the need for alternative, safer CDK inhibitors. Studies have shown that polyphenols can significantly inhibit CDKs and their associated cyclins, modulate key regulatory pathways, and induce the expression of tumor suppressors such as p21 and p27, ultimately affecting cancer cell cycle progression and metastasis. This review summarizes the in vitro and in vivo investigations on the CDK-inhibition-based antiproliferative activity of polyphenols against various cancer types, as well their synergistic anticancer effects observed when combined with other chemotherapeutic agents. Furthermore, bifunctional conjugates of various polyphenols have demonstrated promising anticancer potential by overcoming the pharmacokinetic limitations of their native forms. Looking ahead, polyphenols hold promise as the potential anticancer drug candidates with CDK inhibitory activity. Therefore, there is a pressing need for more in-depth investigations and the initiation of clinical trials to validate these findings.

We previously developed LJ-4378, a dual ligand for A_2A and A₃ adenosine receptors, as a potential anti-obesity agent. In this study, we compared the anti-obesity effects of LJ-4378 with those of tirzepatide (TZP), a dual agonist of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, and one of the most potent FDA-approved obesity therapeutics. Using a mouse model of diet-induced obesity, we assessed the effects of LJ-4378 and TZP on body weight loss, metabolic parameters, and post-treatment weight rebound. Mice fed a high-fat diet (HFD) for 10 weeks were treated with vehicle, LJ-4378, or TZP for 14 days. Both LJ-4378 and TZP significantly reduced body weight, adipose tissue mass, and abdominal fat volume; improved glucose tolerance; reduced white adipose tissue inflammation; and enhanced energy expenditure. To assess the durability of the treatment effects, drug administration was discontinued after 14 days, and the mice remained on the HFD for an additional 4 weeks. Notably, LJ-4378-treated mice exhibited attenuated body weight regain, stable food intake, persistent metabolic benefits, and sustained enhancement of energy metabolism, compared to TZP-treated mice. These findings highlight LJ-4378 as an anti-obesity agent that functions independently of appetite suppression and may offer superior long-term benefits by limiting post-treatment weight rebound and preserving metabolic improvements.

Salvianolic acid A (SAA), a major water-soluble bioactive compound extracted from Salvia miltiorrhiza, has been extensively studied for its diverse pharmacological properties in cerebrovascular diseases. However, its immunomodulatory effects on lymphocytes in stroke remain incompletely understood. This study systematically investigated the therapeutic efficacy and underlying mechanisms of SAA in a murine model of transient middle cerebral artery occlusion (tMCAO). Early administration of SAA (20 mg/kg) to ischemic stroke (IS) mice demonstrated neuroprotective effects, characterized by reduced infarct volume and improved behavioral outcomes, alongside creating a T_reg-favorable environment in the spleen. In T cells differentiation assays and a luciferase reporter gene system, SAA was further identified as the primary active component in Salvia miltiorrhiza extract responsible for promoting in vitro T_reg differentiation. Flow cytometry analysis revealed that SAA treatment significantly enhanced the accumulation of T_reg cells in the brain after tMCAO, potentiated the immunosuppressive profile of the cerebral microenvironment, alleviated inflammatory responses, and avoided inducing systemic immunosuppression, ultimately leading to substantial neurological improvement. T_reg depletion abolished SAA-induced neuroprotection. Mechanistically, SAA appeared to regulate T_reg differentiation through the RUNX1/CBFβ/FOXP3 axis independent of TGF-β signaling. In summary, these findings suggest that SAA improved stroke outcomes via upregulation of cerebral Treg cells abundance, a process linked to the RUNX1/CBFβ/FOXP3 pathway. Collectively, this study offers new perspectives on the therapeutic potential of SAA in ischemic stroke management.

Chromanes and chromenes with various biological activities are widespread in nature and have now been found in a variety of plants, fungi and marine organisms. To date, 79 previously undescribed chromanes and 161 previously undescribed chromenes have been isolated and identified. The chromanes were further classified into four skeleton types, and the chromenes were further classified into five skeleton types. In this review, natural chromanes and chromenes were classified according to their skeleton types, and their biological activities and biosynthetic pathways were also summarized. Pharmacological research has demonstrated that chromanes and chromenes possess a range of biological activities, including antimicrobial, anti-inflammatory, anticancer, antidiabetic, and insecticidal properties. This review provides an important reference for structural analysis, pharmacological activity studies, and biosynthetic pathways of chromanes and chromenes.

Metabolically-dysfunction-associated steatohepatitis (MASH) represents one spectrum of MASLD, affecting over 5.27% of adults globally. Until the approval of resmetirom, no pharmacological therapies were available for MASH. Resmetirom is prescribed for the management of non-cirrhotic MASH in adults with moderate to advanced hepatic fibrosis, specifically at Stages F2 to F3. This drug is uniquely transported via liver-targeted transporters and exerts its effects by closely replicating the physiological actions of T3 (FT3). It exhibits a 28-fold selectivity for the thyroid hormone receptor beta (THR-β), predominant in the liver, over THR-α in functional assays. The approval of resmetirom marks a significant milestone, addressing a critical unmet need in MASH treatment while initiating a new chapter in therapeutic strategies for this complex chronic liver disease.

Inflammatory bowel disease (IBD) is a chronic and recurrent gastrointestinal disorder, which is typically characterized by symptoms such as abdominal pain, diarrhea, and weight loss, significantly impairing patients' quality of life. The etiology of IBD is multifactorial, involving complex interactions among genetic predisposition, immune dysregulation, environmental influences, and gut microbiota imbalance. Curcumin (CUR), a natural polyphenolic compound derived from the traditional Chinese medicine Curcuma longa, attracted considerable interest in pharmacological research due to its potent anti-inflammatory, antioxidant, and immunomodulatory properties. In the context of IBD, CUR exerts therapeutic effects by modulating key inflammatory signaling pathways, maintaining the integrity of the intestinal mucosal barrier, and restoring microbial homeostasis. Clinical studies demonstrated that CUR can alleviate IBD symptoms, suppress inflammatory responses, and improve patients’ quality of life. Nevertheless, its clinical application is limited by poor aqueous solubility and low oral bioavailability. To address these limitations, a variety of nanodelivery systems—including polymeric nanoparticles, lipid-based carriers, and nanofibers—have been developed to enhance the solubility, stability, and targeted delivery of CUR. This review provides a comprehensive overview of recent advances in the mechanistic insights, clinical applications, and drug delivery strategies of CUR in IBD therapy, to support future research and clinical translation.

Twenty-seven sesquiterpenes, including twenty-one new germacrane-type ones (1–5, 8–16, and 19–25) and a new humulane-type one (27), were isolated from the roots and rhizomes of Valeriana officinalis var. latifolia. The structures and absolute configurations of the new compounds were elucidated using extensive spectroscopic techniques (1D and 2D NMR, and HRESIMS) and quantum chemical calculations. Structurally, compound 20 was a new germacrane-type norsesquiterpene, while compound 27 was a new humulane-type norsesquiterpene. In addition, compound 27 significantly inhibited the production of nitric oxide with an IC₅₀ value of 3.65 ± 1.06 μM. It reduced the expression of cytokines such as IL-1 and IL-6, as well as inflammation-related proteins induced by LPS or influenza A virus in macrophages, thereby exhibiting significant anti-inflammatory activity. This effect may be related to blocking the formation of the inflammasome and the activation of the NF-κB signaling pathway. Furthermore, compound 10 showed anti-influenza virus activity with an EC₅₀ value of 27.28 ± 5.63 µM. The study may provide a scientific basis for the development and utilization of functional foods and medicines derived from V. officinalis var. latifolia.

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are typical ABC efflux transporters that play important physiological and pharmacological roles. At the blood–brain barrier (BBB), P-gp and BCRP function cooperatively as the main efflux transporters, hindering the entry of drugs into the brain. Therefore, dual inhibition of P-gp and BCRP is needed to deliver drugs effectively to the brain. This study sought potential dual P-gp/BCRP inhibitors to determine their ability to enhance brain penetration of the anticancer drug mitoxantrone (MX) and thereby improve its therapeutic efficacy against brain cancer. Candidate compounds for dual P-gp/BCRP inhibitors were extracted using in silico algorithms. The dual P-gp/BCRP inhibitory activity of 75 extracted candidates was investigated through MX accumulation studies in breast cancer cell lines overexpressing P-gp (MCF-7/ADR) and BCRP (MCF-7/MX100). The 5 compounds selected as final candidates were CDK 4/6 inhibitor IV, BX795, foretinib, BI-D1870, and CGP60474. Each of these 5 candidates increased MX accumulation and reversed MX resistance in MCF-7/ADR and MCF-7/MX100 cells. Additionally, they increased MX permeability across the BBB in an in vitro model. In situ brain perfusion studies showed that CDK 4/6 inhibitor IV, BX795, and CGP60474 improved the brain delivery of MX in rats. Moreover, in a mouse brain tumor model, CDK 4/6 inhibitor IV and BX795 potentiated the anticancer effect of MX against brain cancer, leading to a considerable reduction in tumor burden. In conclusion, potential dual P-gp/BCRP inhibitors were discovered through in silico screening and verified through in vitro and in vivo studies. CDK 4/6 inhibitor IV was the most effective dual P-gp/BCRP inhibitor candidate for enhancing the brain penetration of an anticancer drug for the treatment of brain tumors.

Extracellular matrix protein 1 (ECM1) is a multifunctional glycosylated protein associated with the cell membrane. Increasing evidence indicates that aberrant ECM1 expression in cancer cells promotes tumor growth and metastasis by regulating proliferation, invasion, migration, and drug resistance. Beyond its direct effects on cancer cells, ECM1 plays a pivotal role in shaping the tumor microenvironment by contributing to angiogenesis, inflammatory responses, and the activation of cancer-associated fibroblasts, which collectively drive malignant progression. Immunohistochemical studies have demonstrated that ECM1 is highly expressed in a wide range of invasive cancers compared with adjacent normal tissues, underscoring its potential as a diagnostic and prognostic biomarker. Moreover, elevated ECM1 expression is consistently associated with poor clinical outcomes across multiple malignancies. In this review, we comprehensively summarize research from the past decade on the role of ECM1 in cancer progression, evaluate its potential as a prognostic biomarker, and highlight recent advances in ECM1-targeted therapeutic strategies. Overall, this review provides new insights into the multifaceted roles of ECM1 in cancer biology and its promise as a molecular target for innovative cancer therapies.

Human bone morphogenetic protein 2 (BMP2) is a key inducer of osteogenesis; however, conventional delivery systems often result in burst release and adverse effects. To address this limitation, we fabricated an ionic complex of BMP2 with the clinically used osteogenesis inducer risedronate drug through an ion-pairing method. Fourier-transform infrared spectroscopy and ultra-resolution imaging confirmed the electrostatic interactions between BMP2 and risedronate. The resulting BMP2—risedronate complex exhibited a uniform particle size of 326 ± 149 nm, a polydispersity index of 0.2–0.3, and a zeta potential of − 38.08 ± 0.12 mV. The complex demonstrated a high complexation efficiency (˃ 95%). In vitro bioactivity studies using C2C12 myoblast cells demonstrated that BMP2, combined with risedronate, effectively induced osteoblastic differentiation. Furthermore, incorporation of the complex into 1.5% hyaluronic acid (HA) and 1% HA–19% poloxamer 407 (P407) hybrid hydrogel mitigated rapid release and retention, achieving a controlled release profile. In vivo studies confirmed that fabricated BMP2—risedronate complex loaded in hydrogels promotes sustained BMP2 release and, in combination with risedronate, enhances osteogenic efficacy. These findings suggest that the BMP2–risedronate ionic complex is a promising candidate for localized BMP2 delivery in osteogenesis therapy.