Major depressive disorder (MDD) represents a significant global health burden, with current treatments showing limited efficacy and considerable side effects. While traditional medicines offer promising alternatives, their mechanisms often remain unclear. Here we demonstrate that Ershiwei Roudoukou Pills (ERP) and its active ingredient Macelignan exhibit potent antidepressant effects through multiple interconnected pathways in a chronic unpredictable mild stress (CUMS) mouse model. Both compounds significantly improved depression-like behaviors in forced swimming, tail suspension, and open field tests. Mechanistically, ERP and Macelignan restored oxidative balance by modulating multiple markers including SOD, CAT, and MDA across serum, hippocampus, and prefrontal cortex. They effectively suppressed neuroinflammation by reducing pro-inflammatory cytokines (IL-6, TNF-α) and microglial activation while increasing anti-inflammatory markers (IL-10). Furthermore, both compounds enhanced synaptic plasticity through upregulation of synaptic proteins (PSD-95, MAP2, SYP) and activation of the BDNF-TrkB signaling pathway. Notably, ERP demonstrated differential anti-inflammatory properties compared to Macelignan, with distinct effects on different inflammatory markers, suggesting potential synergistic effects from its multiple components. These findings reveal the multi-target therapeutic potential of ERP and Macelignan in treating depression, providing new insights for developing more effective antidepressant strategies, particularly for treatment-resistant cases.

Macrophages are innate immune cells distributed throughout the body that play vital roles in organ development, tissue homeostasis, and immune surveillance. Macrophages acquire a binary M1/M2 polarized phenotype through signaling cascades upon sensing different signaling molecules in the environment, thereby playing a core role in a series of immune tasks, rendering precise regulation essential. M1/M2 macrophage phenotypes regulate inflammatory responses, while controlled activation of inflammatory signaling pathways is involved in regulating macrophage polarization. Among the relevant signaling pathways, we focus on the six well-characterized NF-κB, MAPK, JAK-STAT, PI3K/AKT, inflammasome, and cGAS-STING inflammatory pathways, and elucidate their roles and crosstalk in macrophage polarization. Furthermore, the effects of many environmental signals that influence macrophage polarization are investigated by modulating these pathways in vivo and in vitro. We thus detail the physiological and pathophysiological status of these six inflammatory signaling pathways and involvement in regulating macrophage polarization in cancer and beyond, as well as describe potential therapeutic approaches targeting these signaling pathways. In this review, the latest research advances in inflammatory signaling pathways regulating macrophage polarization are reviewed, as targeting these inflammatory signaling pathways provides suitable strategies to intervene in macrophage polarization and various tumor and non-tumor diseases.

SETD5, an atypical member of the histone lysine methyltransferase family known for its association with cancer stemness, is a significant predictor of unfavorable survival outcomes in non-small cell lung cancer (NSCLC). However, the function of SETD5 in NSCLC stemness remains unclear, and whether it is an active H3K36me3 is controversial. Consequently, further investigation is required to clarify the pivotal role of SETD5 in NSCLC stemness and its related mechanism. Thus, this study employed the NSCLC tissue microarray and bioinformatics tools to analyze SETD5 expression and determine its effect on stemness and investigated the role of SETD5 in the metastasis of NSCLC using in vitro and in vivo analyses. The findings indicated high SETD5 expression in embryonic and NSCLC tissues, which was related to the pathological tumor stage, lymph node metastasis, and clinical stage, indicating that SETD5 could be used as a biomarker and prognostic factor in NSCLC. In addition, we found that SETD5 can promote glycolysis, thereby inhibiting ferroptosis and promoting the stemness of NSCLC, causing tumor metastasis and adverse prognosis in patients. In terms of mechanism, SETD5 as H3K36me3 facilitates the m6A modification of METTL14 and the recruitment of YTHDF1 and mediates PKM2 nuclear translocation and phosphorylation of p-PKM2 Tyr105, regulating GPX4 mediated ferroptosis resistance and SOX9 mediated stemness in NSCLC. The findings emphasize that SETD5 may serve as a promising indicator of stemness in NSCLC, which can help develop therapeutic targets for NSCLC and prognostic evaluation. This study provides evidence that SETD5 as H3K36me3 facilitates the m6A modification of METTL14 and the recruitment of YTHDF1 and mediates the nuclear translocation of PKM2, regulating GPX4 mediated ferroptosis resistance and SOX9 mediated stemness, causing tumor metastasis and adverse prognosis in patients.

Advanced cancer patients frequently endure severe pain from bone metastases, and few effective treatments for bone cancer pain (BCP) exist. Although Anwulignan is known for its antioxidant, anti-inflammatory, and antitumor properties, its effects on BCP remain unclear. This study aims to explore the analgesic effects and mechanisms of Anwulignan on bone cancer pain.

Western blotting and immunofluorescence assessed molecular expression and localization. X-ray, micro-CT, TRAP, and ALP staining examined bone destruction in rats. MTT, colony formation assays, and in vivo imaging analyzed tumor changes. RNA-Seq identified differentially expressed genes, validated by ChIP analysis.

Here, we showed that Anwulignan alleviated mechanical, thermal, and cold hypersensitivity and spontaneous pain, prevented bone destruction, and suppressed local tumor growth in rats with BCP. Furthermore, Anwulignan was firmly bound to proliferator-activated receptor alpha (PPARα), increasing its thermal stability. Intrathecal (i.t.) injection of PPARα siRNA increased pain sensitivity in naive rats, and PPARα siRNA abrogated the analgesic effect of Anwulignan in BCP model rats. Moreover, the PPARα agonist pirinixic acid reduced BCP hypersensitivity and abrogated the upregulation of CXC chemokine receptor 2 (CXCR2). Importantly, PPARα bound to the CXCR2 promoter region, and Anwulignan could reverse the reduced binding of PPARα to CXCR2 caused by BCP.

Taken together, these results indicate that Anwulignan is a potential antitumor and analgesic agent that exerts its effects via upregulation of PPARα expression to inhibit the expression of CXCR2 and could be used for treating BCP.

Metastasis is a hallmark of advanced cancer, and the liver is a common site for secondary metastasis of many tumor cells, including colorectal, pancreatic, gastric, and prostate cancers. Macrophages in the tumor microenvironment (TME) promote tumor cell metastasis through various mechanisms, including angiogenesis and immunosuppression, and play a unique role in the development of liver metastasis. Macrophages are affected by a variety of factors. Under conditions of hypoxia and increased acidity in the TME, more factors are now found to promote the polarization of macrophages to the M2 type, including exosomes and amino acids. M2-type macrophages promote tumor cell angiogenesis through a variety of mechanisms, including the secretion of factors such as VEGF, IL-1β, and TGF-β1. M2-type macrophages are subjected to multiple regulatory mechanisms. They also interact with various cells within the tumor microenvironment to co-regulate certain conditions, including the creation of an immunosuppressive microenvironment. This interaction promotes tumor cell metastasis, drug resistance, and immune escape. Based on the advent of single-cell sequencing technology, further insights into macrophage subpopulations in the tumor microenvironment may help in exploring new therapeutic targets in the future. In this paper, we will focus on how macrophages affect the TME, how tumor cells and macrophages as well as other immune cells interact with each other, and further investigate the mechanisms involved in liver metastasis of tumor cells and their potential as therapeutic targets.

Colorectal cancer (CRC) is currently ranked as the third most common type of cancer, contributing significantly to mortality and morbidity worldwide. Epigenetic and genetic changes occurred during CRC progression resulted in the cell proliferation, cancer progression, angiogenesis, and invasion. Angiogenesis is one of the crucial steps during cancer progression required for the delivery of essential nutrients to cancer cells and removes metabolic waste. During angiogenesis, different molecules are secreted from tumoral cells to trigger vascular formation including epidermal growth factor and the vascular endothelial growth factor (VEGF). The production and regulation of the secretion of these molecules are modulated by different subcellular pathways such as NF-κB. NF-κB is involved in regulation of different homeostatic pathways including apoptosis, cell proliferation, inflammation, differentiation, tumor migration, and angiogenesis. Investigation of different aspects of this pathway and its role in angiogenesis could provide a comprehensive overview about the underlying mechanisms and could be used for development of further therapeutic targets. In this review of literature, we comprehensively reviewed the current understanding and potential of NF-κB-related angiogenesis in CRC. Moreover, we explored the treatments that are based on the NF-κB pathway.

Colorectal cancer (CRC) exhibits a substantial morbidity and mortality rate, with its aetiology and pathogenesis remain elusive. It holds significant importance within the tumour microenvironment (TME) and exerts a crucial regulatory influence on tumorigenesis, progression, and metastasis. TAMs possess the capability to foster CRC pathogenesis, proliferation, invasion, and metastasis, as well as angiogenesis, immune evasion, and tumour resistance. Furthermore, TAMs can mediate the prognosis of CRC. In this paper, we review the mechanisms by which natural compounds target TAMs to exert anti-CRC effects from the perspective of the promotional effects of TAMs on CRC, mainly regulating the polarization of TAMs, reducing the infiltration and recruitment of TAMs, enhancing the phagocytosis of macrophages, and regulating the signalling pathways and cytokines, and discuss the potential value and therapeutic strategies of natural compounds-targeting the TAMs pathway in CRC clinical treatment.

Macrophage polarization is closely associated with obesity-induced chronic inflammation and insulin resistance. Proton pump inhibitor Rabeprazole has long been used to treat gastritis and gastric ulcers. However, whether Rabeprazole plays a role in macrophage polarization during obesity is unknown. Here, we show that Rabeprazole suppresses M1-type macrophage-mediated inflammation, leads to increased M2-type macrophages and alters the polarization status from M1 to M2 in vitro. Mechanistically, Rabe-regulated macrophage polarization is associated with inhibition of NF-κB and activation of STAT6 signaling pathways. Furthermore, Rabeprazole induces M2-type adipose tissue macrophages and alleviates chronic inflammation, improving glucose tolerance and insulin sensitivity in high-fat diet-fed mice. In addition, Rabeprazole increases CD206+ M2-type liver macrophages and relieves liver inflammation, alleviating liver injury and lipid accumulation. Thus, our findings show that Rabeprazole effectively regulates macrophage polarization and controls obesity-associated chronic inflammation and insulin resistance, thus providing a potential therapeutic strategy against obesity-associated metabolic diseases.