The role of tumor-associated macrophages in lung cancer: From mechanism to small molecule therapy.

Tumor-associated macrophages (TAMs) are the main component of tumor-infiltrating immune cells in the lung tumor microenvironment. TAMs recruited to the lung cancer can create a suitable microenvironment for the growth and metastasis of lung cancer by secreting tumor promoting factors and interfering with the function of T cells. Currently, numerous studies have reported that small molecular drugs affect lung cancer progression by selectively targeting TAMs. The main ways include blocking the recruitment of monocytes or eliminating existing TAMs in tumor tissue, reprogramming TAMs into pro-inflammatory M1 macrophages or inhibiting M2 polarization of macrophages, interrupting the interaction between tumor cells and macrophages, and modulating immune function. Signaling pathways or cytokines such as CCL8, CCL2/CCR2, CSF-1/CSF-1R, STAT3, STAT6, MMPs, Caspase-8, AMPK α1, TLR3, CD47/SIRPα, have been reported to be involved in this process. Based on summarizing the role and mechanisms of TAMs in lung cancer progression, this paper particularly focuses on systematically reviewing the effects and mechanisms of small molecule drugs on lung cancer TAMs, and classified the small molecular drugs according to the way they affect TAMs. The study aims to provide new perspectives and potential therapeutic drugs for targeted macrophages treatment in lung cancer, which is of great significance and will provide more options for immunotherapy of lung cancer.

Salvianolic Acid B Inhibits Oxidative Stress in Glomerular Mesangial Cells Alleviating Diabetic Nephropathy by Regulating SIRT3/FOXO1 Signaling.

INTRODUCTION: Oxidative stress is pivotal in advancing diabetic nephropathy (DN). Salvianolic acid B (SAB), derived from Radix Salviae miltiorrhizae, exhibits renoprotective effects. However, the mechanisms underlying its action in DN are not fully elucidated. This study explores SAB's protective effect on DN, focusing on its antioxidative properties in glomerular mesangial cells. METHODS: The renoprotective effects of various SAB dosages on DN rats were assessed by evaluating kidney tissue pathological alterations through hematoxylin and eosin, periodic acid-Schiff, Masson, TUNEL staining, and kidney function through biochemical detection. Cell counting kit-8 and lactate dehydrogenase cytotoxicity assays were utilized to evaluate the viability of high glucose (HG)-induced HBZY-1 cells treated with various SAB dosages. Oxidative stress and inflammation levels were measured using enzyme-linked immunosorbent assay kits. The Sirtuin 3 (SIRT3)/Forkhead box transcription factor O1 (FOXO1) pathway was examined through Western blot and immunohistochemistry. RESULTS: SAB mitigated kidney histopathological alterations and function and cell apoptosis in DN rats at various dosages. It enhanced the activity of glutathione peroxidase and superoxide dismutase while decreasing reactive oxygen species and malondialdehyde levels both in vivo and in vitro. SAB also suppressed the levels of pro-inflammatory cytokines (IL-1ß, IL-6, MCP-1, and TNF-α) and the expression of collagen IV and fibronectin in HG-induced HBZY-1 cells. Furthermore, SAB activated the SIRT3/FOXO1 signaling pathway. CONCLUSION: Our findings suggest that SAB may alleviate oxidative stress in DN both in vivo and in vitro, potentially through the activation of the SIRT3/FOXO1-mediated signaling pathway. This study provides initial insights into the possible antioxidative and renoprotective effects of SAB, indicating its potential utility as a therapeutic agent for DN.

Inhibition of Influenza A virus propagation by benzoselenoxanthenes stabilizing TMPRSS2 Gene G-quadruplex and hence down-regulating TMPRSS2 expression.

Proteolytic cleavage of influenza A virus (IAV) hemagglutinin by host proteases is crucial for virus infectivity and spread. The transmembrane serine protease TMPRSS2 was previously identified as the essential protease that can cleave hemagglutinin of many subtypes of influenza virus and spike protein of coronavirus. Herein, we found that a guanine rich tract, capable of forming intramolecular G-quadruplex in the presence of potassium ions, in the promoter region of human TMPRSS2 gene was quite important for gene transcriptional activity, hence affecting its function. Furthermore, 7 new synthesized benzoselenoxanthene analogues were found to enable stabilizing such G-quadruplex. More importantly, compounds can down-regulate TMPRSS2 gene expression, especially endogenous TMPRSS2 protein levels, and consequently suppress influenza A virus propagation in vitro. Our results provide a new strategy for anti-influenza A virus infection by small molecules targeting the TMPRSS2 gene G-quadruplex and thus inhibiting TMPRSS2 expression, which is valuable for developing small molecule drugs against influenza A virus and also may be a potential candidate as anti- SARS-CoV-2 (Severe Acute Respiratory Syndrome CoV 2) lead molecules.

Knockdown of TGF-ß1 expression in human umbilical cord mesenchymal stem cells reverts their exosome-mediated EMT promoting effect on lung cancer cells.

The effect of mesenchymal stem cells (MSCs) on lung cancer cells is controversial, and the underlying mechanisms remain unclear, which harms the utilization of MSCs in tumor therapy. In this study, we found that human umbilical cord MSC-conditioned medium (MSC-CM) promotes EMT, invasion, and migration, yet inhibits proliferation and promotes apoptosis of lung cancer cells. The EMT-promoting effect of MSCs was mediated by exosomes derived from MSCs (MSC-exo) and eliminated by inhibiting exosome release. Moreover, silencing TGF-ß1 expression in MSCs can revert the EMT-promoting effect and enhance the anti-proliferative and pro-apoptotic effect of MSCs on lung cancer cells via MSC-exo. Further investigation found that Smad2/3, Akt/GSK-3ß/ß-catenin, NF-κB, ERK, JNK, and p38 MAPK in TGF-ß1 signaling pathways could be activated by MSC-exo in lung cancer cells, while silencing TGF-ß1 expression in MSCs may deactivate these pathways. These findings suggest a method by which MSCs may be safely employed in lung cancer therapy.

Stress-responsive heme oxygenase-1 isoenzyme participates in Toll-like receptor 4-induced inflammation during brain ischemia.

Toll-like receptors (TLRs) are involved in the progression of ischemic brain injury and hence vascular dementia; however, the underlying mechanisms are largely unknown. Here, we have investigated the interrelationship between stress-responsive heme oxygenase (HO)-1 isoenzyme and TLR4 during chronic brain hypoperfusion. The right unilateral common carotid artery occlusion was performed by ligation of the right common carotid artery in C57BL/6J mice. The brain cortex or hippocampus was removed for western blotting and confocal immunofluorescence analysis. The link between HO-1 and TLR4 was further examined by silencing TLR4 and pharmacological inhibition of HO-1 in primary cultured cortical neurons. Cognitive dysfunction and decrease in cerebral blood flow in mice were observed 4 weeks after the occlusion. Our data further show that common carotid artery occlusion induced an increase in TLR4 and HO-1 protein levels. Although the administration of CoPP (10 mg/kg), HO-1 agonist, improved the cognitive dysfunction in a mice model of occlusion, western blot analysis in primary cultured cortical neurons showed that HO-1 was upregulated after lipopolysaccharide treatment; this was partially abolished by the TLR4 siRNA interference. The flow cytometry analysis showed that pharmacological inhibition of HO-1 by ZnPP (100 µM) further exaggerated lipopolysaccharide-induced neuronal cell death. Hence, stress-responsive HO-1 isoenzyme participates in TLR4-induced inflammation during chronic brain ischemia. The pharmacological manipulation of TLR4 or the HO-1 antioxidant defense pathway may represent a novel treatment strategy for neuronal protection in vascular dementia.