Expressed in macrophages and endothelial cells, the receptor for angiopoietin, tyrosine kinase with immunoglobulin and epidermal growth factor homology-2 (Tie2), is required for the reconstruction of blood vessels in tumor recurrence after chemotherapy. Thus, small therapeutic peptides that target and block Tie2 activity are promising as a therapeutic for the prevention of tumor relapse after chemotherapy. However, such small peptides often have low bioavailability, undergo rapid enzymatic degradation, and exhibit a short circulation half-life, making them ineffective in cancer therapy. Herein, we designed a dual-responsive amphiphilic peptide (mPEG1000-K­(DEAP)-AAN-NLLMAAS) to modify the small peptide T4 (NLLMAAS) as a Tie2 inhibitor, endowing it with the ability to endure in circulation and specifically target tumor tissue. The ultimate nanoformulation (P-T4) releases T4 in response to the combination of the acidic tumor microenvironment and the presence of legumain, which is commonly overexpressed in tumor tissue. Compared with free T4, P-T4 decreases vessel density significantly (free T4: 2.44 ± 1.20%, P-T4: 0.90 ± 0.75%), delays tumor regrowth after chemotherapy (free T4: 43.2 ± 11.8%, P-T4: 63.6 ± 13.9%), and reduces distant metastasis formation (free T4: 4.50 ± 2.40%, P-T4: 0.67 ± 0.32%). These effects of P-T4 are produced by the local blockage of Tie2 signals in Tie2-positive macrophages and endothelial cells. In addition to describing a potential strategy to enhance circulation half-life and the accumulation of an active peptide at tumor sites, our approach exemplifies the successful targeting of multiple cell types that overexpress a key molecule in conditions associated with tumors.

Cancer‐associated fibroblasts (CAFs) activation is crucial for the establishment of a tumour promoting microenvironment, but our understanding of CAFs activation is still limited. In this study, we found that hypoxia‐inducible factor‐1α (HIF‐1α) was highly expressed in CAFs of human lung cancer tissues and mouse spontaneous lung tumour. Accordingly, enhancing the expression of HIF‐1α in fibroblasts via hypoxia induced the conversion of normal fibroblasts into CAFs. HIF‐1α‐specific inhibitor or HIF‐1α knockout (KO) significantly attenuated CAFs activation, which was manifested by the decreased expression of COL1A2 and α‐SMA. In vivo, during tumour formation, the expression of Ki‐67 and proliferating cell nuclear antigen (PCNA) in the tumour tissue with HIF‐1α KO fibroblasts was significantly lower than that of normal fibroblasts. Moreover, HIF‐1α in fibroblasts could activate the NF‐κB signalling pathway and enhance a subsequent secretion of CCL5, thus promoting the tumour growth. In conclusion, our results suggest that HIF‐1α is essential for the activation and tumour‐promotion function of CAFs in lung cancer (LC). And targeting HIF‐1α expression on CAFs may be a promising strategy for LC therapy.

The PDK1/Akt/PDE4D axis serves as a novel asthma target, which may benefit airflow obstruction.

Tumour‐derived exosomes have been shown to induce pre‐metastatic niche formation, favoring metastatic colonization of tumour cells, but the underlying molecular mechanism is still not fully understood. In this study, we showed that exosomes derived from the LLC cells could indeed significantly enhance their intrapulmonary colonization. Circulating LLC‐derived exosomes were mainly engulfed by lung fibroblasts and led to the NF‐κB signalling activation. Further studies indicated that the exosomal miR‐3473b was responsible for that by hindering the NFKB inhibitor delta's (NFKBID) function. Blocking miR‐3473b could reverse the exosome‐mediated NF‐κB activation of fibroblasts and decrease intrapulmonary colonization of lung tumour cells. Together, this study demonstrated that the miR‐3473b in exosomes could mediate the interaction of lung tumour cells and local fibroblasts in metastatic sites and, therefore, enhance the metastasis of lung tumour cells.

No abstract

Inflammaging is associated with an increased risk of chronic disease. Monocytes are the principal immune cells for the production of inflammatory cytokines and contribute to inflammaging in the elderly. However, the underlying mechanisms remain largely unknown. Here, we found that monocytes from aged individuals contained high levels of lipid droplets (LDs), and this increase was correlated with impaired fatty acid oxidation. Downregulated peroxisome proliferator-activated receptor (PPAR)-a may be responsible for the pro-inflammatory phenotype of monocytes in aged individuals, as it was positively correlated with LD accumulation and increasing TNF-a concentration. Interestingly, interventions that result in PPAR-a upregulation, such as fenofibrate treatment, TNF-a neutralization, or calorie restriction, reversed the effect of aging on monocytes. Thus the downregulation of PPAR-a and LD levels in monocytes represents a novel biomarker for inflammaging. Furthermore, PPAR-a activation in the elderly may also alleviate long-term inflammaging, preventing the development of life-limiting chronic diseases.Recent progress in the study of immunometabolism has indicated that macrophage lipid metabolism and inflammatory activation are closely intertwined. For example, saturated fatty acids (SFAs) activate Toll-like receptor (TLR) signaling in both human and murine macrophages to elicit inflammatory responses (Milanski et al., 2009;Rocha et al., 2016). Mechanistically, SFAs induce endoplasmic reticulum (ER) stress by activating the c-Jun N-terminal kinase (JNK) and nuclear factor-kB signaling pathways, which can lead to inflammation (Hu et al., 2006;Urano et al., 2000). Conversely, fatty acid (FA) catabolism, including fatty acid oxidation (FAO), sustains anti-inflammatory macrophage differentiation and attenuates ER stress and inflammatory responses in mice and humans (Namgaladze and Brü ne, 2016). Therefore, maintaining an optimal FA level is necessary to ensure efficient mitochondrial respiration and prevent macrophage-mediated inflammation through mitochondrial dysfunction (Jana et al., 2019). In addition, aging is accompanied by modifications to nutrient sensing and metabolic pathways (Saare et al., 2020). These findings have led many to consider whether lipid metabolism reprogramming might alleviate inflammaging by altering lipid metabolism in aging monocytes.The steroid receptor superfamily of peroxisome proliferator-activated receptors (PPARs) has emerged as a link between lipid metabolism and innate immunity. For example, PPAR-a agonists inhibit interferon-g

No abstract

Polysaccharides from Lentinus edodes (L. edodes) have been successfully used as adjuvant chemotherapy drug to treat lymphatic metastasis in some malignancies, such as colorectal cancer (CRC), lung cancer and gastric cancer. The CRC could metastasize via lymphatic vessels. Lymphatic metastasis is commonly thought to be the cause of poor prognosis of CRC. The mechanism of polysaccharides from L. edodes inhibiting lymphatic metastasis of CRC is still unclear. In this study, we explored how MPSSS, a novel polysaccharide component of L. edodes, influences lymphangiogenesis and lymph node metastasis. The results show that MPSSS can reduce lymphangiogenesis and lymphatic metastasis of CRC in mouse model. And combined with in vitro study, a likely mechanism is that MPSSS reduce the secretion of VEGF-C by cancer associated fibroblasts (CAFs). This effect can be suppressed by a TLR4 inhibitor, which suggests that MPSSS plays a role in CAFs through the TLR4/JNK signaling pathway. In conclusion, MPSSS may reduce lymphangiogenesis by decreasing the VEGF-C secretion of CAFs, which may provide a new strategy for the comprehensive treatment of CRC.