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ObjectivePancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy.DesignTwo unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33–ST2–CXCL3–CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models.ResultsIL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33–ST2–MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3–CXCR2 signalling. Type III collagen was identified as the CXCL3–CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis.ConclusionsOur work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer.

Cervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. Clarification of the detailed mechanisms underlying LNM may provide potential clinical therapeutic targets for CC patients with LNM. However, the molecular mechanism of LNM in CC is unclear. In the present study, we demonstrated that fatty acid synthase (FASN), one of the key enzymes in lipid metabolism, had upregulated expression in the CC samples and was correlated with LNM. Moreover, multivariate Cox proportional hazards analysis identified FASN as an independent prognostic factor of CC patients. Furthermore, gain-of-function and loss-of-function approaches showed that FASN promoted CC cell migration, invasion, and lymphangiogenesis. Mechanistically, on the one hand, FASN could regulate cholesterol reprogramming and then activate the lipid raft-related c-Src/AKT/FAK signaling pathway, leading to enhanced cell migration and invasion. On the other hand, FASN induced lymphangiogenesis by secreting PDGF-AA/IGFBP3. More importantly, knockdown of FASN with FASN shRNA or the inhibitors C75 and Cerulenin dramatically diminished LNM in vivo, suggesting that FASN plays an essential role in LNM of CC and the clinical application potential of FASN inhibitors. Taken together, our findings uncover a novel molecular mechanism in LNM of CC and identify FASN as a novel prognostic factor and potential therapeutic target for LNM in CC.

The effects of heat treatment at various temperatures on mechanically separated bamboo fibers and parenchyma cells were examined in terms of color, microstructure, chemical composition, crystallinity, and thermal properties. The heat-treated parenchyma cells and fibers were characterized by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), chemical composition analysis, and thermogravimetric analysis (TGA). The results revealed that the colors of bamboo fibers and parenchyma cells were darkened as treatment temperature increased. The microstructure of the treated fibers and parenchyma cells slightly changed, yet the shape of starch granules in parenchyma cells markedly altered at a temperature of above 160 °C. The chemical compositions varied depending on the heat treatment temperature. When treated at 220 °C, the cellulose content was almost unchanged in fibers but increased by 15% in parenchyma cells; the hemicellulose content decreased and the lignin content increased regardless of fibers and parenchyma cells. The cellulose crystal structure was nearly unaffected by heat treatment, but the cellulose crystallinity of fibers changed more pronouncedly than that of parenchyma cells. The thermal stability of parenchyma cells after heat treatment was affected more substantially compared to fibers.

FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2 + tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2 + pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2 + tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2 + breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers. Anti-VEGF therapy has many limitations that might be resolved by using combination treatment approaches. Here, the authors demonstrate that the dual-targeting of VEGF and PDGF is required for targeting resistant FGF2+ tumors which depend on the recruitment of pericytes on tumor microvessels.

Deep eutectic solvents (DES), as a new type of green solvent, show great advantages of easy preparation and no need of purification after synthesis and great potential applications in various fields. Osthole has shown wide variety of pharmacological functions like antimicrobial, anti-inflammatory, antioxidant, or anti-cancerous. To explore the efficient delivery of osthole, we have designed a new DES based on osthole and DL-menthol with molar ratio of 1:15. The interaction between osthole and DL-menthol was checked and verified by 1HNMR and FT-IR spectra. The physicochemical properties and anti-bacterial activity of the DES were investigated. Low viscosity and higher anti-bacterial activity against S. aureus make the DES suitable for the dermal or transdermal delivery of osthole. Therefore, the results presented herein indicated that DES may serve as a new strategy for the application of active pharmaceutical ingredients.

The aim of this research was to investigate the effect of freeze–thaw treatment on bamboo with different initial moisture content (water-saturated, air-dried and oven-dried). Bamboo ( Phyllostachys pubescens ) were treated with two freeze treatments and its microstructure, chemical composition, mechanical properties and thermal conductivity were characterized by field emission scanning electron microscopy (FE-SEM), Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), mechanical testing machine and thermal conductivity tester, respectively. The results showed that the freeze–thaw treatment had little influence on the microstructure of bamboo, the chemical composition content and the cellulose crystalline structure of bamboo were also not altered. The crystallinity index was found to increase with the increase of initial moisture content. The bending strength and elastic modulus of the treated bamboo increased, the extent of the increase was dependent on the initial moisture content and the freezing temperature. The thermal conductivity of the treated bamboo increased remarkably, which might be possibly determined by the cellulose crystallinity, moisture content, and density of bamboo.

Despite bamboo slivers having long been used to manufacture bamboo weaving products, the flexibility is still well below satisfactory, especially for those split from inner layer of bamboo culm. Here, a facile approach was reported to obtain strong and flexible bamboo slivers, in which the slivers from the outer and inner layer of bamboo culm were processed with 5 wt% alkali treatment at various temperatures (23, 40, 60, and 80 °C), respectively. Compared with untreated bamboo slivers, the treated ones were investigated in terms of the microstructure, chemical composition, morphology, tensile and bending performances. The results showed that tensile and bending properties of all treated bamboo slivers were significantly improved, especially for those from inner layer of bamboo culm. The tensile strength of outer bamboo sliver treated at 60 °C and the inner ones treated at 40 °C increased up to the maximum, respectively, increasing by 86.6% and 132.0% compared with the untreated ones. The highest flexibility of the outer- and inner bamboo sliver can be achieved at 80 °C and 60 °C alkali treatment, respectively. The slivers can be completely wound around a nylon rod with a diameter of 10 mm without fracture. The excellent tensile and bending performance of bamboo slivers alkali-treated at proper temperature was largely attributed to tightly cellulose molecule aggregating induced by substantially increasing hydrogen bonding after the partial removal of lignin and hemicellulose. A denser and interlocking cellular structure due to the collapse of parenchyma cells after alkali treatment at proper temperature also partly contributed to the increased tensile and bending strength. The results suggest that strong and flexible bamboo slivers can be prepared by one-spot alkali treatment at a proper temperature, which may widen the application scope of bamboo slivers.

Metabolic reprogramming in malignant cells is a hallmark of cancer that relies on augmented glycolytic metabolism to support their growth, invasion, and metastasis. However, the impact of global adipose metabolism on tumor growth and the drug development by targeting adipose metabolism remain largely unexplored. Here we show that a therapeutic paradigm of drugs is effective for treating various cancer types by browning adipose tissues. Mirabegron, a clinically available drug for overactive bladders, displays potent anticancer effects in various animal cancer models, including untreatable cancers such as pancreatic ductal adenocarcinoma and hepatocellular carcinoma, via the browning of adipose tissues. Genetic deletion of the uncoupling protein 1, a key thermogenic protein in adipose tissues, ablates the anticancer effect. Similarly, the removal of brown adipose tissue, which is responsible for non-shivering thermogenesis, attenuates the anticancer activity of mirabegron. These findings demonstrate that mirabegron represents a paradigm of anticancer drugs with a distinct mechanism for the effective treatment of multiple cancers. Targeting metabolism is currently a promising approach for cancer treatment. Here, the authors show that the beta3 agonist mirabegron inhibits tumor progression by browning adipose tissues in preclinical murine models.

The primary function of the nucleolus is ribosome biogenesis, which is an extremely energetically expensive process. Failures in ribosome biogenesis cause nucleolar stress with an altered energy status. However, little is known about the underlying mechanism linking nucleolar stress to energy metabolism. Here we show that nucleolar stress is triggered by inactivation of RSKS-1 (ribosomal protein S6 kinase), RRP-8 (ribosomal RNA processing 8), and PRO-2/3 (proximal proliferation), all of which are involved in ribosomal RNA processing or inhibition of rDNA transcription by actinomycin D (AD), leading to excessive lipid accumulation in Caenorhabditis elegans . The transcription factor PHA-4/FoxA acts as a sensor of nucleolar stress to bind to and transactivate the expression of the lipogenic genes pod-2 (acetyl-CoA carboxylase), fasn-1 (fatty acid synthase), and dgat-2 (diacylglycerol O -acyltransferase 2), consequently promoting lipid accumulation. Importantly, inactivation of pha-4 or dgat-2 is sufficient to abolish nucleolar stress-induced lipid accumulation and prolonged starvation survival. The results revealed a distinct PHA-4-mediated lipogenesis pathway that senses nucleolar stress and shifts excessive energy for storage as fat. Nucleolar stress can disrupt ribosome biogenesis and in turn energy metabolism and lipid storage, but how this is regulated is unclear. Here, the authors show in C. elegans that the transcription factor PHA-4/FOXA acts as a sensor for nucleolar stress and can regulate expression of lipogenic genes

Low-light stress during winter compromises the sensory quality of off-season oriental melons ( L. var. Makino) in cultivation. Although LED supplemental lighting is commonly used to alleviate low-light stress in horticulture, its long-term programming effects on fruit quality remain largely unknown. This study investigated whether early light signals from different LED spectra (red:blue ratios of 1:1 and 5:1) and intensities (full‑spectrum white at 18, 48, and 60 W) could persistently shape the texture and eating quality of mature fruits in two cultivars, 'Green Gem' and 'Young White Lady'. Seedling-stage lighting treatments were applied, and subsequent fruit quality parameters-including perceived sweetness, fruit firmness, total soluble solids (TSS), titratable acidity (TA), and sugar-acid ratio-were measured. Key cultivar‑specific programming effects were identified. For 'Green Gem', seedling‑stage lighting with R:B = 5:1 at 18 W most effectively enhanced perceived sweetness and fruit firmness. For 'Young White Lady', full‑spectrum light at 48 W optimally boosted TSS (11.9 ± 1.5 °Brix), while 60 W reduced TA, yielding a superior sugar‑acid ratio (95.5 ± 7.0). Additionally, a high R:B ratio strongly correlated with increased acidity (ρ = 0.579). These findings reveal a trade‑off between flavor and texture, as high R:B ratios promote acidity but may affect other quality attributes. Seedling‑stage spectral management offers an energy‑efficient strategy for precision quality control in protected horticulture.