Synthesis and biological evaluation of panaxadiol ester derivatives possessing pyrazole and pyrrole moiety as HIF-1α inibitors.

Hypoxia-inducing factor-1α (HIF-1α) is overexpressed in variety of tumor patients and plays an important role in the regulation of hypoxia response in tumor cells. Therefore, its inhibitors have become one of the targets for the treatment of a variety of cancers. Two series of panaxadiol (PD) ester derivatives containing pyrazole (18a-j) and pyrrole (19a-n) moiety were synthesized and their HIF-1α inhibitory activities were evaluated. Among all the target compouds, compounds 18c, 19d, and 19n (IC50 = 8.70-10.44 µM) showed better HIF-1α inhibitory activity than PD (IC50 = 13.35 µM). None of these compounds showed cytotoxicity above 100 µM and inhibited HIF-1α transcription in a dose-dependent manner. These compounds showed good antitumor activity and provide lead compounds for further design and activity study of PD ester derivatives.

Similar construction of spicules and shell plates: Implications for the origin of chiton biomineralization.

The hard shells of mollusks are products of biomineralization, a distinctive feature of the Cambrian explosion. Despite our understanding of shell structure and mechanical properties, their origin remains mysterious. In addition to their shell plates, most chitons have calcium deposits on their girdles. However, the similarity of these two mineralized structures still needs to be determined, limiting our comprehension of their origins. In our study, we analyzed the matrix proteins in the spicules of chiton (Acanthopleura loochooana) and compared them with the matrix proteins in the shells of the same species. Proteomics identified 96 unique matrix proteins in spicules. Comparison of biomineralization-related matrix proteins in shell plates and spicules revealed shared proteins, including carbonic anhydrases, tyrosinase-hemocyanin, von Willebrand factor type A, cadherin, and glycine-rich unknown proteins. Based on similarities in key matrix proteins, we propose that spicules and shell plates originated from a common mineralization system in their ancestral lineage, suggesting the existence of a common core or toolkit of matrix proteins among calcifying organisms. SIGNIFICANCE: In this study, we try to understand the types and diversity of matrix proteins in the biomineralization of chiton shell plates and spicules. Through a comparative analysis, we seek insights into the core biomineralization toolkit of ancestral mollusks. To achieve this, we conducted LC-MS/MS and RT-qPCR analyses to identify the types and relative expression levels of matrix proteins in both shell plates and spicules. The analysis revealed 96 matrix proteins in the spicules. A comparison of biomineralization-related matrix proteins in shell plates and spicules from the same species revealed shared proteins including many unknown proteins unique to chitons. Blast searching reveals a universal conservation of these proteins among other chitons. Hence, we propose that spicules and shell plates originated from a common mineralization system in their ancestral lineage. Our work provides a molecular basis for studying biomineralization in polyplacophoran mollusks and understanding biomineralization evolution. In addition, it identifies potential matrix proteins that could be applied to control crystal growth.

Identification of RNA silencing suppressor encoded by citrus chlorotic dwarf-associated virus.

Introduction: Citrus chlorotic dwarf-associated virus (CCDaV) is an economically important citrus virus associated with leaf curling, deformation, and chlorosis found in China. Plants have evolved RNA silencing to defend against viral infections; however, the mechanism by which CCDaV suppresses RNA silencing in citrus remains unknown. Methods: Six proteins encoded by CCDaV were ectopically expressed in Nicotiana benthamiana 16c using the pCHF3 vector to identify RNA-silencing suppression activities. Results: V2 protein encoded by CCDaV suppressed local RNA silencing and systemic RNA silencing triggered by GFP RNA, but did not impede short-distance movement of the RNA silencing signal in N. benthamiana 16c. GFP fluorescence observations showed that the ability of V2 protein to suppress RNA silencing was weaker than tomato bushy stunt virus P19. Deletion analysis showed that the putative nuclear localization signal (NLS, 25-54 aa) was involved in the RNA silencing suppression activity of V2 protein. Furthermore, V2 protein cannot block dsRNA-triggered RNA silencing. The subcellular localization assay suggested that V2 protein was localized to nucleus of N. benthamiana. Conclusion: Overall, the results of this study demonstrate that CCDaV-V2 acts as an activity of silencing suppression. This is the first reported RNA-silencing suppressor encoded by Citlodavirus and will be valuable in revealing the molecular mechanism of CCDaV infection.

The adsorption and its mechanism of venlafaxine by original and aged polypropylene microplastic and the changes of joint toxicity.

Conjugation with the increment of consumption of polypropylene (PP) masks and antidepressants during pandemic, PP microplastics (MPs) and Venlafaxine (VEN) widely co-existed in surface waters. However, their environmental fate and the combined toxicity were unclear. Hence, we investigated the adsorption behaviors, and associated mechanisms of PP MPs for VEN. The impact factors including pH, salinity, and MPs aging were estimated. The results indicated PP MPs could adsorb amount of VEN within 24 h. The pseudo second-order kinetic model (R2 = 0.97) and Dubinin-Radushkevich model (R2 = 0.89) fitted well with the adsorption capacity of PP MPs for VEN, implying that chemical adsorption accompanied by electrostatic interaction might be the predominant mode for the interactions between PP MPs and VEN. Meanwhile, the adsorption capacity of PP MPs declined from pH of 2.5-4.5 and then increased from 4.5 to 9.5. The increased salinity (5-35 ppt) significantly suppressed the adsorption capacity. Aging by sunlight and UV triggered the formation of new functional group (carbonyl) on MPs, and then enhanced the adsorption capacity for VEN. Gaussian Model analysis further evidenced the electrostatic adsorption occurring in PP MPs and VEN. The combined exposure to PP MPs and VEN showed significantly antagonistic toxicity on Daphnia magna. The adsorption of VEN by PP MPs mitigated the lethal effects and behavioral function impairment posed by VEN on animals, implying the potential protective effects on zooplankton by PP MPs. This study for the first time provides perspective for assessing the environmental fate of MPs and antidepressants in aquatic system.

Metformin facilitates anti-PD-L1 efficacy through the regulation of intestinal microbiota.

Metformin is a synthetic biguanide proven to have beneficial effects against various human diseases. Research has confirmed that metformin exerts its effects by regulating the composition of intestinal microbiota. The composition of intestinal microbiota influences the efficacy of anti-PD-L1 immunotherapy. We assume that the regulation of metformin on intestinal microbiota could enhance the therapeutic efficiency of anti-PD-L1 antibodies. In Lewis lung cancer-bearing C57BL/6J mice, we find that metformin enhances PD-L1 antibody efficacy mainly depending on the existence of gut microbiota, and metformin increases the anti-tumor immunity through modulation of intestinal microbiota and affects the integrity of the intestinal mucosa. Antibiotic depletion of gut microbiota abolished the combination efficacy of PD-L1 antibody and metformin, implying the significance of intestinal microbiota in metformin's antitumor action. Combining anti-PD-L1 antibody with metformin provoked tumor necrosis by causing increased CD8 T-cell infiltration and IFN-γ expression. In conclusion, metformin could be employed as a microecological controller to prompt antitumor immunity and increase the efficacy of anti-PD-L1 antibodies. Our study provided reliable evidence that metformin could be synergistically used with anti-PD-L1 antibody to enhance the anti-cancer effect.

The mechanism of Shenlong Jianji treatment of idiopathic pulmonary fibrosis inhibits fibroblast-to-myofibroblast transformation via the TGF-ß1/smads signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenlong Jianji (SLJJ) is a Chinese herbal compound composed of traditional medicines for supplementing Qi, nourishing Yin, promoting blood circulation, and removing obstruction in channels. It is widely used to treat idiopathic pulmonary fibrosis (IPF) in China. However, the underlying mechanism of SLJJ remains unclear. AIM OF THIS STUDY: To elucidate the efficacy and mechanisms of SLJJ in the treatment of IPF through in vivo and in vitro experiments. MATERIAL AND METHODS: 84 Wistar rats were randomly and equally divided into 7 groups: the control group (CTRL), the sham operation group (SHAM), the model group (IPF), the low dose of SLJJ group (L-SLJJ), the middle dose of SLJJ group (M-SLJJ), the high dose of SLJJ group (H-SLJJ), and the pirfenidone group (PFD). The rats in the CTRL, SHAM, and IPF groups were given normal saline each time for 28 days; the SLJJ groups were given Shenlong Jianji (9 g kg-1·d-1, 18 g kg-1·d-1, 36 g kg-1·d-1), and pirfenidone was administered as a sequential dose. After 28 days, the general condition of the rats was evaluated, and samples were collected. The lung coefficient was measured. The pathological changes of lung in each group were observed by H&E staining and Masson staining. α-SMA, collagen 1, and E-cadherin proteins were detected by immunohistochemistry. α-SMA, collagen 1, vimentin, E-cadherin, N-cadherin, TGF-ß1, smad2, and smad3 proteins were detected by WB in vivo.In vitro, A scratch test was used to assess the ratio of cell migration. α-SMA, vimentin, E-cadherin, and N-cadherin protein levels were evaluated by a cellular immunofluorescence assay. TGF-ß1/smads signaling pathway was detected by WB. HPLC-Q-TOF/MS analysis was used to identify the active compounds in the SLJJ. Molecular docking determined the free binding energy of the compound with the TGF-ß1 protein. RESULTS: SLJJ significantly improved the respiratory symptoms, heart rate, mental state, and food intake of IPF group rats and decreased the lung coefficient. In the IPF group, inflammatory cells were infiltrated, and the thickened alveoli wall and alveoli collapse were shown, while significantly alleviating pathological changes in the SLJJ and PFD groups. Masson staining showed that SLJJ and PFD decreased the collagen expression. Immunohistochemical results showed that the expressions of α-SMA, collagen 1, and N-cadherin decreased in the SLJJ and PFD groups, while E-cadherin increased significantly compared with the IPF group. SLJJ regulates TGF-ß1/smads signaling pathway proteins in vivo. SLJJ decreased the ratio of migration in HFL-1 cells; SLJJ reduced the fluorescence intensity of α-SMA, vimentin, and N-cadherin and increased the fluorescence intensity of E-cadherin in primary rat lung (PRL) fibroblast cells and HFL-1 cells. WB results showed that SLJJ significantly down-regulated α-SMA, Vimentin, N-cadherin, TGF-ß1, smad2, and p-smad2/3 proteins expression and up-regulated E-cadherin protein expression in vitro, whereas SRI-011381 (a TGF-ß1 agonist) antagonized the effects of SLJJ. CONCLUSION: SLJJ inhibits idiopathic pulmonary fibrosis. The TGF- ß1/Smads signaling pathway can be the target of SLJJ, which inhibits fibroblast-to-myofibroblast transformation and is expected to be a new drug for the treatment of IPF.

Proteomic analysis of shell matrix proteins from the chiton Acanthopleura loochooana.

Most molluscs have mineralized shells to protect themselves. Although the remarkable mechanical properties of shells have been well-studied, the origin of shells is still elusive. Chitons are unique in molluscs because they are shelly Aculifera which diverged from Conchifera (comprising all the shell-bearing classes of molluscs) in the early pre-Cambrian. We developed a method to extract shell proteins from chiton shell plates (removing embedded soft tissues) and then compared the shell proteome to that of Conchifera groups. Sixteen shell matrix proteins from Acanthopleura loochooana were identified by proteomics, in which Nacrein-like, Pif-like proteins, and protocadherin were found. Additional evidences from shell proteome in another species Chiton densiliratus and comparative sequence alignment in five chitons supported a conserved biomineralization toolkit in chitons. Our findings shed light on the evolution of mineralization in chitons and pose a hypothesis that ancestral molluscs have already evolved biomineralization toolkits, which may facilitate the formation of mineralized shells.

Nanosensitizer-mediated augmentation of sonodynamic therapy efficacy and antitumor immunity.

The dense stroma of desmoplastic tumor limits nanotherapeutic penetration and hampers the antitumor immune response. Here, we report a denaturation-and-penetration strategy and the use of tin monosulfide nanoparticles (SnSNPs) as nano-sonosensitizers that can overcome the stromal barrier for the management of desmoplastic triple-negative breast cancer (TNBC). SnSNPs possess a narrow bandgap (1.18 eV), allowing for efficient electron (e-)-hole (h+) pair separation to generate reactive oxygen species under US activation. More importantly, SnSNPs display mild photothermal properties that can in situ denature tumor collagen and facilitate deep penetration into the tumor mass upon near-infrared irradiation. This approach significantly enhances sonodynamic therapy (SDT) by SnSNPs and boosts antitumor immunity. In mouse models of malignant TNBC and hepatocellular carcinoma (HCC), the combination of robust SDT and enhanced cytotoxic T lymphocyte infiltration achieves remarkable anti-tumor efficacy. This study presents an innovative approach to enhance SDT and antitumor immunity using the denaturation-and-penetration strategy, offering a potential combined sono-immunotherapy approach for the cancer nanomedicine field.

Beraprost sodium attenuates the development of myocardial fibrosis after myocardial infarction by regulating GSK-3ß expression in rats.

OBJECTIVE: The aim of this study was to elucidate the mechanism of beraprost sodium (BPS) in the intervention of myocardial fibrosis after myocardial infarction (MI) through glycogen synthase kinase-3ß (GSK-3ß) and to provide new ideas for intervention in myocardial fibrosis. MATERIALS AND METHODS: MI model rats given BPS and cardiac fibroblasts (CFs) treated with BPS and TGF-ß. HE staining and Masson staining were used to detect the pathological changes of myocardial tissue. Fibrotic markers were detected by immunohistochemical staining. The expressions of GSK-3ß, cAMP response element binding protein (CREB), and p-CREB were analyzed by qPCR and western blot analysis. EDU staining was used to detect the proliferation of CFs. The promoter activity of GSK-3ß was detected by luciferase assay. Chromatin immunoprecipitation assay was used to detect the binding levels of GSK-3ß promoter and Y-box binding protein 1 (YBX1). The levels of intracellular cyclic adenosine monophosphate (cAMP) were analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS: After operation, BPS improved myocardial fibrosis and upregulated GSK-3ß protein expression in male SD rats. BPS can down-regulate α-smooth muscle actin (α-SMA) level and up-regulate GSK-3ß protein expression in CFs after TGF-ß stimulation. Furthermore, GSK-3ß knockdown can reverse the effect of BPS on TGF-ß-activated CFs, enhance α-SMA expression, and promote the proliferation of CFs. BPS could regulate GSK-3ß expression by promoting the binding of GSK-3ß promoter to YBX1. BPS induced upregulation of p-CREB and cAMP, resulting in reduced fibrosis, which was reversed by the knockdown of GSK-3ß or prostaglandin receptor (IPR) antagonists. CONCLUSION: BPS treatment increased the binding of YBX1 to the GSK-3ß promoter, and GSK-3ß protein expression was upregulated, which further caused the upregulation of p-CREB and cAMP, and finally inhibited myocardial fibrosis.

Inhaled mRNA nanoparticles dual-targeting cancer cells and macrophages in the lung for effective transfection.

Messenger RNA (mRNA)-based therapeutics are transforming the landscapes of medicine, yet targeted delivery of mRNA to specific cell types while minimizing off-target accumulation remains challenging for mRNA-mediated therapy. In this study, we report an innovative design of a cationic lipid- and hyaluronic acid-based, dual-targeted mRNA nanoformulation that can display the desirable stability and efficiently transfect the targeted proteins into lung tissues. More importantly, the optimized dual-targeted mRNA nanoparticles (NPs) can not only accumulate primarily in lung tumor cells and inflammatory macrophages after inhalation delivery but also efficiently express any desirable proteins (e.g., p53 tumor suppressor for therapy, as well as luciferase and green fluorescence protein for imaging as examples in this study) and achieve efficacious lung tissue transfection in vivo. Overall, our findings provide proof-of-principle evidence for the design and use of dual-targeted mRNA NPs in homing to specific cell types to up-regulate target proteins in lung tissues, which may hold great potential for the future development of mRNA-based inhaled medicines or vaccines in treating various lung-related diseases.

Predictive value of platelet-to-lymphocyte ratio combined with CA199 levels in postoperative survival of patients with gastric cancer: A retrospective study.

OBJECTIVE: To develop a new scoring system based on platelet-to-lymphocyte ratio (PLR) and CA199 to predict the prognosis of gastric cancer. METHODS: PLR-CA199 was identified in a retrospective study that was conducted in a training cohort of 990 gastric cancer patients who underwent curable resection from 2012 to 2014 and validated in a validation cohort of 625 patients between 2015 and 2016. RESULTS: In the training cohort, PLR-CA199 was related to gender (P = 0.041), age (P = 0.014), tumor location (P = 0.015), tumor size (P < 0.001), Bormann type (P < 0.001), vascular invasion (P < 0.001), perineural invasion (P < 0.001), and TNM staging (P < 0.001). In the validation cohort, PLR-CA199 was related to tumor size (P < 0.001), Bormann type (P = 0.007), vascular invasion (P < 0.001), perineural invasion (P < 0.001), and TNM staging (P < 0.001). Survival analysis showed that in the training cohort the mean disease-free survival (DFS) was 70.699 months for patients PLR-CA199 = 0, 51.223 months for patients PLR-CA199 = 1, and 32.152 months for patients PLR-CA199 = 2 (P < 0.001). The correlation between PLR-CA199 and DFS was further confirmed in the validation cohort (50.640 vs. 41.842 vs. 22.382, P < 0.001). Survival analysis showed that the mean disease special survival (DSS) was 76.668 months for patients PLR-CA199 = 0, 61.218 months for patients PLR-CA199 = 1, and 44.665 months for patients PLR-CA199 = 2 in the training cohort (P < 0.001). The correlation between PLR-CA199 and DSS was further confirmed in the validation cohort (53.858 vs. 46.385 vs. 44.665, P < 0.001). Furthermore, univariate and multivariate analyses showed that PLR-CA199 was an independent prognostic factor for DFS and DSS. CONCLUSIONS: Preoperative PLR-CA199 may be a useful prognostic indicator, and is a promising tool for predicting the prognosis for gastric cancer.

[Inhibitory effect and molecular mechanism of sinomenine on human hepatocellular carcinoma HepG2 and SK-HEP-1 cells].

This study aimed to investigate the effect and molecular mechanism of sinomenine on proliferation, apoptosis, metastasis, and combination with inhibitors in human hepatocellular carcinoma HepG2 cells and SK-HEP-1 cells. The effect of sinomenine on the growth ability of HepG2 and SK-HEP-1 cells were investigated by CCK-8 assay, colony formation assay, and BeyoClick~(TM) EdU-488 staining. The effect of sinomenine on DNA damage was detected by immunofluorescence assay, and the effect of sinomenine on apoptosis of human hepatocellular carcinoma cells was clarified by Hoechst 33258 staining and CellEvent~(TM) Cystein-3/7Green ReadyProbes~(TM) reagent assay. Cell invasion assay and 3D tumor cell spheroid invasion assay were performed to investigate the effect of sinomenine on the invasion ability of human hepatocellular carcinoma cells in vitro. The effect of sinomenine on the regulation of protein expression related to the protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/signal transducer and activator of transcription 3(STAT3) signaling pathway in HepG2 and SK-HEP-1 cells was examined by Western blot. Molecular docking was used to evaluate the strength of affinity of sinomenine to the target cysteinyl aspartate specific proteinase-3(caspase-3) and STAT3, and combined with CCK-8 assay to detect the changes in cell viability after combination with STAT3 inhibitor JSI-124 in combination with CCK-8 assay. The results showed that sinomenine could significantly reduce the cell viability of human hepatocellular carcinoma cells in a concentration-and time-dependent manner, significantly inhibit the clonogenic ability of human hepatocellular carcinoma cells, and weaken the invasive ability of human hepatocellular carcinoma cells in vitro. In addition, sinomenine could up-regulate the cleaved level of poly ADP-ribose polymerase(PARP), a marker of apoptosis, and down-regulate the protein levels of p-Akt, p-mTOR, and p-STAT3 in human hepatocellular carcinoma cells. Molecular docking results showed that sinomenine had good affinity with the targets caspase-3 and STAT3, and the sensitivity of sinomenine to hepatocellular carcinoma cells was diminished after STAT3 was inhibited. Therefore, sinomenine can inhibit the proliferation and invasion of human hepatocellular carcinoma cells and induce apoptosis, and the mechanism may be attributed to the activation of caspase-3 signaling and inhibition of the Akt/mTOR/STAT3 pathway. This study can provide a new reference for the in-depth research and clinical application of sinomenine and is of great significance to further promote the scientific development and utilization of sinomenine.

[Morin induces autophagy and apoptosis in hepatocellular carcinoma cells through Akt/mTOR/STAT3 pathway].

This study investigated the effect and mechanism of morin in inducing autophagy and apoptosis in hepatocellular carcinoma cells through the protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/signal transducer and activator of transcription protein 3(STAT3) pathway. Human hepatocellular carcinoma SK-HEP-1 cells were stimulated with different concentrations of morin(0, 50, 100, 125, 200, and 250 µmol·L~(-1)). The effect of morin on the viability of SK-HEP-1 cells was detected by Cell Counting Kit-8(CCK-8). The effect of morin on the proliferation and apoptosis of SK-HEP-1 cells was investigated using colony formation assay, flow cytometry, and BeyoClick~(TM) EdU-488 with different concentrations of morin(0, 125, and 250 µmol·L~(-1)). The changes in the autophagy level of cells treated with morin were examined by transmission electron microscopy and autophagy inhibitors. The impact of morin on the expression levels of proteins related to the Akt/mTOR/STAT3 pathway was verified by Western blot. Compared with the control group, the morin groups showed decreased viability of SK-HEP-1 cells in a time-and concentration-dependent manner, increased number of apoptotic cells, up-regulated expression level of apoptosis marker PARP, up-regulated phosphorylation level of apoptosis-regulating protein H2AX, decreased number of positive cells and the colony formation rate, an upward trend of expression levels of autophagy-related proteins LC3-Ⅱ, Atg5, and Atg7, and decreased phosphorylation levels of Akt, mTOR, and STAT3. These results suggest that morin can promote apoptosis, inhibit proliferation, and induce autophagy in hepatocellular carcinoma cells, and its mechanism of action may be related to the Akt/mTOR/STAT3 pathway.

Glutathione-sensitive mesoporous nanoparticles loaded with cinnamaldehyde for chemodynamic and immunological therapy of cancer.

Chemodynamic therapy as a novel type of chemotherapy can damage the DNA structures and induce cell apoptosis and immunogenic cell death (ICD) through generating reactive oxygen species (ROS) to aggravate oxidative stress. Nonetheless, as an intrinsic antioxidative response of tumor cells, the expression of glutathione (GSH) can be upregulated to maintain the cellular redox balance and protect the tumor cells from ROS-mediated damage. In this context, it is feasible to simultaneously boost ROS generation and GSH depletion in tumor cells; however, the precise delivery and release of GSH scavengers at specific subcellular sites is of great importance. Herein, we propose a GSH-responsive mesoporous organosilica nanoparticle (MON)-based nanomedicine MON-CA-TPP@HA through sequentially covalently attaching triphenylphosphine (TPP) and electrostatically coating hyaluronic acid (HA) onto the surface of cinnamaldehyde (CA)-loaded MONs, known as MON-CA-TPP@HA, which has been demonstrated to be an extremely effective therapeutic strategy for cancer treatment through inducing ICD and apoptosis of breast cancer cells. Systematic in vitro experimental results clearly revealed that the nanomedicine can actively target the tumor cells with the help of HA, subsequently enter the tumor cells, and precisely bind with the mitochondria through TPP residues. Upon cleavaging the disulfide bond in the MONs triggered by over-expressed GSH within tumors, the CA molecules can be released inducing the excessive ROS in situ surrounding the mitochondria to activate oxidative stress to induce apoptosis and ICD of breast cancer cells. The results of the in vivo experiments confirm that the MON-CA-TPP@HA nanomedicine can effectively promote dendritic cell (DC) maturation and CD 8+ T cell activation and regulate the ratio of M1/M2 macrophages, which improve tumor immunosuppressive microenvironment. It is thus believed that the current nanomedicine has paved a new way for future cancer therapy.

KRTA6A and FA2H Are Hub Genes Associated With Cgas-STING-related Immunogenic Cell Death in Lung Adenocarcinoma.

BACKGROUND/AIM: The immunogenic cell death (ICD) pathway plays a crucial prognostic role in lung adenocarcinoma (LUAD) therapy. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an upstream mechanism that drives ICD activation, but the interaction of hub genes remains unclear. The present study aimed to investigate the hub genes involved in ICD and the cGAS-STING pathway. The prognostic performance for hub genes and related Gene Ontology (GO) terms were also investigated. MATERIALS AND METHODS: Gene expression data of ICD induction and cGAS-STING pathway activation samples were extracted from the Gene Expression Omnibus (GEO) database, and gene expression as well as clinical data of LUAD patients who received pharmaceutical therapy were extracted from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) were identified, and protein-protein interaction (PPI) analysis was used to identify hub genes. Hazard risk (HR) scores were identified using Kaplan-Meier (K-M) and COX analyses. Gene set enrichment analysis (GSEA) was performed to identify the related GO terms, and receiver operating characteristic (ROC) analysis was used to evaluate the prognosis performance of the related gene sets. RESULTS: A total of 22 DEGs were identified in the two GEO datasets, and six hub genes were identified by PPI analysis. Keratin 6A (KRTA6A) and fatty acid 2-hydroxylase (FA2H) were selected as the hub genes after survival analysis. GSEA and ROC analysis indicated that there was no difference between the KRTA6A and FA2H gene sets on prognosis performance. CONCLUSION: KRTA6A and FA2H are hub genes associated with the induction of cGAS-STING-related ICD in LUAD.

Magnetic coagulation and flocculation of kaolin suspension using Fe3O4 with plant polyphenol self-assembled flocculants.

In this work, magnetic flocculant (Fe3O4@PP) was synthesized using plant polyphenol (PP) as a shaping ligand via in situ self-assembly. Characterization results revealed that Fe3O4@PP exhibited uniform particle size and excellent dispersibility with PP coating amount of 16.4 %. Experimental results suggested that Fe3O4@PP showed excellent turbidity removal efficiency in a wide pH range (3.0-10) and initial turbidity range (50-2000 NTU). Under the optimal conditions, Fe3O4@PP achieved 95.2 % of turbidity removal for simulated kaolin suspension and 96.9 % for actual wastewater. Fe3O4@PP exhibited excellent recycling and reusability properties, with high recycling efficiency of 93.3 % even after the fifth cycle. Microscopic observation revealed the formation process of magnetic flocs, involving particle aggregation, chain and cluster formation, and dense network aggregate formation. The structural characteristics and size of magnetic flocs were found to be significantly influenced by the combined effects of magnetic force, electric charge, van der Waals force, and functional groups on the surface of PP. The extended Deryaguin-Landau-Verwey-Overbeek models indicated that magnetic interactions were the primary mechanism for magnetic flocculation, accompanied by charge neutralization, adsorption bridging, sweeping, and net trapping.

Recent Advances in Research on Active Compounds Against Hepatic Fibrosis.

BACKGROUND: Almost all chronic liver diseases cause fibrosis, which can lead to cirrhosis and eventually liver cancer. Liver fibrosis is now considered to be a reversible pathophysiological process and suppression of fibrosis is necessary to prevent liver cancer. At present, no specific drugs have been found that have hepatic anti-fibrotic activity. OBJECTIVE: The research progress of anti-hepatic fibrosis compounds in recent ten years was reviewed to provide a reference for the design and development of anti-hepatic fibrosis drugs. METHODS: According to the structure of the compounds, they are divided into monocyclic compounds, fused-heterocyclic compounds, and acyclic compounds. RESULTS: In this article, the natural products and synthetic compounds with anti-fibrotic activity in recent ten years were reviewed, with emphasis on their pharmacological activity and structure-activity relationship (SAR). CONCLUSION: Most of these compounds are natural active products and their derivatives, and there are few researches on synthetic compounds and SAR studies on natural product.

In situ Engineering of Tumor-Associated Macrophages via a Nanodrug-Delivering-Drug (ß-Elemene@Stanene) Strategy for Enhanced Cancer Chemo-Immunotherapy.

Tumor-associated macrophages (TAMs) play a critical role in the immunosuppressive solid tumor microenvironment (TME), yet in situ engineering of TAMs for enhanced tumor immunotherapy remains a significant challenge in translational immuno-oncology. Here, we report an innovative nanodrug-delivering-drug (STNSP@ELE) strategy that leverages two-dimensional (2D) stanene-based nanosheets (STNSP) and ß-Elemene (ELE), a small-molecule anticancer drug, to overcome TAM-mediated immunosuppression and improve chemo-immunotherapy. Our results demonstrate that both STNSP and ELE are capable of polarizing the tumor-supportive M2-like TAMs into a tumor-suppressive M1-like phenotype, which acts with the ELE chemotherapeutic to boost antitumor responses. In vivo mouse studies demonstrate that STNSP@ELE treatment can reprogram the immunosuppressive TME by significantly increasing the intratumoral ratio of M1/M2-like TAMs, enhancing the population of CD4+ and CD8+ T lymphocytes and mature dendritic cells, and elevating the expression of immunostimulatory cytokines in B16F10 melanomas, thereby promoting a robust antitumor response. Our study not only demonstrates that the STNSP@ELE chemo-immunotherapeutic nanoplatform has immune-modulatory capabilities that can overcome TAM-mediated immunosuppression in solid tumors, but also highlights the promise of this nanodrug-delivering-drug strategy in developing other nano-immunotherapeutics and treating various types of immunosuppressive tumors.