Colorectal cancer (CRC) is the third most common malignancy and the second most lethal cancer worldwide and has become a significant burden on global healthcare. The primary treatments for CRC include surgery, chemotherapy, and targeted therapy. However, these approaches face several limitations, such as invasive administration, poor patient compliance, systemic toxicity, drug resistance, and recurrence. Thus, alternative therapeutic strategies to overcome these challenges are urgently needed. Oral administration represents a promising approach for CRC treatment because of its noninvasive nature, safety, ease of self-administration, and high patient compliance. Moreover, when applied in CRC treatment, oral therapies can potentially increase therapeutic efficacy and reduce systemic toxicity via local treatment. Furthermore, the unique pathophysiological features of CRC, such as the overexpression of certain receptors and dysbiosis, present valuable opportunities for the development of advanced oral therapies. This review focuses on cutting-edge oral therapies for CRC, including nanomedicine-based and bacteria-modulating strategies. These approaches show significant promise for improving therapeutic outcomes and can be combined with existing treatment modalities to improve efficacy and minimize adverse effects. Additionally, we provide critical perspectives on the challenges and future perspectives of these strategies for CRC management. This review aims to provide novel insights into the design and advancement of oral therapies, paving the way for more effective and patient-friendly CRC treatments.

The fusion of neurotrophic tyrosine receptor kinase (NTRK) is a novel target for cancer therapy and offers hope for patients with gastric cancer (GC). However, there are few studies on the prevalence and detection methods of NTRK fusions in GC. In this study, we used immunohistochemistry (IHC) as a screening method to select cases for molecular testing and evaluated the effectiveness of IHC, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). We retrospectively collected 1970 patients with GC. Pan-TRK IHC was conducted in all cases, and three cases were positive: one with strong and diffuse cytoplasmic staining, while two with weak cytoplasmic staining. All three cases were validated using NTRK1/2/3 FISH. FISH results revealed a single 3' signal of NTRK1 in 95% of the tumor cells in the first case, while the remaining two cases were negative. NGS confirmed LMNA-NTRK1 fusion in the first case, with no gene fusion detected in the other two cases. Out of 46 negative controls, one had a non-functional fusion of IGR-NTRK1, and four had point mutations. The case with LMNA-NTRK1 fusion were negative for pMMR, EBV, HER2, and AFP. The pan-TRK IHC showed a 33.33% (1/3) concordance rate with RNA-based NGS. If the criterion for positivity was 3+ cytoplasmic staining, the agreement between IHC and RNA-based NGS was 100% (1/1). In conclusion, the incidence of NTRK fusion in GC is extremely low (0.05%). If the criteria are strict, pan-TRK IHC is highly effective for screening NTRK fusions. FISH could complement NGS detection, particularly when NTRK fusion is detected by DNA sequencing. NTRK fusion in GC may not be limited to specific subtypes.

The printable multicolor microgels exhibit excellent discoloration behavior and can act as fluorescent anti-counterfeiting inks, which are ascribed to the water-responsive FRET effect and changes in the aggregation state of fluorescent dyes.

Background: Metabolic dysfunction -associated steatotic liver disease (MASLD) is a common complication of obesity and, in severe cases, progresses to metabolic dysfunction -associated steatohepatitis (MASH). Small heterodimer partner (SHP) is an orphan member of the nuclear receptor superfamily and regulates metabolism and inflammation in the liver via a variety of pathways. In this study, we investigate the molecular foundation of MASH progression in mice with hepatic SHP deletion and explore possible therapeutic means to reduce MASH. Methods: Hepatic SHP knockout mice (SHPDhep) and their wild -type littermates (SHPfl/fl) of both sexes were fed a fructose diet for 14 weeks and subjected to an oral glucose tolerance test. Then, plasma lipids were determined, and liver lipid metabolism and inflammation pathways were analyzed with immunoblotting, RNAseq, and qPCR assays. To explore possible therapeutic intersections of SHP and inflammatory pathways, SHPDhep mice were reconstituted with bone marrow lacking interferon y (IFNy-/-) to suppress inflammation. Results: Hepatic deletion of SHP in mice fed a fructose diet decreased liver fat and increased proteins for fatty acid oxidation and liver lipid uptake, including UCP1, CPT1a, ACDAM, and SRBI. Despite lower liver fat, hepatic SHP deletion increased liver inflammatory F4/80+ cells and mRNA levels of inflammatory cytokines (IL -12, IL -6, Ccl2, and IFNy) in both sexes and elevated endoplasmic reticulum stress markers of Cox2 and CHOP in female mice. Liver bulk RNAseq data showed upregulation of genes whose protein products regulate lipid transport, fatty acid oxidation, and inflammation in SHPDhep mice. The increased inflammation and fibrosis in SHPDhep mice were corrected with bone marrow -derived IFNy-/- myeloid cell transplantation. Conclusion: Hepatic deletion of SHP improves fatty liver but worsens hepatic inflammation possibly by driving excess fatty acid oxidation, which is corrected by deletion of IFNy specifically in myeloid cells. This suggests that hepatic SHP limits fatty acid oxidation during fructose diet feeding but, in doing so, prevents pro -MASH pathways. The IFNy-mediated inflammation in myeloid cells appears to be a potential therapeutic target to suppress MASH. Published by Elsevier GmbH. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This study aimed to explore potential biomarkers and mechanisms following bariatric surgery. Two gene expression profiles from the Gene Expression Omnibus (GEO) were analysed to identify differentially expressed genes (DEGs) in subcutaneous adipose tissue (AT) post-bariatric surgery. Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene-Set Enrichment Analysis (GSEA), and Protein-Protein Interaction (PPI) network analyses were employed to identify hub genes and associated pathways. Among the DEGs, 29 genes were downregulated. Enrichment analysis revealed that the downregulated DEGs significantly participated in inflammatory responses. GSEA provided comprehensive evidence that most genes were enriched in pro-inflammatory pathways before surgery, while after surgery, most genes were enriched in metabolism. In the PPI network, five key genes, including TREM2, MNDA, HP, C5AR1, and S100A8, were identified, with most validated as highly expressed in obesity by the Attie Lab Diabetes and another dataset, GSE72158. Bariatric surgery induces a significant shift from an obesity-promoting inflammatory state to an anti-inflammatory state, accompanied by improvements in adipocyte metabolic function. This represents a key mechanism for the enhancement of adipose tissue function following bariatric surgery. This study deepens the understanding of the benefits of bariatric surgery and provides potential biomarkers or therapeutic targets.

Cervical cancer (CxCa) is the fourth most frequent cancer in women. This study aimed to determine the role and underlying mechanism of fibronectin type III domain-containing protein 5 (FNDC5) in inhibiting CxCa growth. Experiments were performed in human CxCa tissues, human CxCa cell lines (HeLa and SiHa), and xenograft mouse model established by subcutaneous injection of SiHa cells in nude mice. Bioinformatics analysis showed that CxCa patients with high FNDC5 levels have a longer overall survival period. FNDC5 expression was increased in human CxCa tissues, HeLa and SiHa cells. FNDC5 overexpression or FNDC5 protein not only inhibited proliferation, but also restrained invasion and migration of HeLa and SiHa cells. The effects of FNDC5 were prevented by inhibiting integrin with cilengitide, activating PI3K with recilisib or activating Akt with SC79. FNDC5 inhibited the phosphorylation of PI3K and Akt, which was attenuated by recilisib. PI3K inhibitor LY294002 showed similar effects to FNDC5 in HeLa and SiHa cells. Intravenous injection of FNDC5 (20 μg/day) for 14 days inhibited the tumor growth, and reduced the proliferation marker Ki67 expression and the Akt phosphorylation in the CxCa xenograft mouse model. These results indicate that FNDC5 inhibits the malignant phenotype of CxCa cells through restraining PI3K/Akt signaling. Upregulation of FNDC5 may play a beneficial role in retarding the tumor growth of CxCa.

Enhanced proliferation and migration of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling in hypertension. Adventitial fibroblasts (AFs)-derived extracellular vesicles (EVs) modulate vascular remodeling in spontaneously hypertensive rat (SHR). This study shows the important roles of EVs-mediated miR-21-3p transfer in VSMC proliferation and migration and underlying mechanisms in SHR. AFs and VSMCs were obtained from aorta of Wistar-Kyoto rat (WKY) and SHR. EVs were separated from AFs culture with ultracentrifugation method. MiR-21-3p content in the EVs of SHR was increased compared with those of WKY. MiR-21-3p mimic promoted VSMC proliferation and migration of WKY and SHR, while miR-21-3p inhibitor attenuated proliferation and migration only in the VSMCs of SHR. EVs of SHR stimulated VSMC proliferation and migration, which were attenuated by miR-21-3p inhibitor. Sorbin and SH3 domain containing 2 (SORBS2) mRNA and protein levels were reduced in the VSMCs of SHR. MiR-21-3p mimic inhibited, while miR-21-3p inhibitor promoted SORBS2 expressions in the VSMCs of both WKY and SHR. EVs of SHR reduced SORBS2 expression, which was prevented by miR-21-3p inhibitor. EVs of WKY had no significant effect on SORBS2 expressions. SORBS2 overexpression attenuated the roles of miR-21-3p mimic and EVs of SHR in promoting VSMC proliferation and migration of SHR. Overexpression of miR-21-3p in vivo promotes vascular remodeling and hypertension. These results indicate that miR-21-3p in the EVs of SHR promotes VSMC proliferation and migration via negatively regulating SORBS2 expression.

Antibody-functionalized targeted nanocarriers have shown great-potential for minimizing the chemoresistance and systemic toxicity of cancer chemotherapies. The combination of chemotherapy and photothermal therapy has great potential in improving therapeutic effect. However, cetuximab-modified nanoparticles based lipids for chemo-phototherapy of EGFR overexpressing colorectal carcinoma (CRC) have seldom been investigated. Hence, this study aimed to fabricate cetuximab-conjugated and near infrared (NIR) light-responsive hybrid lipidpolymer nanoparticles (abbreviated as Cet-CINPs) for targeted delivery of irinotecan. Cet-CINPs were prepared with copolymer PLGA and various lipids DSPE-PEG, DSPE-PEG-Mal, lecithin as carriers. Cetuximab was conjugated on the surface of nanoparticles to achieve targeting anti-tumor efficacy. Cet-CINPs were characterized in terms of morphology (spherical), size (119 nm), charge (-27.2 mV), drug entrapment efficiency (43.27 %), and antibody conjugation efficiency (70.87 %). Cet-CINPs showed preferable photothermal response, pH/NIRtriggered drug release behavior, enhanced cellular uptake and ROS level compared with free ICG and CINPs. Meanwhile, in vitro cytotoxicity assay showed that Cet-CINPs with NIR irradiation had a higher cytotoxicity against Lovo cells than non-targeted or non-NIR activated nanoparticles. The IC50 values of Cet-CINPs with NIR irradiation was 22.84 +/- 1.11 mu M for 24 h and 5.01 +/- 1.06 mu M for 48 h, respectively. These investigations demonstrate that Cet-CINPs with good tumor-targeting ability and enhanced antitumor activity, are a promising multifunctional nanoplatform for CRC therapy.

Surface-enhanced Raman scattering (SERS) has attracted attention because of its enormous potential to detect molecules with low concentrations. The method of fabricating SERS substrates is of great importance for improving the detection resolution. However, SERS substrates with different triangular pyramid tips fabricated by using the tip-based nanoindentation method has not been reported. Here, we prepared arrayed micro/nanocavities on copper-based graphene using the continuous indentation method with a Berkovich tip and a cube-corner tip, which have different face angles. Gold nanoparticles were then sputtered onto the graphene-copper micro/nanocavities to form the Au@GR@Cu micro/nanocavities SERS substrates. The substrates formed using the Berkovich tip and cube-corner tip were labeled B2-B9 and C2-C9, respectively, in which the numbers indicate the machining feed. Rhodamine 6G (R6G) was employed, and the Raman intensities of R6G on the differently arrayed Au@GR@Cu micro/nanocavities were measured. The Raman intensities of R6G were stronger on the pile-ups than on the inverted triangular pyramid cavities. The Raman intensities of R6G were highest on the C2 and B2 structures and lowest on the C9 and B9 structures. The Raman intensities of R6G on the arrayed Au@GR@Cu micro/nanocavities fabricated by the cube-corner tip were stronger than those on the arrayed Au@GR@Cu micro/nanocavities fabricated using the Berkovich tip with the same machining feed. In addition, the electric field intensity and distribution of the B9 and C9 arrayed Au@GR@Cu were simulated using Comsol software. Au@GR@Cu structures fabricated by the cube-corner tip were generated with higher electric field intensities. Furthermore, the relative standard deviations at 1362 cm-1 of R6G were 6.19 and 6.62% on the C2 and C4 surfaces, respectively, showing good homogeneity. The SERS spectra of 10-9 mol/L malachite green solution and 10-6 mol/L carbaryl solution were recognized on the C1, C2, and C4 surfaces on day 1 and after 3 months, respectively. After storage at room temperature for 3 months, the reductions in the Raman intensities were less than 10%, indicating excellent stability. The results showed that the arrayed Au@GR@Cu micro/nanocavities fabricated using the cube-corner tip performed better than those fabricated using the Berkovich tip and exhibited excellent uniformity, availability, and stability, providing great potential for detecting pesticides at low concentrations.

Objective: To investigate the effects of bosutinib on the malignant behavior of thyroid papillary carcinoma B-CPAP cells and its possible mechanisms. Methods: Thyroid papillary carcinoma B-CPAP cells were cultured in vitro with a concentration gradient of(1、2、3、4 and 5 μmol/L)bosutinib intervened for 24 hours, DMSO was used as the control group. Five parallel compound holes were set in each group. Cell counting kit (CCK-8 method) method was used to detect cell proliferation. Transwell assay and cell wound healing assay were used to detect cell invasion and migration. TUNEL staining assay and flow cytometry were used to detect cell apoptosis. Western blot was used to detect the expressions of autophagic proteins (Beclin-1, LC3, p62) and signal pathway proteins (SIK2, p-mTOR, mTOR, p-ULK1, ULK1). Results: Compared with the control group, the cell proliferation activity, migration ability and invasion ability were decreased (P＜0.01), while the cell apoptosis rate was increased (P＜0.01) in the bosutinib concentration groups of 2, 3, 4 and 5 μmol/L . In the concentration groups of 4 and 5 μmol/L, the expression of Beclin-1 (P＜0.05), LC3- Ⅱ/LC3- Ⅰ (P＜0.05), SIK2 (P＜0.01) and p-ULK1 (P＜0.01) protein was decreased, while the expression of p62 (P＜ 0.05) and p-mTOR (P＜0.01) protein was increased. Conclusion: Bosutinib may inhibit the autophagy of thyroid papillary carcinoma cells through SIK2-mTOR-ULK1 signaling pathway to inhibit their proliferation, invasion and migration and promote apoptosis, thereby weakening their malignant behavior.

为提高顺铂的治疗效果并减少副作用,构建了一种具有化学-光热联合疗效的靶向铂药递送体系.以聚乙二醇-聚乳酸共聚物为载体,采用超声乳化法制备负载顺铂和光敏剂吲哚菁绿的纳米微球,再由西妥昔单抗进行表面修饰,从而制备西妥昔单抗修饰的近红外活化的载药纳米微球(CPINPs).通过表征平均粒径、Zeta电位、单抗偶联率、光热效应等考察其理化性质;通过激光共聚焦显微镜测定体外细胞摄取情况;通过CCK8实验评价体外抗肿瘤活性.结果表明,所制备的CPINPs纳米微球平均粒径为(263.9±3.73)nm,多分散指数为0.18±0.03,Zeta电位为-(23.43±0.42)mV,单抗偶联率为(44.0±1.72)％;体外光热实验显示,经近红外光照射后的CPINPs会产生导致肿瘤细胞死亡的光热效应;体外细胞摄取实验结果表明,近红外光对细胞摄取有促进作用,A549细胞会选择性地摄取更多受近红外照射过的CPINPs;体外细胞毒性实验表明,近红外光照射处理的CPINPs具有化学-光热联合治疗效果,其抑制A549细胞增殖的能力高过游离顺铂和无光照处理组,给药24 h的IC50为(8.67±0.04)μmol/L.实验结果表明,本研究构建的多功能给药系统有望成为一种更为高效的肺癌靶向治疗方法.

Platinum-based drugs are the mainstay of chemotherapy regimens in a clinic, but their use is seriously limited by severe side effects and drug resistance. A cetuximab-decorated drug delivery system can selectively deliver drugs into EGFR-highexpressing cancer cells to prevent the shortcomings of platinum-based chemotherapy. Here, cetuximab-decorated and near-infrared (NIR)-activated nanoparticles based on Pt(IV)-prodrug (abbreviated as Cetuximab-Pt-INPs) was constructed. First, PEGylated Pt(IV)-prodrug was synthesized by a condensation reaction between c,c,t-[Pt(NH3)2Cl2(OOCCH2CH2COOH)(OH)] and MPEG-PLA. Then, Pt(IV)-prodrug and indocyanine green co-encapsulated nanoparticles (Pt-INPs) were prepared through an ultrasonic emulsification method. Finally, Cetuximab-Pt-INPs were obtained by decorating Pt-INPs with cetuximab as a targeting vector. The optimized Cetuximab-Pt-INPs exhibited a spherical core-shell shape of 138.5 ± 0.96 nm. In-vitro cellular uptake and cytotoxicity assays revealed that more Cetuximab-Pt-INPs with NIR irradiation were selectively taken up by A431 cells, thereby leading to higher cytotoxicity. These multifunctional nanoparticles may have promising potential for targeted and effective therapy against EGFR-highexpressing cells of epidermoid carcinoma.

Brucein D (BD) is a naturally occurring major active quassinoid extracted from the Chinese medicinal herb Brucea javanica, which has been previously demonstrated to exhibit anticancer activities. The present study aimed to investigate the anticancer effects of BD on MDA-MB-231 cells, a human triple-negative breast cancer (TNBC) cell line. An MTT assay was performed to assess cell viability, whilst wound healing and Transwell assay were applied to measure cell migration and invasion, respectively. Western blot analysis was performed to assess the expression of E-cadherin, vimentin and β-catenin, which are proteins associated with epithelial-mesenchymal transformation (EMT), and PI3K, AKT and p-AKT, which are key components of the PI3K/AKT signaling pathway. BD was indicated to reduce cell viability in a dose- and time-dependent manner, whilst cell invasion and migration were also significantly inhibited in a dose-dependent manner. Western blot analysis demonstrated that BD treatment significantly upregulated the expression of E-cadherin and downregulated the expression of vimentin and β-catenin. Additionally, BD downregulated the expression of PI3K and reduced AKT phosphorylation. In conclusion, BD can inhibit MDA-MB-231 cell viability, migration and invasion, suggesting the potential use of BD for the treatment of TNBC.

Bruceine D (BD), a major quassinoid extracted from the Chinese medicinal herb Brucea javanica, has been demonstrated to exert anticancer effects on various tumor cells. However, the anti-metastatic effect of BD has not been reported. The present study was designed to investigate the anti-metastatic effect of BD on MDA-MB-231 cells. The effects of BD on cell viability, migration and invasion were examined by MTT assay, wound healing assay and transwell assay, respectively. The effect of BD on epithelial-mesenchymal transition (EMT)-associated proteins, including E-cadherin and vimentin was tested by Western blot. At the same time, we detected the expression of p-catenin, which is a key molecular target for promoting cell metastasis. The results showed that BD inhibited the viability of MDA-MB-231 cells in a dose and time-dependent manner, and it also reduced cell migration and invasion in a dose-dependent manner. Western blot showed that BD reversed EMT through suppressing vimentin but enhancing E-cadherin expression. Furthermore, BD obviously decreased the expression of beta-catenin in a dose-dependent manner. Taken together, all these results suggest that BD suppresses viability, metastasis and EMT of human breast cancer MDA-MB-231 cells.

Ailanthone, which is extracted from the traditional Chinese medicinal plant Ailanthus altissima, has been thoroughly demonstrated to have anti-tumor, anti-HIV, anti-inflammatory, anti-malarial, anti-allergic and anti-microbial activities. However, the anti-proliferative effects of ailanthone on HL-60 cells and potential mechanisms underlying those effects have not been reported. In the present study, we demonstrated the potent cytotoxicity of ailanthone against HL-60 cells. Annexin V-APC/7-ADD staining assay indicated that ailanthone increased the number of apoptotic cells in a dose-dependent manner. PI staining showed that ailanthone increased the percentage of G0/G1-phase cells in a dose-dependent manner. Acridine orange staining suggested that ailanthone induced the formation of acidic vesicular organelles in HL-60 cells and pretreatment with BaF-A1 could attenuate this process. Western blotting showed that ailanthone up-regulated the protein expression levels of beclin-1 and LC3-II and down-regulated those of LC3-I and p62 in a dose-dependent manner. Use of BaF-A1 showed that the anti-proliferative effects of ailanthone on HL-60 cells may be partly attributable to the induction of autophagy-mediated apoptosis by MTT assay and annexin V-APC/7-ADD staining assay.