Inflammatory bowel diseases (IBD) are a group of chronic gastrointestinal disorders with increasing incidence and prevalence that represent a major challenge for healthcare systems worldwide. Owing to their intricate and largely unknown etiologies, these patients are difficult to diagnose and treat. Intestinal barriers, including biological (gut microbes), chemical, and physical barriers, are crucial for maintaining normal intestinal function; thus, damage to intestinal barriers plays a role in the progression of intestinal inflammatory responses and hence in possible IBD. Intestinal epithelial cells (IECs), which contain mitochondria, play pivotal roles in intestinal barriers, which are indispensable for numerous functions, including energy production, signal transduction, cell-fate determination, epigenetic modifications, and inter-organelle crosstalk in cells. This review focuses on the current understanding of how mitochondria in IECs maintain and disturb intestinal-barrier homeostasis. We also discuss mitochondria-targeted therapeutics for IBD. These findings offer new insights into the etiological underpinnings of IBD, leading to the proposal of innovative therapeutic strategies. In the future, much remains to be done to understand the contribution of mitochondria in IECs to the functions of intestinal barriers.

BACKGROUND AND AIMS:Mono (2-ethylhexyl) phthalate (MEHP), the active metabolite of di-(2-ethylhexyl) phthalate (DEHP), is a widely used plasticizer in food packaging materials. While DEHP/MEHP has been linked to various health risks, the underlying mechanisms between DEHP/MEHP exposure and inflammatory bowel disease (IBD) remain poorly understood. This study aims to explore this relationship using a comprehensive approach integrating epidemiology, Mendelian randomization (MR), network toxicology, and animal experiments. METHODS:Using data from the National Health and Nutrition Examination Survey (NHANES), we first assessed the association between takeout frequency and MEHP exposure among 17,859 participants. MR analysis was employed to evaluate the relationship between MEHP exposure and IBD risk using large-scale genome-wide association studies (GWAS). To elucidate the molecular mechanisms, network toxicology was employed to identify key molecular targets and pathways. The roles of hub genes were validated in vitro cell line experiments and molecular docking based on public databases. Additionally, our study assessed the direct impact of DEHP/MEHP exposure on colitis phenotypes in mice. RESULTS:Our analysis demonstrated that individuals who consumed takeout more than 7 times per week exhibited significantly higher urinary MEHP levels (β = 2.06, 95 % CI: 1.06-3.06; p < 0.001). MR analysis indicated that MEHP exposure increased the risk of IBD (OR = 1.08, 95 % CI: 1.011-1.163; p = 0.024). Through network toxicology, we identified IL-1β, MMP9, and PPARG as central mediators of MEHP-induced intestinal barrier disruption and immune dysregulation, with their roles confirmed via public transcriptomic data and in vitro validation. Molecular docking further substantiated strong binding interactions between MEHP and these protein targets. Our experiments also confirmed that DEHP exposure had a detrimental impact on the colon of mice, resulting in weight loss, colon length reduction, inflammation increase, and histopathological changes. CONCLUSIONS:Collectively, our findings establish the correlation between dietary DEHP/MEHP exposure and IBD and reveal the potential mechanism of DEHP-induced colitis.

The emergence of antibiotic resistance represents a significant and growing threat to global public health. The development of novel and antibiotic-free antibacterial strategies is therefore highly importance. In this context, chemodynamic therapy (CDT), which is based on Fenton or Fenton-like chemistry, is a promising strategy. CDT utilizes Fe2+ to convert H2O2 into highly reactive hydroxyl radicals (center dot OH), which can oxidize biomolecules to achieve antibacterial effects. The antibacterial efficacy of CDT is contingent upon both the catalyst and substrate. We developed a straightforward, convenient and economical approach to fabricate Fe-caffeic acid metal-polyphenol networks (Fe-CA MPNs) by mixing CA and Fe3+. The Fe-CA MPNs are acid-sensitive and selfenhanced CDT agents with remarkable antibacterial efficacy against both Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA). Antibacterial efficacy was evaluated via a variety of methods, including the zone of inhibition, spread plate, turbidimetric, and live/dead bacterial staining tests. Specifically, the inhibition rates of Fe-CA MPNs for S. aureus and MRSA were 96.33 +/- 0.33 % and 96.33 +/- 0.15 %, respectively. CaO2@Fe-CA nanocomposites with H2O2 self-supply properties were synthesized by depositing Fe-CA MPNs on the surface of CaO2 nanoparticles which function as a sustained-release source of H2O2. The antibacterial effect of the CaO2@Fe-CA nanocomposites was comparable to that of Fe-CA MPNs combined with H2O2. Both Fe-CA MPNs and CaO2@Fe-CA possess favorable in vitro biosafety profiles. This work will facilitate the development of innovative antibiotic-free CDT antibacterial strategies based on center dot OH.

Metabolic reprogramming of cancer-associated fibroblasts (CAFs) plays an important role in colorectal cancer (CRC) progression. However, the mechanisms by which dysfunctional amino acid metabolism in CAFs contributes to cancer progression remain unclear. Here, we investigated amino acid metabolism in fibroblasts derived from human CRC tissues and the molecular interactions of this regulation with CRC progression. We revealed that amino acid metabolism, especially de novo glycine synthesis, was significantly activated in CAFs compared with normal fibroblasts in CRC tissues. Mechanistically, transforming growth factor beta 1 (TGF-beta 1) secreted by CRC cells was identified as a key factor that induced the activation of glycine synthesis and collagen production in CAFs. The inhibition of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo glycine synthesis, attenuated TGF-beta 1-induced collagen production in CAFs. Additionally, we found that collagen levels were significantly elevated in human CRC tissues. Collectively, these findings reveal a novel mechanism by which CRC cells enhance collagen production in CAFs through TGF-beta 1-induced de novo glycine synthesis. Our data not only highlight the pivotal role of de novo glycine synthesis in CRC progression but also provide a potential strategy for CRC treatment by targeting PHGDH.

Serine metabolism provides important metabolic intermediates that support the rapid proliferation of tumor cells. However, the role of serine metabolism in esophageal squamous cell carcinoma (ESCC) and the underlying mechanism remains unclear. Here, we show that serine starvation predominantly inhibits ESCC cell proliferation by suppressing purine nucleotides and NADPH synthesis. Mechanistically, serine depletion led to the accumulation of aminoimidazole carboxamide ribonucleoside (AICAR), an intermediate metabolite of de novo purine synthesis, and AMP/ATP ratio. These increases activated 5'-AMP-activated kinase (AMPK), which subsequently inhibited the mTORC1 pathway by phosphorylating Raptor at Ser792. Moreover, serine depletion decreased NADPH level followed by elevated reactive oxygen species (ROS) production and DNA damage, which induced p53-p21 mediated G1 phase cell cycle arrest. Conversely, serine starvation activated transcription factor 4 (ATF4)-mediated robust expression of phosphoserine aminotransferase 1 (PSAT1) which in turn promoted compensatory endogenous serine synthesis, thus maintaining ESCC cell survival under serine-limited conditions. Accordingly, serine deprivation combined with PSAT1 inhibition significantly suppressed ESCC tumor growth both in vitro and in vivo. Taken together, our findings demonstrate that serine starvation suppresses the proliferation of ESCC cells by disturbing the synthesis of purine nucleotides and NADPH, and the combination of serine deprivation and PSAT1 inhibition significantly impairs ESCC tumor growth. Our study provides a theoretical basis for targeting serine metabolism as a potential therapeutic strategy for ESCC.

Bestrophin isoform 4 ( BEST4 ) is a newly identified subtype of the calcium-activated chloride channel family. Analysis of colonic epithelial cell diversity by single-cell RNA-sequencing has revealed the existence of a cluster of BEST4 + mature colonocytes in humans. However, if the role of BEST4 is involved in regulating tumour progression remains largely unknown. In this study, we demonstrate that BEST4 overexpression attenuates cell proliferation, colony formation, and mobility in colorectal cancer (CRC) in vitro, and impedes the tumour growth and the liver metastasis in vivo. BEST4 is co-expressed with hairy/enhancer of split 4 ( HES4 ) in the nucleus of cells, and HES4 signals BEST4 by interacting with the upstream region of the BEST4 promoter. BEST4 is epistatic to HES4 and downregulates TWIST1, thereby inhibiting epithelial-to-mesenchymal transition (EMT) in CRC. Conversely, knockout of BEST4 using CRISPR/Cas9 in CRC cells revitalises tumour growth and induces EMT. Furthermore, the low level of the BEST4 mRNA is correlated with advanced and the worse prognosis, suggesting its potential role involving CRC progression.

Serine metabolism provides important metabolic intermediates that support rapid proliferation of tumor cells. However, the role of serine metabolism in esophageal squamous cell carcinoma (ESCC) and the underlying mechanisms remains unclear. Here, we show that serine starvation predominantly inhibits ESCC cell proliferation by suppressing purine nucleotide and NADPH synthesis, which inducing by inhibition of one-carbon metabolism. Mechanistically, aminoimidazole carboxamide ribonucleoside (AICAR), an intermediate metabolite for de novo synthesis of purine nucleotides, accumulated during serine starvation, activated 5’-AMP-activated kinase (AMPK), and then inhibited the mTORC1 pathway by directly phosphorylating Raptor at Ser792. Conversely, p53-p21 mediated G1 phase cell cycle arrest induced by DNA oxidative damage and Activating transcription factor 4 (ATF4)-mediated robust expression of phosphoserine aminotransferase 1 (PSAT1), which in turn promoted compensatory endogenous serine synthesis, which maintained cell survival in serine starvation. Accordingly, serine deprivation combined with PSAT1 inhibition significantly suppressed tumor growth in vitro and in vivo . Taken together, our findings demonstrate a novel mechanism by which serine supports the proliferation of ESCC via one-carbon metabolism to synthesize NADPH and purine nucleotide, which maintaining the mTORC1 activation. Our study provides a theoretical basis for targeting serine metabolism as a potential therapeutic strategy for ESCC.

Sunitinib based adjuvant chemotherapy combined with chloroquine (CQ) for the treatment of renal cell carcinoma (RCC) is in clinical trials; however, its anti-RCC effect and the mechanism remain unclear. In the present study, the anti-RCC effect of sunitinib with CQ and the underlying mechanism was investigated. An MTT assay demonstrated that CQ enhanced the proliferation inhibitory effect of sunitinib against the OS-RC-2 RCC cell line. CQ inhibited sunitinib-induced autophagy in OS-RC-2, which was evidenced by the inhibition of autophagic vacuoles, acidic vesicular organelle formation, light chain 3 (LC3)-II recruitment to the autophagosomes and the conversion of LC3-I to LC3-II, as induced by sunitinib. The inhibition of autophagy by CQ enhanced sunitinib-induced apoptosis, which was characterized by the activation of caspase-3, caspase-9, Bcl-2 and p53. Additionally, the exposure of OS-RC-2 cells to CQ and sunitinib resulted in the inhibition of AKT, tuberous sclerosis complex 2, mechanistic target of rapamycin and p70 ribosomal S6 kinase, which are associated with cell proliferation. In in vivo study, a combination of sunitinib with CQ in mice significantly reduced OS-RC-2 cell xenograft growth compared with the sunitinib alone group. In conclusion, the present study demonstrated that CQ may enhance the anti-RCC effect of sunitinib by inhibiting the autophagy induced by sunitinib, and enhance the rate of apoptosis. Inhibiting cell proliferation may also serve a role in the synergistic antitumor effect of sunitinib and CQ. These data suggest that combination therapy of sunitinib with CQ may be a promising strategy for adjuvant chemotherapy in RCC.

·AIM:To explore the predictive value of the combination of triglyceride-glucose(TyG)index,nesfatin-1,and retinol-binding protein 4(RBP4)for diabetic retinopathy,and provide evidence for early prediction of DR. ·METHODS:The clinical data of 164 patients with type 2 diabetes mellitus(T2DM)who admitted to the hospital between February 2022 and December 2023 were retrospectively collected.Based on the fundus examination results,these patients were divided into two groups:the DR group(n=43),including proliferative DR(PDR,n=19)and non-proliferative DR(NPDR,n=24),and the T2DM without DR group(n=121).The TyG index and the level of nesfatin-1 and RBP4 were measured after admission. ·RESULTS:T2DM patients with DR had a longer disease duration compared with T2DM patients without DR,and the DR group had higher fasting blood glucose,glycosylated hemoglobin,triglyceride,total cholesterol,low-density lipoprotein,TyG index,and RBP4 levels,while lower high-density lipoprotein and nesfatin-1 levels(all P＜0.001).Multivariate Logistic regression analysis indicated that the duration of T2DM(OR=1.338,95％CI:1.059-1.690),glycosylated hemoglobin(OR=5.065,95％CI:1.659-15.470),low density lipoprotein(OR=12.715,95％Cl:2.385-67.790),TyG index(OR=23.057,95％CI:2.936-181.073)and RBP4(OR=1.319,95％CI:1.028-1.692)were the independent risk factors for DR,while nesfatin-1(OR=0.007,95％Cl:0.003-0.016)was an independent protective factor for DR.The ROC curves were drawn,and the results indicated that the TyG index,nesfatin-1,and RBP4 had certain predictive values for DR patients with T2DM,with areas under curve(AUC)of 0.804,0.878 and 0.738,respectively.The combined AUC of the TyG index,nesfatin-1,and RBP4 was 0.946,sensitivity was 83.72％,and specificity was 92.56％.Patients with PDR had a higher TyG index,higher RBP4 level,and lower nesfatin-1 level than patients with NPDR(all P＜0.05).Spearman's correlations indicated a positive association between the TyG index,RBP4 and DR degree,and a negative association between nesfatin-1 and DR degree(rs=0.557,0.392,-0.359,repectively,all P＜0.05).Pearson correlation analysis indicated a negative correlation between the TyG index and the levels of nesfatin-1,a positive correlation between the TyG index and the levels of RBP4,and a negative correlation between the levels of nesfatin-1 and RBP4 in DR patients with T2DM(r=-0.486,0.538,-0.592,all P＜0.05). ·CONCLUSION:The serum of TyG index and the levels of nesfatin-1 and RBP4 were early predictive markers for DR and were associated with the risk of the occurrence and severity of the disease.Besides,the combined prediction performance of TyG index,nesfatin-1,and RBP4 was better for DR.

Alzheimer's disease (AD) is a complex neurodegenerative condition characterized by metabolic imbalances and neuroinflammation, posing a formidable challenge in medicine due to the lack of effective treatments. Despite considerable research efforts, a cure for AD remains elusive, with current therapies primarily focused on symptom management rather than addressing the disease's underlying causes. This study initially discerned, through Mendelian randomization analysis that elevating pantothenate levels significantly contributes to the prophylaxis of Alzheimer's disease. We explore the therapeutic potential of pantothenate encapsulated in liposomes (Pan@TRF@Liposome NPs), targeting the modulation of CRM1-mediated PKM2 nuclear translocation, a critical mechanism in AD pathology. Additionally, we investigate the synergistic effects of exercise, proposing a combined approach to AD treatment. Exercise-induced metabolic alterations share significant similarities with those associated with dementia, suggesting a potential complementary effect. The Pan@TRF@Liposome NPs exhibit notable biocompatibility, showing no liver or kidney toxicity in vivo, while demonstrating stability and effectiveness in modulating CRM1-mediated PKM2 nuclear translocation, thereby reducing neuroinflammation and neuronal apoptosis. The combined treatment of exercise and Pan@TRF@Liposome NP administration in an AD animal model leads to improved neurofunctional outcomes and cognitive performance. These findings highlight the nanoparticles' role as effective modulators of CRM1-mediated PKM2 nuclear translocation, with significant implications for mitigating neuroinflammation and neuronal apoptosis. Together with exercise, this dual-modality approach could offer new avenues for enhancing cognitive performance and neurofunctional outcomes in AD, marking a promising step forward in developing treatment strategies for this challenging disorder.

Lysine-specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cell-derived and patient-derived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damage-inducible gene 45beta (GADD45B) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B, a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, co-administration of ZY0511 and DTP3, which specifically enhanced the pro-apoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively active in ovarian cancer (OC) with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other DNA repair pathway members. We sought molecular targeted therapy that induce HRD in HR-proficient cells to induce synthetic lethality with PARPi and extend the utility of PARPi. Here, we demonstrate that lysine-specific demethylase 1 (LSD1) is an important regulator for OC. Importantly, genetic depletion or pharmacological inhibition of LSD1 induces HRD and sensitizes HR-proficient OC cells to PARPi in vitro and in multiple in vivo models. Mechanistically, LSD1 inhibition directly impairs transcription of BRCA1/2 and RAD51, three genes essential for HR, dependently of its canonical demethylase function. Collectively, our work indicates combination with LSD1 inhibitor could greatly expand the utility of PARPi to patients with HR-proficient tumor, warranting assessment in human clinical trials.

Colorectal cancer (CRC), a tumor of the digestive system, is characterized by high malignancy and poor prognosis. Currently, targeted therapy of CRC is far away from satisfying. The molecular mechanisms of regulated cell death (RCD) have been clearly elucidated, which can be intervened by drug or genetic modification. Numerous studies have provided substantial evidence linking these mechanisms to the progression and treatment of CRC. The RCD includes apoptosis, autophagy-dependent cell death (ADCD), ferroptosis, necroptosis, and pyroptosis, and immunogenic cell death, etc, which provide potential targets for anti-cancer treatment. For the last several years, small-molecule compounds targeting RCD have been a well concerned therapeutic strategy for CRC. This present review aims to describe the function of small-molecule compounds in the targeted therapy of CRC via targeting apoptosis, ADCD, ferroptosis, necroptosis, immunogenic dell death and pyroptosis, and their mechanisms. In addition, we prospect the application of newly discovered cuproptosis and disulfidptosis in CRC. Our review may provide references for the targeted therapy of CRC using small-molecule compounds targeting RCD, including the potential targets and candidate compounds.

Background Lung metastasis is a common metastasis site of colorectal cancer which largely reduces the quality of life and survival rates of patients. The discovery of potential novel diagnostic biomarkers is very meaningful for the early diagnosis of colorectal cancer with lung metastasis. Methods In the present study, the metabonomic profiling of serum samples of lung metastasis mice was analyzed by 1H-nuclear magnetic resonance (1H-NMR). Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to elucidate the distinguishing metabolites between different groups, and all achieved excellent separations, which indicated that metastatic mice could be differentiated from control mice based on the metabolic profiles at serum levels. Furthermore, during lung metastasis of colorectal cancer, metabolic phenotypes changed significantly, and some of metabolites were identified. Results Among these metabolites, approximately 15 were closely associated with the lung metastasis process. Pathway enrichment analysis results showed deregulation of metabolic pathways participating in the process of lung metastasis, such as synthesis and degradation of ketone bodies pathway, amino acid metabolism pathway and pyruvate metabolism pathway. Conclusion The present study demonstrated the metabolic disturbances of serum samples of mice during the lung metastasis process of colorectal cancer and provides potential diagnostic biomarkers for the disease.

Objectives Extensive application of anti-HER2 targeted therapy improves significantly the HER2-positive advanced breast cancer (BC) prognosis, however, it is still difficult to treat brain metastasis. In current study, we explored effective approaches via combining pyrotinib to treat brain metastasis in patients with HER2-positive advanced BC based upon clinical data.Materials and methods Current study included 61 HER2-positive BC patients with brain metastases (BM) who were treated by pyrotinib-based regimens. The systemic regimens included pyrotinib combined with capecitabine, pyrotinib combined with nab-paclitaxel, and pyrotinib combined with vinorelbine. Patients’ progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and objective response rate (ORR), as well as drug-related adverse events (AEs) in regard of each combination regimen were analyzed.Results Pyrotinib-based systemic therapy resulted in 8.6 months median PFS (mPFS) and 18.0 months median OS (mOS) among the BM patients. Regarding different regimens, the combination of pyrotinib with nab-paclitaxel was superior to the combination with capecitabine and vinorelbine with respect to PFS and OS. The central nervous system (CNS) ORR did not showcase significant difference among 3 regimens, however, nab-paclitaxel combined regimen obtained the best peripheral ORR (84.6%) (p ≤ .05).Conclusions Pyrotinib-based combination therapy is safe for HER2-positive brain metastasis treatment. Compared with vinorelbine or capecitabine, pyrotinib combined with nab-paclitaxel is more effective with less toxicity, which is the preferable regimen for HER2-positive brain metastasis.KEY MESSAGESPresent investigation investigated effective methods through combining pyrotinib to treat brain metastasis with HER2-positive advanced brain cancer. The outcomes verified that pyrotinib-based combination therapy was safe and efficient to treat HER2-positive brain metastasis. Therefore, it is effective to treat brain metastasis applying anti-HER2 targeted therapies although pyrotinib showcases efficiency regarding its treatments for the metastasis.

Lipid metabolic alterations are associated with cancer progression. Lysine-specific demethylase 1 (LSD1) plays a crucial role in cancer and has become a promising target for cancer therapy. However, the effect of LSD1 on lipid metabolism remains unclear. In the present study, we used a LC-MS/MS-based lipidomics approach to investigate the impact of LSD1 on cancer cell lipid metabolism using ZY0511, a specific LSD1 inhibitor developed by our group as a specific probe. ZY0511 profoundly modified the human colorectal and cervical cancer cell lipid metabolism. A total of 256 differential metabolites were identified in HeLa cells, and 218 differential metabolites were identified in HCT116 cells, respectively. Among these lipid metabolites, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and sphingomyelin (SM) were downregulated by ZY0511. In contrast, ceramide (Cer) and a small portion of glycerophospholipids such as phosphatidylinositol and phosphatidylethanolamine were upregulated by ZY0511. These results revealed a disturbance in sphingolipids (SPs) and glycerophospholipids, which may be correlated with the progression of cancer. Furthermore, a marked increase in Cer and prominent decrease in SM were consistent with the upregulated expression of key enzymes in the Cer synthesis process including de novo synthesis, hydrolysis of SM and the salvage pathway after ZY0511 exposure. In conclusion, our research reveals a link between LSD1 and lipid metabolism in cancer cells, offering more comprehensive evidence for the application of LSD1 inhibitors for cancer therapy. The underlying mechanisms of how the LSD1 inhibitor regulates lipid metabolism warrant further investigation.

A series of phthalide alkyl tertiary amine derivatives were designed, synthesized and evaluated as potential multi-target agents against Alzheimer's disease (AD). The results indicated that almost all the compounds displayed significant AChE inhibitory and selective activities. Besides, most of the derivatives exhibited increased self-induced Aβ1-42 aggregation inhibitory activity compared to the lead compound dl-NBP, and some compounds also exerted good antioxidant activity. Specifically, compound I-8 showed the highest inhibitory potency toward AChE (IC50 = 2.66 nM), which was significantly better than Donepezil (IC50 = 26.4 nM). Moreover, molecular docking studies revealed that compound I-8 could bind to both the catalytic active site and peripheral anionic site of AChE. Furthermore, compound I-8 displayed excellent BBB permeability in vitro. Importantly, the step-down passive avoidance test indicated that I-8 significantly reversed scopolamine-induced memory deficit in mice. Collectively, these results suggested that I-8 might be a potent and selective AChE inhibitor for further anti-AD drug development.

Background: Lysine-specific histone demethylase 1 (LSD1) is a potential target of cancer therapy. In the present study, we aimed to investigate the combined antitumor activity of a novel LSD1 inhibitor (ZY0511) with 5-fluorouracil (5-FU) and elucidate the underlying mechanism in colorectal cancer (CRC). Methods: We evaluated LSD1 expression in CRC tissues from patients who received 5-FU treatment. The synergistic antitumor effect of 5-FU with ZY0511 against human CRC cells was detected both in vitro and in vivo. The underlying mechanism was explored based on mRNA sequencing (mRNA-seq) technology. Results: Overexpression of LSD1 was observed in human CRC tissues, and correlated with CRC development and 5-FU resistance. ZY0511, a novel LSD1 inhibitor, effectively inhibited CRC cells proliferation, both in vitro and in vivo. Notably, the combination of ZY0511 and 5-FU synergistically reduced CRC cells viability and migration in vitro. It also suppressed Wnt/β-catenin signaling and DNA synthesis pathways, which finally induced apoptosis of CRC cells. In addition, the combination of ZY0511 with 5-FU significantly reduced CRC xenograft tumor growth, along with lung and liver metastases in vivo. Conclusions: Our findings identify LSD1 as a potential marker for 5-FU resistance in CRC. ZY0511 is a promising candidate for CRC therapy as it potentiates 5-FU anticancer effects, thereby providing a new combinatorial strategy for treating CRC.

A series of salicylamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu2+-induced A beta(1-42) aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward RatAChE and EeAChE with IC50 value of 10.4 mu M and 15.2 mu M, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu2+ -induced A beta(1-42) aggregation inhibitory potency (42.5% and 31.4% at 25.0 mu M, respectively) and moderate disaggregation ability to self- and Cu2+-induced A beta(1-42) aggregation fibrils (23.4% and 27.0% at 25 mu M, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment.

A series of novel tetrahydropyridine derivatives were prepared and evaluated using cell-based measurements. Systematic optimization of general structure G-1 led to the identification of compound 35 (EC50 = 4.9 nM) and 37 (EC50 = 8.8 nM) with high GPR119 agonism activity and moderate clog P. Through single and long-term pharmacodynamic experiments, we found that compound 35 showed a hypoglycemic effect and may have an effect on improving basal metabolic rate in DIO mice. Both in vitro and in vivo tests indicated that compound 35 was a potential potent GPR119 agonist in allusion to T2DM treatment.