Bipolaristeroid A, a 5,6-seco-9,10-seco-steroid with cytotoxic activity from the fungus Bipolaris maydis.

Eleven undescribed steroids, bipolaristeroids A-K, and one known compound, demethylincisterol A3, were isolated from the fungus Bipolaris maydis. Bipolaristeroid A is a 5,6-seco-9,10-seco-steroid with a rearranged B ring, in which the A and C rings are connected by an ester bond. Bipolaristeroid B is a rearranged 1(10 â†’ 6)-abeosteroid with an aromatic B ring. Their planar structures and absolute configuration were determined using NMR, HRESIMS, DP4+ analysis, ECD calculation, and single-crystal X-ray diffraction. Bipolaristeroid A shows excellent inhibitory effects against the cancer cell lines HepG2, A549, SW620, and C4-2B with IC50 values of 7.94, 5.11, 5.13, and 3.83 µM, respectively.

Liver Cancer Etiology: Old Issues and New Perspectives.

PURPOSE OF REVIEW: This review aims to synthesize the old issues and current understandings of the etiology of liver cancer, focusing on the diverse causative factors influenced by geographical, socioeconomic, and lifestyle variations across different regions. RECENT FINDINGS: We highlight significant geographic disparities in liver cancer risk factors. While hepatitis B and C viruses, aflatoxin exposure, and alcohol consumption remain globally established contributors; metabolic dysfunction-associated steatotic liver disease and metabolic syndromes are increasingly prominent in the West. Chronic HBV and aflatoxin continue to dominate as risk factors in Asia and Africa. Dietary factors, metabolic diseases like diabetes and obesity, genetic predispositions, environmental risk factors and lifestyle choices such as smoking and alcohol use play substantial roles in specific populations. Protective factors like coffee and tea consumption, along with aspirin use, vegetables and fruits have shown potential in reducing HCC risk, although findings vary by population and dietary habits. Liver cancer etiology is influenced by various factors that differ by region. Established risk factors include hepatitis B and C, aflatoxin, and alcohol. Emerging risks, such as metabolic dysfunction-associated steatotic liver disease, are more prevalent in Western countries, while aflatoxin and HBV remains significant in Asia and Africa. Diet, metabolic conditions like diabetes and obesity, genetic predispositions, and lifestyle choices also play crucial roles. Coffee, tea, aspirin, vegetables, and fruits may reduce HCC risk, but effectiveness varies. Future research should integrate epidemiology, genetics, and nutrition, with global cooperation and data sharing essential for effective cancer control strategies.

An improved YOLOv7 model based on Swin Transformer and Trident Pyramid Networks for accurate tomato detection.

Accurate fruit detection is crucial for automated fruit picking. However, real-world scenarios, influenced by complex environmental factors such as illumination variations, occlusion, and overlap, pose significant challenges to accurate fruit detection. These challenges subsequently impact the commercialization of fruit harvesting robots. A tomato detection model named YOLO-SwinTF, based on YOLOv7, is proposed to address these challenges. Integrating Swin Transformer (ST) blocks into the backbone network enables the model to capture global information by modeling long-range visual dependencies. Trident Pyramid Networks (TPN) are introduced to overcome the limitations of PANet's focus on communication-based processing. TPN incorporates multiple self-processing (SP) modules within existing top-down and bottom-up architectures, allowing feature maps to generate new findings for communication. In addition, Focaler-IoU is introduced to reconstruct the original intersection-over-union (IoU) loss to allow the loss function to adjust its focus based on the distribution of difficult and easy samples. The proposed model is evaluated on a tomato dataset, and the experimental results demonstrated that the proposed model's detection recall, precision, F1 score, and AP reach 96.27%, 96.17%, 96.22%, and 98.67%, respectively. These represent improvements of 1.64%, 0.92%, 1.28%, and 0.88% compared to the original YOLOv7 model. When compared to other state-of-the-art detection methods, this approach achieves superior performance in terms of accuracy while maintaining comparable detection speed. In addition, the proposed model exhibits strong robustness under various lighting and occlusion conditions, demonstrating its significant potential in tomato detection.

Chemical synthesis and application of aryldihydronaphthalene derivatives.

Aryldihydronaphthalenes (ADHNs) and their derivatives are widely found in many types of natural products, bioactive compounds, and functional materials, and are also important synthetic intermediates in organic chemistry, attracting widespread attention from both organic and pharmaceutical chemists. In the past two decades, the chemical synthesis and biological activity of ADHNs and their derivatives have become two hot spots. This review summarizes the synthetic protocols of ADHN derivatives, introduces some representative examples of the reaction mechanism, and focuses on the research progress of ADHNs in natural product chemistry and chemical biology since 2000.

Does sedentary time and physical activity predict chronic back pain and morphological brain changes? A UK biobank cohort study in 33,402 participants.

BACKGROUND: The relationship between sedentary time, physical activity, and chronic back pain remains unclear. The study aims to investigate whether sedentary time and physical activity predict chronic back pain and morphological brain changes. METHODS: This cohort study recruited adults aged 37-73 years enrolled between 2006 and 2010, with follow-up until 2014. The total cohort comprised 33,402 participants (mean age: 54.53). Data were collected on daily sedentary time, physical activity, lifestyle factors, and health outcomes. RESULTS: After nearly 8-year follow-up, 3,006 individuals (9.00%) reported chronic back pain in total. Individuals with daily sedentary time exceeding 6 h had a 33% higher risk of chronic back pain compared to those with sedentary time of 2 h or less (RR, 1.33, 95%CI, 1.17-1.52). Sedentary time was also associated with decreased grey matter volume in several brain regions, including bilateral primary somatosensory cortex (S1), secondary somatosensory cortex, putamen, primary motor cortex (M1), insula, hippocampus, amygdala, as well as right supplementary motor area, left medial frontal cortex, and right anterior cingulate cortex (FDR-corrected p-value < 0.05). Compared to individuals who sat for more than 6 h with light physical activity, those engaging in moderate physical activity with sedentary time of 2 h or less (RR, 0.71, 95%CI, 0.52-0.99) exhibited a significant decrease in chronic back pain risk. In addition, replacing sedentary time with equivalent amount of physical activity also demonstrated a reduction in the risk of chronic back pain (RR, 0.87, 95%CI, 0.77-0.99) and increased the reginal grey matter volumes including the amygdala, insula, M1, putamen and S1. CONCLUSIONS: Prolonged sedentary time is associated with heightened risks of chronic back pain and deterioration in brain health.

Prevalence and risk factors of low back pain in military personnel: a systematic review.

Purpose: Low back pain (LBP) has a significant impact on the general population, especially on military personnel. This study aimed to systematically review the relevant literature to determine the prevalence and risk factors of low back pain among military personnel from different military occupational categories. Methods: For this systematic review, we searched Embase, PubMed, and Cochrane. We performed study selection, data extraction, and assessed the quality of the evidence using the adapted risk of bias assessment tool by Hoy et al. This review process was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This study is registered on the Center for Open Science, registration DOI: 10.17605/OSF.IO/HRGE8. Results: Out of 860 papers, 19 studies met the inclusion criteria. More than 360 000 military people with lumbar pain situation were considered for inclusion in this systematic review. The 1-year prevalence of LBP could be up to 81.7% in the Army, 5.2% in the Marines, and 48.1% in the Air Force. Age (OR = 0.494-2.89), history of LBP (OR = 2.2-8.91), and sedentary position (OR = 0.55-3.63) were the most common physical, sociodemographic, and occupational risk factors, respectively. Conclusions: Low back pain was prevalent among military personnel. There was heterogeneity in studies and a significant difference in prevalence and incidence across various occupational categories. Physical, sociodemographic, and occupational risk factors were researched more than psychological risk factors in the military.

TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet's disease.

TNF inhibitors have been used to treat autoimmune and autoinflammatory diseases. Here we report an unexpected mechanism underlying the therapeutic effects of TNF inhibitors in Behçet's disease (BD), an autoimmune inflammatory disorder. Using serum metabolomics and peripheral immunocyte transcriptomics, we find that polymorphonuclear neutrophil (PMN) from patients with BD (BD-PMN) has dysregulated mevalonate pathway and subsequently increased farnesyl pyrophosphate (FPP) levels. Mechanistically, FPP induces TRPM2-calcium signaling for neutrophil extracellular trap (NET) and proinflammatory cytokine productions, leading to vascular endothelial inflammation and damage. TNF, but not IL-1ß, IL-6, IL-18, or IFN-γ, upregulates TRPM2 expression on BD-PMN, while TNF inhibitors have opposite effects. Results from mice with PMN-specific FPP synthetase or TRPM2 deficiency show reduced experimental vasculitis. Meanwhile, analyses of public datasets correlate increased TRPM2 expressions with the clinical benefits of TNF inhibitors. Our results thus implicate FPP-TRPM2-TNF/NETs feedback loops for inflammation aggravation, and novel insights for TNF inhibitor therapies on BD.

Border Trap-Enhanced Ga2O3 Nonvolatile Optoelectronic Memory.

Nonvolatile deep ultraviolet optoelectronic memory (DUVOEM) holds immense potential in cyberphysical systems, offering high storage density, swift conversion speeds, and robust data security. However, the current data retention time, typically limited to milliseconds or hours, mostly underperforms the expectations of years as a nonvolatile memory. In this work, we present a ß-Ga2O3/SiO2/Si thin-film transistor DUVOEM with an enhanced data storage capability via trapping and releasing of photogenerated holes in border traps. Specifically, the photogenerated holes in ß-Ga2O3 will tunnel through SiO2 and be captured by these defects. Innovatively, the much slower holes' release process from the border traps has been harnessed in developing outstanding nonvolatile optoelectronic memories. Rapid writing and erasing speeds, long-time retention (≥10 years), and high robustness demonstrate its practical application values. This study not only provides a novel strategy for nonvolatile DUVOEM but also provides an instance of functionalizing ß-Ga2O3 memory with common defects in Si technology.

Maydisens, Sesterterpenoids with Anti-MDR Activity from Bipolaris maydis.

Fourteen previously undescribed sesterterpenoids (1-14) were isolated from Bipolaris maydis. Their structures with absolute configurations were elucidated by NMR, HRESIMS, DP4+ calculations, ECD calculations, single-crystal X-ray diffraction analyses, and the modified Mosher's method. Compounds 1-5 possess an uncommon 5/11 bicyclic ring system identified from B. maydis for the first time. Compounds 6-14 have a 5/8/5 tricyclic ring system, and these compounds both possess carbonyl groups in ring A. Compound 10 showed significant reversal of paclitaxel resistance in cancer cells.

Engineering of in-plane SnS2-SnO2 nanosheets heterostructures for enhanced H2S sensing.

In-plane heterostructures has attracted considerable interest due to exceptional electron transport properties, high specific surface area, and abundant active sites. However, synthesis of in-plane SnS2-SnO2 heterostructures are rarely reported, and the deep investigation of the fine structure on reactivity is of great significance. Here, we propose partial in-situ oxidation strategy to construct the in-plane SnS2-SnO2 heterostructures and the surface properties, the ratio of two components can be finely tuned by precisely adjusting the treatment temperature. In particular, the SnS2-SnO2 heterostructures formed after annealing of SnS2 nanosheets at 350 °C exhibits a unique electronic structure and surface properties due to rich grain boundaries, which exhibits excellent gas sensing performance to H2S (Ra/Rg = 169.81 for 5 ppm H2S at 160 °C, fast response and recovery dynamic (41/101 s), excellent reliability (σ = 0.01) and sensing stability (φ = 0.11 %)). Notably, the in-plane heterostructures endow the material with abundant grain boundaries and effectively regulates the electronic structure of the Sn p-orbital, which facilitate the formation of active oxygen species (O-(ad)), thus contributing to the sensing performance. Our work provides a promising platform to design in-plane heterostructures for various advanced applications.

Y9, a Gboxin analog, displays anti-tumor effect in non-small cell lung cancer by inducing lysosomal dysfunction and apoptosis.

Non-small cell lung cancer (NSCLC) ranks among the most prevalent malignancies globally. Gboxin, a novel inhibitor of mitochondrial complex V that exerts unique anti-tumor effects via oxidative phosphorylation inhibition, but shows no efficacy against NSCLC in vivo. Through chemical structure optimization, we designed and synthesized Gboxin analog Y9, which demonstrates significantly enhanced potency over its predecessor. Specifically, Y9 inhibited NSCLC significantly more strongly than Gboxin and possessed the ability to inhibit cell cycle progression and induce oxidative stress similar to Gboxin. Further investigation revealed that unlike Gboxin, Y9 selectively acidifies lysosomes and induces lysosomal dysfunction. This leads to hyperactive autophagy with impaired substrate clearance, and ultimately resulting in apoptosis. Animal studies confirmed the efficacy of Y9 in suppressing tumor growth in a xenograft mouse model. Collectively, Y9 is a distinctive Gboxin analog that outperforms its prototype by inducing lysosomal dysfunction and apoptosis, and has the potential to be developed as a novel anti-NSCLC lead compound.

Unprecedented nor-seco-diterpene lactones inhibited osteogenic differentiation of valve interstitial cells.

The first examples of ent-atisane and ent-isopimarane diterpene lactones with an unusual 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one nucleus, eufislactones A (1) and B (2), were isolated from the roots of Euphorbia fischeriana, together with a new (3) and fifteen known biosynthetic congeners (4-18). Their structures incorporating absolute configurations were elucidated via the comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculation, and single-crystal X-ray diffraction analyses. Biogenetically, compounds 1 and 2 were constructed by the plausible monomeric precursors, ent-atis-16-ene-3,14-dione (6) and ent-isopimara-8(14),15-dien-3-one (17), respectively, via key Baeyer-Villiger oxidation, decarboxylation, and semi-acetalization reactions to create a unique 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one core. Our bioassays have revealed that eufislactone A (EFA, 1) displayed significant inhibitory effect on the osteogenic differentiation of human valvular interstitial cells (VICs), highlighting its potential as a preventive agent against the progression of human calcific aortic valve disease (CAVD).

Naringin alleviates gefitinib-induced hepatotoxicity through anti-oxidation, inhibition of apoptosis, and autophagy.

Objectives: Gefitinib (GEF) is a targeted medicine used to treat locally advanced or metastatic non-small cell lung cancer (NSCLC). However, GEF's hepatotoxicity limits its clinical use. This study aims to investigate the protective effect of naringin (NG) against GEF-induced hepatotoxicity. Materials and Methods: Fifty female ICR mice were randomly divided into 5 groups: Control, GEF (200 mg/kg), NG (50 mg/kg) + GEF (200 mg/kg), NG (100 mg/kg) +GEF (200 mg/kg), NG (200 mg/kg) +GEF (200 mg/kg). After 4 weeks of continuous administration, the mice were euthanized. The blood and liver tissue samples were collected. Results: The results indicated that the GEF group showed increased liver index, liver enzyme activities, and decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities. Some hepatocytes showed hydropic degeneration and focal necrosis. Cell apoptosis, Cleaved-caspase3, and Poly (ADP-ribose) polymerase 1 (PARP1) increased. Transmission electron microscopy revealed the presence of numerous autophagic lysosomes or autophagosomes around the cell nucleus. Compared to the GEF group, NG can reverse these changes. Conclusion: In summary, NG alleviates GEF-induced hepatotoxicity by anti-oxidation, inhibiting cell apoptosis, and autophagy. Therefore, this study suggests the use of NG to mitigate GEF's toxicity to the liver.

Strong associations between fasting lipids and glucose concentrations and ALT levels strengthened with increasing ALT quantiles.

BACKGROUND: A persistent redox state and excessive reactive species involved in carbohydrate and lipid metabolism lead to oxidative damage in the liver, however, how fasting plasma concentrations of lipids and glucose are associated with fasting blood levels of alanine transaminase (ALT) and aspartate transaminase (AST) remains to be evaluated in large-scale population. METHODS: A cross-sectional study with 182,971 residents aged 18 to 92 years; multidimensional stratified analyses including quantile linear regression analysis and sex stratification were adopted to improve the quality of the evidence. RESULTS: The associations between the concentrations of non-HDL-C and triglyceride and ALT levels were positive, stronger in males in each quantile of ALT levels and the coefficients expanded with increasing ALT levels at slopes of 3.610 and 5.678 in males and 2.977 and 5.165 in females, respectively. The associations between the HDL-C concentrations and ALT levels were negative, also stronger in males in each quantile and the coefficients expanded with increasing ALT levels at slopes of -7.839 in females and - 5.797 in males. The associations between glucose concentrations and ALT levels were positive, but stronger in females in each quantile and the coefficients expanded with increasing ALT levels at slopes of 1.736 in males and 2.177 in females, respectively. Similar pattern consist of relatively weaker coefficients and slops were observed between concentrations of non-HDL-C, triglyceride and glucose and AST levels. The associations between albumin concentration and concentrations of blood lipids and glucose were relatively steady across all quantiles. CONCLUSIONS: The dose dependent effect between blood concentrations of lipids and glucose and liver function changes suggests that excessive carbohydrate and lipid metabolism may cause subclinical liver damage. Long term sustained primary and secondary inflammatory factors produced in the liver might be transmitted to adjacent organs, such as the heart, kidneys, and lungs, to cause and/or exacerbate pathological changes in these visceral organs.

Michael Acceptor Pyrrolidone Derivatives and Their Activity against Diffuse Large B-cell Lymphoma.

OBJECTIVE: This study aimed to design and evaluate the efficacy of pyrrolidone derivatives as potential therapeutic agents against diffuse large B-cell lymphoma (DLBCL), a common and heterogeneous malignancy of the adult lymphohematopoietic system. Given the limitations of current therapies, there is a pressing need to develop new and effective drugs for DLBCL treatment. METHODS: A series of pyrrolidone derivatives were synthesized, and their antitumor activities were assessed, particularly against DLBCL cell lines. Structure-activity relationship (SAR) analysis was conducted to identify key structural components essential for activity. The most promising compound, referred to as compound 7, was selected for further mechanistic studies. The expression levels of relevant mRNA and protein were detected by RT-qPCR and Western blotting, and the expression of mitochondrial membrane potential and ROS was detected using flow cytometry for further assessment of cell cycle arrest and apoptosis. RESULTS: The compound 7 exhibited good antitumor activity among the synthesized derivatives, specifically in DLBCL cell lines. SAR analysis highlighted the critical role of α, ß-unsaturated ketones in the antitumor efficacy of these compounds. Mechanistically, compound 7 was found to induce significant DNA damage, trigger an inflammatory response, cause mitochondrial dysfunction, and disrupt cell cycle progression, ultimately leading to apoptosis of DLBCL cells. CONCLUSION: The compound 7 has good antitumor activity and can induce multiple cellular mechanisms leading to cancer cell death. These findings warrant further investigation of the compound 7 as a potential therapeutic agent for DLBCL.

Prevalence and related factors for neck pain in military personnel: a systematic review.

Purpose: In the military, neck pain is second to low back pain among musculoskeletal disorders. However, the prevalence and related factors of neck pain in military personnel have not been systematically investigated, which may lead to the lack of neck pain prevention and the generation of additional medical expenses, posing challenges to medical care. This review aimed to obtain the prevalence and related factors for neck pain in military personnel in an attempt to provide directions for prevention and intervention. Methods: We searched PubMed, Embase, and Cochrane databases in December 2021. Two researchers independently screened studies according to eligibility criteria and assessed study quality. Results: We screened titles and abstracts of 503 articles, and 17 articles met the inclusion criteria. Sixteen articles received moderate to high-quality evaluations. Neck pain is common in the military, with 1-year prevalence as high as 83% and lifetime prevalence as high as 78%. Old age (OR = 5.0), poor neck mobility (OR = 3.61), shoulder pain (OR = 4.9), low back pain (OR = 2.3), high-G pilots (OR = 1.6), longer flight time (OR = 2.53), type of aircraft (OR = 3.93), and use of helmets and night vision systems (OR = 1.9) may be associated with the prevalence of neck pain. Conclusion: Neck pain is highly prevalent in military personnel and exhibits a substantial lifetime prevalence rate. The high prevalence rate of neck pain in the military is related to many individual-related factors and work-related factors. The in-depth assessment and prevention of specific factors is an important direction of future research.

Quantifying Bevacizumab Efficacy in Recurrent Respiratory Papillomatosis.

OBJECTIVES: To develop and validate a novel method for quantifying the efficacy of Bevacizumab (Bev) in treating Recurrent Respiratory Papillomatosis (RRP), and to evaluate the clinical outcomes of a three-dose Bev induction therapy followed by surgical intervention. METHODS: Twenty-one RRP patients treated with a three-dose Bev regimen were included. A novel efficacy evaluation method using ImageJ software was developed to calculate the standardized lesion volume from laryngoscopic images. This was compared with the Derkay score. Clinical outcomes, including reduction rate, cumulative reduction rate, efficacy grading, recurrence, and adverse reactions, were analyzed. RESULTS: In the study cohort, the reduction rate was significantly higher after the first treatment compared with subsequent treatments. The overall response rate increased from 75% after the first treatment to 100% after the third. Among patients with localized lesions who underwent surgery, 76% experienced recurrence with a mean recurrence time of 114.23 days. Most recurrent lesions were smaller than at baseline. Adverse reactions included increased blood pressure in seven patients, which resolved without intervention. The new method showed a significant positive correlation with the Derkay score. CONCLUSION: In conclusion, based on the above findings, systemic Bev treatment for RRP is a safe and effective therapeutic approach, though further research is needed. Moreover, the new efficacy evaluation method we developed can significantly aid in studying the effectiveness of Bev treatment for RRP. LEVEL OF EVIDENCE: 2 Laryngoscope, 2024.

Enhanced light extraction efficiency for the inclined-sidewall-shaped AlGaN-based DUV LED by using an omni-directional reflector with a thin hybrid dielectric layer.

In this Letter, an omni-directional reflector (ODR) with a thin hybrid dielectric layer (hybrid-ODR) is proposed to enhance the light extraction efficiency (LEE) for inclined-sidewall-shaped AlGaN-based deep ultraviolet light-emitting diode (DUV LED) by inserting a thin diamond with high refraction index into a conventional Al/Al2O3-based ODR. The three-dimensional finite-difference time-domain (3D FDTD) simulation results show that the LEE of TM-polarized light for the DUV LED with hybrid-ODR is enhanced by 18.5% compared with Al/Al2O3-based ODR. It is because the diamond can transform the evanescent wave in Al2O3 into the propagating light wave in diamond, thereby preventing effective excitation of the surface plasmon polariton (SPP) on the surface of the metal Al. Moreover, the Brewster's angle effect causes the TM-polarized light in diamond to propagate effectively into AlGaN. Furthermore, decreasing the total thickness of the dielectric layer also improves the scattering effect of the inclined sidewall. However, the utilization of hybrid-ODR results in a slight reduction in the LEE for transverse electric (TE) polarized light because the light is confined to the diamond layer and eventually absorbed by the metal Al.

Oxygen Vacancy Enabled Electronic Structure Engineering of Pt-WO3 Nanosheets toward Highly Efficient BTEX Sensing.

A Pt nanoparticle-immobilized WO3 material is a promising candidate for catalytic reactions, and the surface and electronic structure can strongly affect the performance. However, the effect of the intrinsic oxygen vacancy of WO3 on the d-band structure of Pt and the synergistic effect of Pt and the WO3 matrix on reaction performance are still ambiguous, which greatly hinders the design of advanced materials. Herein, Pt-decorated WO3 nanosheets with different electronic metal-support interactions are successfully prepared by finely tuning the oxygen vacancy structure of WO3 nanosheets. Notably, Pt-modified WO3 nanosheets annealed at 400 °C exhibit excellent benzene series (BTEX) sensing performance (S = 377.33, 365.21, 348.45, and 319.23 for 50 ppm ethylbenzene, benzene, toluene, and xylene, respectively, at 140 °C), fast response and recovery dynamics (10/7 s), excellent reliability (σ = 0.14), and sensing stability (φ = 0.08%). Detailed structural characterization and DFT results reveal that interfacial Ptδ+-Ov-W5+ sites are recognized as the active sites, and the oxygen vacancies of the WO3 matrix can significantly affect the d-band structure of Pt nanoparticles. Notably, Pt/WO3-400 with improved surface oxygen mobility and medium electronic metal-support interaction facilitates the activation and desorption of BTEX, which contributes to the highly efficient BTEX sensing performance. Our work provides a new insight for the design of high-performance surface reaction materials for advanced applications.

Discovery of Cytotoxic Nitric Oxide-Releasing Piperlongumine Derivatives Targeting Wnt/ß-Catenin in Colon Cancer Cells.

Piperlongumine (1) increases reactive oxygen species (ROS) levels and induces apoptosis in cancer cells through various pathways. Nitric oxide (NO) donors have demonstrated potent anticancer activities with exogenous NO being oxidized by ROS in the tumor microenvironment to form highly reactive N-oxides (RNOS). This amplifies oxidative stress cascade reactions, ultimately inducing cancer cell apoptosis. To exploit this synergy, a series of NO-releasing piperlongumine derivatives (2-5) were designed and synthesized. These compounds were expected to release NO in cancer cells, simultaneously generating piperlongumine derivative fragments to enhance the anticancer effects. Compound 6, structurally similar to compounds 2-5 but not releasing NO, served as a control. Among these derivatives, compound 5 exhibited the most potent antiproliferative activity against HCT-116 cells and efficiently released NO in this cell line. Further investigation revealed that compound 5 inhibited colon cancer cell proliferation by modulating ß-catenin expression, which is a pivotal protein in the Wnt/ß-catenin signaling pathway. These findings highlight compound 5 as a promising candidate for colon cancer treatment targeting the Wnt/ß-catenin pathway.