Increasing the expression of ATP-binding cassette transporter A1 (ABCA1) can lower cellular cholesterol levels and prevent foam cell formation. In this study, a series of 5, 6-dihydro-8H-isoquinolino[1, 2-b]quinazolin-8-one derivatives were synthesised and assessed for their ability to up-regulate ABCA1 expression. The structure-activity relationship was explored and summarised. Among the 28 derivatives, compound 3 exhibited the most potent activity in activating the ABCA1 promoter (2.50-fold), significantly up-regulating both ABCA1 mRNA and protein levels in RAW264.7 macrophage cells. Mechanism studies revealed that compound 3 acted by targeting the LXR-involved pathway. In a foam cell model, compound 3 reduced ox-LDL-induced lipid accumulation and thereby inhibited foam cell formation. Moreover, compared to the LXR agonist T0901317, compound 3 led to minimal accumulation of unwanted lipids and triglycerides in HepG2 cells. With little cytotoxicity towards all the tested cell lines, compound 3 holds promise as a novel potential anti-atherogenic agent for further exploration.

The Hippo/YAP1 signaling pathway regulates normal development by controlling contact inhibition of growth. In cancer, YAP1 activation is often dysregulated, leading to excessive tumor growth and metastasis. SRC kinase can cross talk to Hippo signaling by disrupting adherens junctions, repressing the Hippo cascade, or activating YAP1 to promote proliferation. Here, we demonstrate that the IGF2 messenger RNA-binding protein 1 (IGF2BP1) impedes the repression of YAP1 by Hippo signaling in carcinomas. IGF2BP1 stabilizes the YAP1 messenger RNA (mRNA) and enhances YAP1 protein synthesis through an m6A-dependent interaction with the 3' untranslated region of the YAP1 mRNA, thereby increasing YAP1/TAZ-driven transcription to bypass contact inhibition of tumor cell growth. Inhibiting IGF2BP1-mRNA binding using BTYNB reduces YAP1 levels and transcriptional activity, leading to significant growth inhibition in carcinoma cells and ovarian cancer organoids. In contrast, SRC inhibition with Saracatinib fails to inhibit YAP1/TAZ-driven transcription and cell growth in general. This is particularly significant in de-differentiated, rather mesenchymal carcinoma-derived cells, which exhibit high IGF2BP1 and YAP1 expression, rendering them less reliant on SRC-directed growth stimulation. In such invasive carcinoma models, the combined inhibition of SRC, IGF2BP1, and YAP1/TAZ proved superior over monotherapies. These findings highlight the therapeutic potential of targeting IGF2BP1, a key regulator of oncogenic transcription networks.

Ferroptosis, an iron-dependent form of regulated cell death, is characterized by the lethal accumulation of lipid peroxides on cellular membranes. It not only inhibits tumor growth but also enhances immunotherapy responses and overcomes drug resistance in cancer therapy. The inhibition of the cystine-glutamate antiporter, system Xc-, induces ferroptosis. Imidazole ketone erastin (IKE), an inhibitor of the system Xc- functional subunit solute carrier family 7 member 11 (SLC7A11), is an effective and metabolically stable inducer of ferroptosis with potential in vivo applications. However, tumor cells exhibited differential sensitivity to IKE-induced ferroptosis. The intrinsic factors determining sensitivity to IKE-induced ferroptosis remain to be explored to improve its efficacy.

Biological sex is a fundamental determinant of physiological differences, including metabolic processes and disease susceptibility. β-carotene (BC), a provitamin A carotenoid, is known for its health benefits, but its sex-specific effects on its metabolism remain largely unexplored. This study investigated male and female BALB/c mice receiving BC or vehicle control via oral gavage for 11 weeks. Hepatic and circulating lipid levels, serum retinol, and the expression of BC cleavage enzymes (Bco1 and Bco2) and estrogen receptors (Esr1 and Esr2) in the liver and gonadal fat were analyzed. BC supplementation increased the hepatic Bco1 and Bco2 expression in males, accompanied by higher serum retinol, while downregulating expressions of these enzymes in male gonadal fat. Additionally, BC supplementation significantly reduced gonadal fat mass and adipogenic gene expression in males, with Cebpa and Esr1/Esr2 positively correlated, suggesting a role for estrogen receptor signaling in adipogenesis. These findings demonstrate that BC exerts sex- and tissue-specific effects on lipid metabolism, with strong regulatory interactions between BC metabolism, lipid homeostasis, and sex hormone signaling in males. The results provide novel insights into the mechanisms underlying sex-dependent differences in lipid metabolism following BC supplementation, with potential implications for metabolic health and disease prevention.

Aging represents a complex biological phenomenon marked by the progressive deterioration of physiological functions over time, reduced resilience, and increased vulnerability to age-related diseases, ultimately culminating in mortality. Recent research has uncovered diverse molecular mechanisms through which metformin extends its benefits beyond glycemic control, presenting it as a promising intervention against aging. This review delves into the anti-aging properties of metformin, highlighting its role in mitochondrial energy modulation, activation of the AMPK-mTOR signaling pathway, stimulation of autophagy, and mitigation of inflammation linked to cellular aging. Furthermore, we discuss its influence on epigenetic modifications that underpin genomic stability and cellular homeostasis. Metformin's potential in addressing age-associated disorders including metabolic, cardiovascular, and neurodegenerative diseases is also explored. The Targeting Aging with Metformin (TAME) trial aims to provide key evidence on its efficacy in delaying aging in humans. Despite these promising insights, significant challenges persist in gaining a more comprehensive understanding into its underlying mechanisms, determining optimal dosing strategies, and evaluating long-term safety in non-diabetic populations. Addressing these challenges is crucial to fully realizing metformin's potential as an anti-aging therapeutic.

Polyphenols have been shown to be utilized as an effective treatment for cancer by acting as a DNMT or HDAC inhibitor, reducing inflammatory processes, and causing cell cycle arrest. While there have been many studies demonstrating the anti-cancerous potential of individual polyphenols, there are limited studies on the combinatorial effects of polyphenols. This review focuses on how combinations of different polyphenols can be used as a chemotherapeutic treatment option for patients. Specifically, we examine the combinatorial effects of three commonly used polyphenols: curcumin, resveratrol, and epigallocatechin gallate. These combinations have been shown to induce apoptosis, prevent colony formation and migration, increase tumor suppression, reduce cell viability and angiogenesis, and create several epigenetic modifications. In addition, these anti-cancerous effects were synergistic and additive. Thus, these findings suggest that using different combinations of polyphenols at the appropriate concentrations can be used as a better and more efficacious treatment against cancer as compared to using polyphenols individually.

Mesoporous titanium dioxide nanoparticles (mTiNPs) are known for their chemical stability, non-toxicity, antimicrobial and anticancer effects, as well as for their photocatalytic properties. When this material is subjected to UV radiation, its electronic structure shifts, and during that process, reactive oxygen species are generated, which in turn exert apoptotic events on the cancer cells.

Dermatophytosis, a prevalent fungal infection of keratinized tissues, is primarily caused by the filamentous fungus Trichophyton rubrum. Sertraline (SRT), an antidepressant with antifungal activity, has already demonstrated therapeutic potential against this fungus. Elucidating the effects of SRT may provide insights into its mechanism of action and fungal adaptation to this drug. Differential gene expression and alternative splicing (AS) facilitate fungal adaptations to various environmental conditions. This study aimed to provide a comprehensive overview of AS events and their implications in T. rubrum cultivated under sub-inhibitory concentrations of SRT.

Glioblastoma is the most common malignant primary brain tumor, characterized by necrosis, uncontrolled proliferation, infiltration, angiogenesis, apoptosis resistance, and genomic instability. Epigenetic modifiers hold promise as adjuvant therapies for gliomas, with synergistic combinations being explored to enhance efficacy and reduce toxicity. This study aimed to evaluate the effects of single or combined treatments with various anticancer drugs (Carboplatin, Paclitaxel, Avastin), natural compounds (Quercetin), and epigenetic modulators (suberoylanilide hydroxamic acid and 5-Azacytidine) on the expression of some long noncoding RNAs and methylation drivers or some functional features in the U87-MG cell line.

Klotho, initially identified as an anti-aging gene, has been shown to play significant roles in cancer biology. Alongside α-Klotho, the β-Klotho and γ-Klotho isoforms have also been studied; these studies showed that Klotho functions as a potential tumor suppressor in many different cancers by inhibiting cancer cell proliferation, inducing apoptosis and modulating critical signaling pathways such as the Wnt/β-catenin and PI3K/Akt pathways. In cancers such as breast cancer, colorectal cancer, hepatocellular carcinoma, ovarian cancer, and renal cell carcinoma, reduced Klotho expression often correlates with a poor prognosis. In addition, Klotho's role in enhancing chemotherapy sensitivity and its epigenetic regulation further underscores its potential as a target for cancer treatments. This review details Klotho's multifaceted contributions to cancer suppression and its potential as a therapeutic target, enhancing the understanding of its significance in cancer treatment and prognoses.

Recently, immune checkpoint inhibitors (ICIs) and cabozantinib, a tyrosine kinase inhibitor (TKI), have been used to treat renal cell carcinoma (RCC); the combination of these agents has become a standard treatment for RCC. TKIs generally target vascular endothelial growth factor. However, cabozantinib is characterized by its targeting of MET. Therefore, cabozantinib can be used as a late-line therapy for TKI-resistant RCC. According to data from The Cancer Genome Atlas (TCGA), heat shock transcription factor 4 (HSF4) expression is higher in RCC tissues than in normal renal tissues. HSF4 binds to the MET promoter in colorectal carcinoma to enhance MET expression and promote tumor progression. However, the functional role of HSF4 in RCC is unclear. We performed loss-of-function assays of HSF4, and our results showed that HSF4 knockdown in RCC cells significantly decreased cell functions. Moreover, MET expression was decreased in HSF4-knockdown cells but elevated in sunitinib-resistant RCC cells. The combination of cabozantinib and HSF4 knockdown reduced cell proliferation in sunitinib-resistant cells more than each monotherapy alone. Furthermore, HSF4 knockdown combined with an ICI showed synergistic suppression of tumor growth in vivo. Overall, our strategy involving HSF4 knockdown may enhance the efficacy of existing therapies, such as cabozantinib and ICIs.

Ankrd2, a mechanoresponsive protein primarily studied in muscle physiology, is emerging as a player in cancer progression. This study investigates the functional role of Ankrd2 in osteosarcoma cells, revealing its critical involvement in cell proliferation and response to chemotherapeutic drugs. We showed that Ankrd2 knockdown impairs the activation of PI3K/Akt and ERK1/2 pathways, reduces levels of cell cycle regulators including cyclin D1 and cyclin B, and counteracts the expression of nuclear lamin A and lamin B, disrupting nuclear morphology and DNA integrity. Strikingly, the loss of Ankrd2 enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin, highlighting Ankrd2 potential as a therapeutic target to improve chemotherapeutic efficacy. Defining a novel mechanistic role for Ankrd2 in promoting tumor progression, we propose that Ankrd2 reduction could be exploited as an adjuvant strategy to enhance the efficacy of chemotherapy, offering new therapeutic opportunities for OS treatment.

Thyroid cancer is the most prevalent endocrine malignancy, and papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy. While PTC generally has a favorable prognosis, a subset dedifferentiates into aggressive forms. However, the molecular mechanisms responsible for aggressiveness and dedifferentiation are still poorly understood. We previously showed that HMGA2, a non-histone architectural transcription factor overexpressed in PTC, is involved in cell invasion. This study aimed to further analyze the role of HMGA2 in PTC tumorigenesis by exploring the expression of thyroid-specific and EMT-related genes following HMGA2 knockdown in thyroid cancer cell lines. Then, the clinical relevance of our data was evaluated in vivo. HMGA2 silencing did not modulate the expression of EMT related genes but led to the increased expression of thyroid differentiation genes. Our data also suggest that the MAPK pathway induces thyroid cell dedifferentiation through HMGA2. On the other hand, forskolin, promoting thyroid differentiation, decreased HMGA2 expression. The negative correlations between HMGA2 and thyroid-specific gene expressions were confirmed in a transgenic mouse model of PTC and in human PTC. Finally, we showed that HMGA2 inhibition by suramin reduced cell invasion and induced differentiation expression in vitro, indicating a new therapeutic strategy for treating thyroid cancer.

Endogenous melatonin (MEL) and abscisic acid (ABA) are involved in the adaptation of plants to environmental stresses. The application of exogenous serotonin (SER) to plants can enhance their tolerance to abiotic stress, such as cold. However, the mechanism associated with serotonin-mediated defense against cold-induced damage in mangroves is still poorly understood. In this study, we demonstrated that mangrove (Kandelia obovata) seedlings sprayed with 200 μmol·L-1 serotonin exhibited enhanced cold tolerance, as shown by reduced damage to leaves and loss of photosynthesis when exposed to low-temperature conditions. The mechanism associated with the cold adaptation of K. obovata seedlings upon treatment with serotonin was subsequently investigated by transcriptomic analysis. Serotonin treatment caused changes in differentially expressed genes (DEGs) involved in the regulation of melatonin (MEL) and ABA biosynthesis and defense responses against cold stress. Under low-temperature stress, serotonin-treated seedlings showed a significant increase in the endogenous levels of melatonin and ABA. By contrast, under normal growth conditions, K. obovata seedlings treated with serotonin displayed no substantial change in melatonin level, whereas ABA level significantly increased. These findings demonstrated that serotonin treatment might play an important role in the enhanced resistance to cold in K. obovata and that such an effect would depend on the activation of endogenous melatonin and ABA synthesis.

Globally, bladder cancer is the sixth most frequently diagnosed cancer among men. Despite the increasing availability of immunomodulatory treatments for bladder cancer, the survival rates are still low, which calls for potential new drug-repurposing targets. This study aimed to investigate the effects of cromolyn, a mast cell (MC) stabilizer in allergic reactions, on a subcutaneous tumor model with a syngeneic mouse MB49 bladder cancer cell line. A concentration of 50 mg/kg of cromolyn was daily administered intraperitoneally in a 4-day therapeutic protocol to mice with established tumors and in a continuous 11-day protocol which started one day prior to the subcutaneous injection of tumor cells. Therapeutic treatment demonstrated a marked downregulation of genes related to angiogenesis and upregulation of genes related to cytotoxic T-cell and NK cell activity. Conversely, continuous cromolyn treatment suppressed genes involved in immune cell recruitment and activation, as well as apoptotic and necroptotic pathways, leading to a greater tumor burden (+142.4 mg [95CI + 28.42, +256.4], p = 0.0158). The same pro-tumorigenic effect was found in mast cell-deficient mice (KitW-sh/W-sh + 301.7 mg [95CI + 87.99, 515.4], p = 0.0079; Cpa3Cre/+ +107.2 mg [95CI - 39.37, +253.57], p = 0.1423), indicating that continuous cromolyn treatment mostly acts through the inhibition of mast cell degranulation. In summary, our results demonstrate the distinct effects of cromolyn on tumor progression, which depend on the protocol of cromolyn administration.

Seed germination is a critical phase during which plants are particularly sensitive to environmental stresses, especially heat stress, due to the high metabolic and physiological activities required for initial growth. Melatonin (MT), a key antioxidant, is crucial for assisting plants in managing abiotic stresses. While the impact of melatonin on heat stress has been explored in other developmental stages or species, this is the first study to specifically focus on its role during maize seed germination under heat stress. The treatment with 50 μM melatonin significantly enhanced seed germination under heat stress by improving antioxidant capacity, osmotic regulation, and hydrolytic enzyme activity, likely through the modulation of key signaling pathways, thus reducing oxidative damage and starch content. Furthermore, melatonin application promoted the accumulation of endogenous gibberellins (GAs) and significantly inhibited abscisic acid (ABA) content, thereby maintaining a dynamic equilibrium between these phytohormones. Principal component analysis and correlation analysis provided deeper insights into the overall effects of these physiological and biochemical parameters. Integrated transcriptomic and metabolomic analysis revealed that melatonin exerted its regulatory effects by modulating key genes and pathways associated with antioxidant defense, stress responses, and plant hormone signal transduction. Furthermore, melatonin significantly modulated the GA and ABA signaling pathways, starch and sucrose metabolism, and phenylpropanoid biosynthesis, thereby reducing oxidative damage induced by heat stress and strengthening the defense mechanisms of maize seeds. The alignment between the qRT-PCR findings and transcriptomic data further validated the robustness of these underlying mechanisms. In conclusion, this study provides novel insights into the role of melatonin in enhancing maize seed germination under heat stress and offers a promising strategy for improving crop heat tolerance through melatonin application in agricultural practices.

Selenium (Se) is an essential micronutrient for the human body and is closely linked to health. Rice (Oryza sativa L.), as a major staple food globally, is the primary source of Se intake for humans. To better achieve Se biofortification in rice, it is crucial to understand the molecular mechanisms behind rice's response to different Se concentrations. This study investigates the morphological and transcriptomic responses of rice seedlings to low (1 µM, LSe) and high (10 µM, HSe) Se concentrations compared to a control (CK). Morphological analyses revealed that LSe promoted growth, enhancing shoot and root length and biomass, whereas HSe treatment inhibited these parameters, indicating Se's dual role in rice growth. Notably, the most significant promotion of rice growth was observed at the Se concentration of 1 µM. The organic Se content and antioxidant enzyme activities (SOD, POD and CAT) in rice seedlings also reached their maximum values simultaneously. Total RNA was extracted for transcriptome sequencing, and differential gene expression analysis was conducted using DESeq2. Transcriptomic sequencing highlighted distinct responses under LSe and HSe conditions. Gene ontology (GO) enrichment analysis revealed significant involvement in processes related to oxidoreductase activity and cellular structures. KEGG pathway analysis emphasized that Se treatments notably enhanced the glutathione metabolism pathway, which is crucial for antioxidant defense. Additionally, significant changes were observed in starch and sucrose metabolism and cysteine (Cys) and methionine (Met) metabolism pathways, showing upregulation under LSe treatment and downregulation under HSe. Six key genes were validated using qRT-PCR, confirming their differential expression under varied Se treatments. The Cys, Met and starch content assays as well as qRT-PCR data demonstrated that LSe promoted the synthesis and accumulation of Cys, Met and starch, supporting enhanced growth and antioxidant capacity. Conversely, HSe inhibited the synthesis and accumulation of Cys, Met and starch in rice seedlings, and these data were also consistent with the physiological phenotype. These findings provide insights into the molecular mechanisms by which rice seedlings adapt to varying Se levels, with implications for Se biofortification and stress management strategies in crops.

HER2 (human epidermal growth factor receptor 2) is overexpressed in approximately 15-20% of breast cancers, leading to aggressive tumour growth and poor prognosis. Anti-HER2 therapies, such as trastuzumab and pertuzumab, have significantly improved the outcomes for patients with HER2-positive breast cancer by blocking HER2 signalling. However, intrinsic and acquired resistance remains a major clinical challenge, limiting the long-term effectiveness of these therapies. Understanding the mechanisms of resistance is essential for developing strategies to overcome it and improve the therapeutic outcomes. We generated multiple HER2-positive breast cancer cell line models resistant to trastuzumab and pertuzumab combination therapy. Using mass spectrometry-based proteomics, we conducted a comprehensive analysis to identify the mechanisms underlying resistance. Proteomic analysis identified 618 differentially expressed proteins, with a core of 83 overexpressed and 118 downregulated proteins. Through a series of advanced bioinformatics analyses, we identified significant protein alterations and signalling pathways potentially responsible for the development of resistance, revealing key alterations in the protein metabolism, mitochondrial function, and signalling pathways, such as MAPK, TNF, and TGFβ. These findings identify mitochondrial activity and detoxification processes as pivotal mechanisms underlying the resistance to anti-HER2 therapy. Additionally, we identified key proteins, including ANXA1, SLC2A1, and PPIG, which contribute to the tumour progression and resistance phenotype. Our study suggests that targeting these pathways and proteins could form the basis of novel therapeutic strategies to overcome resistance in HER2-positive breast cancer.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with a poor prognosis and limited effective treatment options. This study investigates the therapeutic potential of Deferasirox (DFO), an iron chelator, in ESCC by targeting TAOK1, an STE20-type kinase implicated in cancer development. We demonstrate that DFO significantly inhibits the proliferation and colony formation of ESCC cells in a dose- and time-dependent manner. Mechanistic investigations reveal that DFO binds directly to TAOK1 and reduces its kinase activity. Proteomics and phosphorylated proteomic sequencing analysis further reveal that TAOK1 knocking down dramatically increased p53-mediated apoptosis. Moreover, the inhibition of TAOK1 by DFO or lenti-virus infection induces apoptosis in ESCC cells, as evidenced by the increased expression of p53, p-p53 (S15), p-p53 (S46), Puma, Noxa, and Bax, and the decreased expression of Bcl-2. Furthermore, in vivo studies using patient-derived xenograft (PDX) mouse models show that DFO treatment significantly reduces tumor volume without observable toxicity. Histological and immunohistochemical analyses confirm the down-regulation of TAOK1 and Ki-67, and the up-regulation of p53 expression in DFO-treated tumors. Our findings suggest that DFO exerts its antitumor effects in ESCC by targeting TAOK1, providing a potential therapeutic strategy for ESCC patients.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated remarkable efficacy in treating non-small cell lung cancer (NSCLC), but acquired resistance greatly reduces efficacy and poses a significant challenge to patients. While numerous studies have investigated the mechanisms underlying EGFR-TKI resistance, its complexity and diversity make the existing understanding still incomplete. Traditional approaches frequently struggle to adequately reveal the process of drug resistance development through mean value analysis at the overall cellular level. In recent years, the rapid development of single-cell RNA sequencing technology has introduced a transformative method for analyzing gene expression changes within tumor cells at a single-cell resolution. It not only deepens our understanding of the tumor microenvironment and cellular heterogeneity associated with EGFR-TKI resistance but also identifies potential biomarkers of resistance. In this review, we highlight the critical role of single-cell RNA sequencing in lung cancer research, with a particular focus on its application to exploring the mechanisms of EGFR-TKI-acquired resistance in NSCLC. We emphasize its potential for elucidating the complexity of drug resistance mechanism and its promise in informing more precise and personalized treatment strategies. Ultimately, this approach aims to advance NSCLC treatment toward a new era of precision medicine.