Ovarian cancer's complexity and heterogeneity pose significant challenges in treatment, often resulting in suboptimal chemotherapy outcomes. This study aimed to leverage machine learning algorithms, gene selection, and gene expression data to improve chemotherapy results.

To investigate whether airborne particle (PM2.5) aggravates Parkinson's disease (PD) and alter expression of key PD-related genes by DNA methylation. Two groups of rats were exposed to either clean air or polluted air for 3, 6, and 12 months. The neurotoxin rotenone was injected intraperitoneally to induce a Parkinson's-like disorder. Immunostaining was used to measure the number of dopaminergic neurons in substantia nigra (SN). Real-time PCR was used to measure mRNA levels of PD-related genes PINK1 and DJ-1 in SN. Bisulfate sequencing (BSP) was used to measure DNA methylation levels in gene promoters. In a cell-based mimic of animal experiments, SH-SY5Y cells were treated with Diesel exhaust PM2.5 (DEP) for 1.5, 6, and 24 h. RT-PCR and BSP methods were used to measure gene expression and methylation of CpG islands in the cells. Persistent exposure to PM2.5 significantly increased the loss of dopaminergic neurons in the SN. Prolonged PM2.5 exposure and DEP treatment significantly reduced the mRNA levels of PINK1 and DJ-1. Both PM2.5 and DEP significantly increased the methylation level of the CpG islands in both genes. PM2.5 induced loss of dopaminergic neurons and aggravated Parkinson's disease. PM2.5 induced dysregulation of DNA methylation, resulting in decreased expression of the PINK1 and DJ-1.

Renal fibrosis is a critical progression of chronic kidney disease, and epithelial-to-mesenchymal transition (EMT) and extracellular matrix(ECM) deposition are crucial pathologic change of renal fibrosis, which still lacks of effective treatment. In this study, it was found that cyanidin-3-O-glucoside (C3G) could inhibit EMT and ECM activated by unilateral ureteral obstruction (UUO) and transforming growth factor-β1 (TGF-β1) stimulation. Moreover, N-Myc downstream-regulated gene 2(NDRG2), which involved in the progression of renal fibrosis, was down-regulated in vivo and in vitro model. However, C3G pretreatment could reverse the reductive expression of NDRG2. Furthermore, we found that the combined treatment of C3G and si-NDRG2 could reverse the decreased EMT and ECM, which induced by C3G treatment only. And the activation of Phosphatidylinositol 3-kinase (PI3K)/ Protein Kinase B (AKT) pathway significantly enhanced EMT and ECM, which was decreased by C3G treatment only in TGF-β1 induced Human Kidney 2 (HK-2) cells. In conclusion, our results demonstrated that C3G alleviated EMT and ECM by elevating NDRG2 expression through the PI3K/AKT pathway, indicating that C3G could be a potential treatment against renal fibrosis.

The roles of γ-aminobutyric acid (GABA) and its receptors in lung cancer development and progression remain controversial. This study aimed to investigate the effects of activating GABA receptor type B (GABA-B receptor) using baclofen, a GABA-B receptor agonist, on the proliferation of lung adenocarcinoma cells and its underlying mechanisms.

Difenoconazole is a widely used agricultural fungicide that has been frequently detected in aquatic environments. Given its stable presence in aquatic environments, long-term exposure of wild fish may pose a risk to offspring embryonic development. This study demonstrated that exposure of zebrafish to environmental concentrations of difenoconazole throughout their life cycle resulted in abnormal development of offspring embryos/larvae, including decreased heart rate, delayed hatching, increased malformation rate, shortened body length, and increased mortality. These changes were significantly correlated with the affected apoptosis, autophagy, energy metabolism and MAPK signaling pathways in F1 generation. This transgenerational toxic effect results from epigenetic alterations in gametes, impaired nutrient supply from the ovum, and maternal transfer of difenoconazole. After exposure to difenoconazole, the development of female fish offspring was affected more than that of male fish offspring, which was mainly caused by the impaired nutrient supply from the ovum and the maternal transfer of difenoconazole. Because this transgenerational developmental toxicity was observed at environmental levels, difenoconazole may pose a threat to the survival of wild larvae and therefore a risk to wild fish populations.

This study elucidates the epigenetic mechanism through which 4-allylanisole, a key monoterpene in Foeniculum vulgare essential oils, regulates plant growth. Integrated RNA-Seq and ChIP-Seq analyses revealed 4-allylanisole enhances histone H3K9 acetylation (H3K9ac) at promoters of growth-related genes in Arabidopsis thaliana, concomitant with improved root development and biomass accumulation. Biochemical assays identified AtHDA9 histone deacetylase as the molecular target, showing 4-allylanisole directly inhibits its enzymatic activity through stable interactions with catalytic residues (Asp95, Phe202, Leu268, His174) confirmed by molecular docking and dynamics simulations. The suppressed deacetylation elevated endogenous indole-3-acetic acid (IAA) levels and amplified auxin signaling transduction. These findings establish a dual mechanism whereby 4-allylanisole epigenetically activates growth-related gene expression through H3K9ac accumulation while coordinately enhancing IAA biosynthesis and signaling. This work provides the first evidence of plant-derived volatile compounds regulating growth through histone modification-auxin crosstalk, proposing novel strategies for developing eco-friendly plant growth regulators.

Aberrant DNA methylation can lead to the onset of pathological phenotypes and is increasingly being implicated in age-related metabolic diseases. In our preceding study we show that the heterozygous ablation of Pcyt2, the rate limiting enzyme in phosphatidylethanolamine (PE) synthesis, causes an age-dependent development of non-alcoholic steatohepatitis (NASH), and that treatment with the Pcyt2 substrate phosphonoethylamine (PEA) can attenuate phenotypic NASH pathologies. Here, we hypothesize that abnormal DNA methylation patterns underly the development of Pcyt2 + /- NASH. In this study, we conduct an epigenome-wide methylation analysis to characterize the differential methylation of Pcyt2 + /- livers and investigate whether the attenuation of NASH with PEA treatment is associated with changes in DNA methylation.

Multiple myeloma (MM) is an incurable hematologic malignancy, driving significant interest in the discovery of novel therapeutic strategies. Bruceine A (BA), a tetracyclic triterpene quassinoid derived from Brucea javanica, has shown anticancer properties by modulating multiple intracellular signalling pathways and exhibiting various biological effects. However, the specific pharmacological mechanisms by which it combats MM remain unclear. In this study, we identified USP13 as a potential target of BA. We observed a significant increase in USP13 expression in patients with MM, which was strongly associated with a poorer prognosis. Furthermore, enhanced USP13 expression can stimulate MM cell proliferation both in vitro and in vivo. Mass spectrometry analysis, combined with co-immunoprecipitation and in vitro ubiquitination experiments, revealed PARP1 as a critical downstream target of USP13. USP13 can stabilize PARP1 protein through deubiquitination, promoting PARP1-mediated DNA damage repair (DDR) and facilitating MM progression. Notably, we utilized MM cell lines, an MM Patient-Derived Tumour Xenograft model, and a 5TMM3VT mouse model to determine the anticancer effects of BA on MM progression, revealing its potential to target USP13/PARP1 signalling and disrupt DDR in MM cells. In conclusion, these findings suggest that BA inhibiting USP13/PARP1-mediated DDR might be a promising therapeutic strategy for MM.

The Mojave rattlesnake venom shows significant geographical variability. The venom of Type A animals primarily contains β-neurotoxin referred to as Mojave Toxin (MTX), which makes bites from this snake particularly feared. We performed a genome-wide transcriptomic analysis of the neurocellular response to Mojave Type A rattlesnake venom using induced pluripotent stem cell-derived neural stem cells to unveil the molecular mechanisms underlying the damage caused by this snake's envenomation. Our results suggest that snake venom metalloproteases, although having a limited repertoire in Type A venom, facilitate venom spread by digesting the tissue's extracellular matrix. The MTX, which is composed of heterodimers of basic and acidic phospholipase-A2, co-opts the host arachidonic acid and Ca2+ second messenger mechanisms and triggers multiple signaling cascades, such as the activation of MAPKs and NF-κB-regulated proinflammatory genes; the neurotransmitter overload in excitatory synapses leading to a presynaptic blockade of nerve signals; and the upregulation of unfolded protein response (UPR) due to the depletion of Ca2+ from the endoplasmic reticulum. The upregulated UPR and the oxidative stress caused by reactive oxygen species generated in cytochromeP4501A1-mediated hydroxylation of arachidonic acid contribute to mitochondrial toxicity. The activation of UPR, mitochondrial toxicity, and oxidative stress synergistically contributed to apoptotic and ferroptotic cell death.

Head and neck cancer (HNC) is one of the most common types of cancer in the world, characterized by resistance to conventional therapies and an unfavorable prognosis due to the presence of tumor stem cells (TSCs). TSCs are cell subpopulations with high potential for invasion, migration, and metastasis, being responsible for the initiation and dissemination of cancer. This study aimed to evaluate the efficacy of treatments with cetuximab and paclitaxel, alone and in combination, in TSCs from oral cavity (SCC-28) and hypopharynx (FADU) cancer cell lines. In addition, the influence of the gene and protein expression of EGFR, NTRK2 (TRKB), KRAS, and HIF-1α on the response to treatments was investigated. TSCs were identified based on ALDH staining, and cell viability assays (MTS) indicated that both TSCs and non-TSCs showed resistance to cetuximab monotherapy, while paclitaxel, either alone or in combination with cetuximab, was more effective in reducing cell viability. Real-time PCR and Western blot analysis revealed increased expression of KRAS and HIF-1α in TSCs, suggesting their possible association with treatment resistance. The results of this study point to specific molecular factors that influence therapeutic responses in HNC, with an emphasis on the efficacy of drug combinations to overcome TSC resistance. The identification of these molecular mechanisms may provide guidelines for the development of more targeted and effective therapies against HNC, improving clinical management and patient prognoses.

Drought severely impacts the growth of cotton, and the application of plant biostimulants offers an effective approach to enhancing crop drought tolerance. γ-Poly-glutamic acid (γ-PGA) is a novel and environmentally friendly biostimulant, but its functions and mechanisms in responding to drought stress in cotton are still unclear.

Mycobacterium species show distinctive characteristics with significant medical implications. Mycobacteria, including Mycobacterium tuberculosis and non-tuberculous mycobacteria, can form biofilms that facilitate their survival in hostile environments and contribute to development of antibiotic resistance and responses by the host immune system. Mycobacterial biofilm development is a complex process involving multiple genetic determinants, notably mmpL genes, which regulate lipid transport and support cell wall integrity, and the groEL gene, which is essential for biofilm maturation. Sliding motility, a passive form of surface movement observed across various mycobacterial species, is closely associated with biofilm formation and colony morphology. The unique sliding motility and biofilm-forming capabilities of Mycobacterium spp. are pivotal for their pathogenicity and persistence in diverse environments. A comprehensive understanding of the regulatory mechanisms governing these processes is crucial for the development of novel therapeutic strategies against mycobacterial infections. This review provides a detailed examination of our current knowledge regarding mycobacterial biofilm formation and motility, with a focus on regulation of these processes, their impact on pathogenicity, and potential avenues for therapeutic intervention. To this end, the potential of natural and synthetic compounds, including nanomaterials, in combating mycobacterial biofilms and inhibiting sliding motility are discussed as well. These compounds offer new avenues for the treatment of drug-resistant mycobacterial infections.

This study assesses the antifungal efficacy of celery flavonoid-rich extract (CFRE) against cucumber powdery mildew, caused by Podosphaera fusca, in a controlled greenhouse setting. The application of CFRE at a concentration of 4 mg mL- 1 resulted in a remarkable 97% reduction in disease severity. High-performance liquid chromatographic (HPLC) analysis identified apigenin as the predominant flavonoid in CFRE. Furthermore, CFRE treatment induced a robust defense response in cucumber leaves, marked by elevated levels of flavonoids, phenolics, chlorophyll, and defense enzymes such as β-1,3-glucanase, chitinase, peroxidase, phenylalanine ammonia-lyase, and polyphenol oxidase. The study also observed upregulation in the expression of three investigated genes associated with β-1,3-glucanase, chitinase, and phenylalanine ammonia-lyase. Notably, a positive correlation was established between the activity of defense enzymes and their gene expression, as well as between defense enzymes and antioxidant compounds. These findings underscore the potential of CFRE as an environmentally benign alternative to chemical fungicides for managing P. fusca infections.

Hybrid molecules can be engineered to target tumors by merging drugs with the same or distinct mechanisms of action. The coexistence of multiple pharmacologically active entities within the cancer cell enhances the therapeutic efficacy of the hybrid molecule compared to single-target inhibitors. KRAS is considered the most common oncogenic gene in human cancers and is targeted by tumor suppressor miR-143. Therefore, an increase in miR-143 expression is a promising way to inhibit CRC cell growth. This research aims to develop a hybrid anticancer drug carrier by combining miR-143 and AS1411 aptamers through a hybridization strand (MAH) and loading doxorubicin (Dox), a chemotherapy drug. The uptake capability of MAH into the SW480 CRC cells was confirmed by detecting fluorescence intensity with a fluorescence microscope. After treatment of MAH in SW480 cells, the level of miR-143 was increased, but KRAS expression was decreased for both mRNA and protein. KRAS downstream target proteins, ERK and AKT, were downregulated as well. Furthermore, it was confirmed that DOX could be gradually released from MAH, with approximately 95% released over 72 h. Treating cells with Dox-MAH resulted in the inhibition of cell proliferation and induction of apoptosis. The protein expression of procaspase-3 and Bcl-2 was decreased, while Bax was increased, confirming that Dox-MAH triggered the cell apoptosis. The success of this research proposed a new strategy for a drug delivery system, which has multiple functions simultaneously; CRC cell-specificity, Dox carrier, and miR-143 delivery.

Cigarette smoke (CS) is a well-known source of several inflammatory, cytotoxic and genotoxic compounds that cause chronic lung diseases. The transient receptor potential ankyrin 1 (TRPA1), a smoking-responsive, non-selective cation channel, is expressed by both capsaicin-sensitive peptidergic sensory nerves and non-neuronal cells of the lung, but there are few and controversial data on its expression and function on macrophages. Here, we investigated TRPA1 mRNA and protein expression in mouse and human lung tissues and human 3D spheroids, with a particular focus on its expression and potential regulatory effects on pro- and anti-inflammatory macrophage functions in response to CS. TRPA1 was stably expressed in both human and mouse alveolar macrophages, being upregulated after CS exposure and its functional activity was demonstrated in mouse macrophage culture. Moreover, besides CS, the TRPA1 genotype itself affected the expression of M1- (Il-1β, Il-23) and M2-type (Il-10, Tgfβ) macrophage cytokines. Furthermore, CS extract increased TRPA1 mRNA in human lung spheroids showing more prominent expression in macrophage-containing 3D aggregates, while CS extract influenced an elevated TGFβ expression specifically in macrophage-containing spheroids. These results suggest the fine-tuning role of TRPA1 activation in CS-induced airway inflammation, particularly in macrophages, but further studies are needed to draw precise conclusions.

Cyclic diguanosine monophosphate is a ubiquitous second messenger that regulates diverse cellular processes. Rhodococcus ruber SD3 has potential for use in removing environmental pollutants such as phenol and toluene. In this study, Tsrp1 was found to be a novel cyclic diguanosine monophosphate effector in this strain. The interaction between Tsrp1 and c-di-GMP was verified by surface plasmon resonance, and the dissociation constant was 64 ± 6.84 μM. Moreover, in comparison with the wild-type strain, the recombinant R. ruber SD3 strain, which exhibited elevated levels tsrp1 gene expression, demonstrated enhanced growth in the presence of toluene and phenol. Both recombinant R. ruber SD3 and the wild-type strain completely degraded toluene (0.3 g/l, 0.6 g/l and 0.9 g/l) and phenol (0.6 g/l, 0.8 g/l and 1.0 g/l) in 72 h. Furthermore, differential expression of key genes encoding transcription factors was identified based on the transcriptomic comparison between the two strains. This study is the first to describe a novel cyclic diguanosine monophosphate effector and its role in the characteristics of R. ruber SD3, which will shed new light on the mechanisms underlying the organic solvent tolerance of R. ruber SD3.

MYC is a master regulatory transcription factor whose sustained dysregulation promotes the initiation and maintenance of numerous cancers. While MYC is a regarded as a potenial therapeutic target in cancer, its intrinsically disordered structure has proven to be a formidable barrier toward the development of highly effective small molecule inhibitors. We rationalized that proteolysis targeting chimeras (PROTACs), which might accomplish the targeted degradation of MYC, would achieve more potent cell killing in MYC-driven cancer cells than reversible inhibitors. PROTACs are bifunctional small molecules designed to produce a ternary complex between a target protein and an E3 ligase leading the target's ubiquitination and degradation by the 26S proteasome. We generated PROTAC MTP3 based on modifications of the previously reported MYC-targeting compound KJ-Pyr-9. We found that MTP3 depletes endogenous full-length MYC proteins and uniquely induces increasing levels of a functional, N-terminally truncated MYC species, tMYC. Furthermore, MTP3 perturbs cellular MYC levels in favor of a tMYC-dominated state whose gene regulatory landscape is not significantly altered compared to that of wild type MYC. Moreover, although it lacks ∼10 kDa of MYC's N-terminal transactivation domain, tMYC is sufficient to maintain an oncogenic proliferative state. Our results highlight the complexities of proximity-inducing compounds against highly regulated and conformationally dynamic protein targets such as MYC and indicate that PROTACs can induce alternative outcomes beyond target protein degradation.

Vitamin D3 (VD3) and its active form calcitriol (Ca) exhibit anti-neoplastic activity against several types of cancer, although the underlying mechanism is not fully understood. Herein, we tested the effects of VD3 and Ca on erythro-leukemogenesis and investigated the underlying mechanism. VD3 and Ca treatment strongly inhibited cancer progression in a mouse model of erythroleukemia induced by the Friend virus. In tissue culture, VD3 and Ca inhibited proliferation of leukemic cell lines. Growth inhibition was associated with induction of G1 phase cell cycle arrest and apoptosis. Transcription of the VD3 receptor, VDR, is strongly induced by Ca, but not VDR. However, leukemia growth suppression by both VD3 and Ca is shown to be independent of VDR. In leukemic cells, both VD3 and Ca induced genes associated with metabolic pathways. Both VD3 and Ca induce the cytosolic glutathione degradase CHAC1 through activation of the ER stress response pathway ATF3/ATF4/CHOP genes. Higher expression of CHAC1 also suppressed the oncogene NOTCH1. Accordingly, knockdown of CHAC1 antagonized the inhibitory effect of VD3 and Ca on leukemic growth leading to higher NOTCH1 expression. Conversely, overexpression of CHAC1 suppressed leukemia cell growth and inhibited the expression of NOTCH1. Additionally, glutathione antagonized leukemia cell suppression induced by VD3 and Ca, demonstrating that this vitamin inhibits the proliferation of leukemic cells via CHAC1. Taken together, our results demonstrated that VD3 and Ca can prolong the survival of leukemia mice and inhibit the proliferation of erythroleukemia cell HEL through CHAC1 or CHAC1-mediated NOTCH1 inhibition.

The focus on breast cancer treatment has shifted from the cytotoxic effects of single drugs on tumor cells to multidimensional multi‑pathway synergistic intervention strategies targeting the tumor microenvironment (TME). The activation of the Wnt signaling pathway in the TME of breast cancer cells serves a key regulatory role in tissue homeostasis and is a key driver of the carcinogenic process. Modulating the crosstalk between the Wnt pathway and TME of breast cancer is key for understanding the biological behavior of breast cancer and advancing the development of novel antitumor drugs. The present review aimed to summarize the complex mechanisms of the Wnt signaling pathway in the breast cancer TME, interactions between the Wnt signaling pathway and components of the breast cancer TME and breast cancer‑associated genes, as well as the interactions between the Wnt signaling pathway and other signaling cascades at the molecular level. Furthermore, the present review aimed to highlight the unique advantages of the Wnt signaling pathway in the macro‑regulation of the TME and the current therapeutic strategies targeting the Wnt signaling pathway, their potential clinical value and future research directions in breast cancer treatment.

To test if encapsulating hydrophobic flavonoids in nanoparticles could offer a new possibility in the therapeutics of non-small cell lung cancer (NSCLC), quercetin was encapsulated in Poly(lactic-co-glycolic acid) (PLGA) nanoparticles by the solvent displacement technique. The synthesized nanoparticles were then characterized by dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), and atomic force microscopy (AFM). The size of the nanoparticles with smooth surface topology was estimated at 110 nm. Treatment with nano-PLGA encapsulated quercetin (NPEQ) triggered the death of K-ras mutated NSCLC cells, A549 and H460, and showed 50% cell cytotoxicity in them at a dose of 406 and 347 ng/ml respectively. NPEQ was able to block uncontrolled cell proliferation by inducing concomitant destruction of BrdU activity and a lower incidence of cell migrations. Cell death was due to the induction of apoptosis rather than necrosis, as revealed by morphological alterations and phosphatidylserine externalization induced by NPEQ. NPEQ also caused the arrest of A549 and H460 cells at the sub-G1 stage. Through network analysis, AKT was identified as a key gene target of quercetin in NSCLC. Moreover, we found that NPEQ induced downregulation of Akt, which is usually hyperactive in NSCLC due to K-ras mutation. This indicates that NPEQ caused target-specific apoptotic and antiproliferative activity by targeting the downregulation of Akt. Further, when NPEQ was generated in the tumour-bearing mice model, it showed antitumor efficacy also modulating the Akt expression along with upregulation in cleaved caspase 3 activation. Besides this, histological alteration of tissue architecture and reduction in tumor volume was also found. This as a whole indicates the prospects and advantages of nanoparticulate quercetin delivery in therapeutic formulations against cancer.