Insect development is primarily controlled by juvenile hormone (JH) and 20-hydroxyecdysone (20E), which regulate gene cascades leading to changes in phenotype, physiology, and behavior. Besides these hormones, microRNAs play a crucial role in insect development by regulating gene expression at the post-transcriptional level. To advance the molecular understanding of holometabolous developmental events, we investigate the pupal phase in the honeybee, Apis mellifera. In this study, we assessed the expression profiles of genes components of JH and 20E cascades - Usp, ftz-f1, EcR, Met, Chd64, InR-2, Kr-h1 and Tai - as well as the microRNAs miRNA-34 and miRNA-281 during pupal development of A. mellifera. We then analyzed the impact of JH and 20E treatments on the expression of these developmental genes and their putative regulators, the microRNAs. Overall, the selected genes and miRNAs remained stable or were downregulated following 20E treatment, while treatments with JH, upregulated most of our candidate developmental genes and microRNAs. Notably, the expression profile of Met, an intracellular receptor of JH, showed a strong correlation with fluctuations in 20E titers during pupal development. Furthermore, a computational analysis, followed by experimental assays, points to both miR-34 and miR-281 as potential regulators of pupal development in A. mellifera. This study paves the way for a better understanding of how JH and 20E hormones interact with developmental genes and microRNAs (miR-34 and miR-281) to regulate pupal development in honeybees, elucidating a piece of this complex network of interactions.

Cisplatin (CDDP) based chemotherapy has emerged as the predominant therapeutic regimen for patients with advanced gastric cancer (GC). However, its efficacy is dampened by the development of chemoresistance, which results in poor prognosis of patients. GLI2, a key transcription factor in the Hedgehog (Hh) signaling pathway, is regarded as a target for cancer therapy. However, the significance of GLI2 for CDDP resistance in GC has not been well established. Here, we show that GLI2 expression was upregulated in EMT-type GC and associated with poor prognosis. GLI2 promotes proliferation, migration, and CDDP resistance of GC cells by inducing EMT. In terms of mechanism, GLI2 binds to the promoter region of DEC1 and enhances its expression, thereby co-transcriptionally regulating ZEB1 expression. Animal experiments have demonstrated that both GLI2 knockdown and GLI2 inhibitor significantly enhance CDDP sensitivity in GC. Our data not only identify a novel GLI2/DEC1/ZEB1/EMT pathway in GC CDDP resistance but also provide novel strategies to treat GC in the future.

Cervical cancer (CC) remains a major health challenge with high mortality rates due to chemoresistance and immune escape. However, the underlying mechanisms remain unclear. We investigated the role of TAB2 in CC using cisplatin-resistant and parental cell lines. Cell proliferation, migration, sphere formation and T cell-mediated killing assays were performed. Western blot and qRT-PCR analysed protein and mRNA expression. NF-κB pathway involvement was examined using the BAY 11-7082 inhibitor. TAB2 expression was significantly elevated in cisplatin-resistant CC cells. TAB2 overexpression promoted chemoresistance and immune escape through NF-κB pathway activation. Conversely, TAB2 knockdown or NF-κB inhibition sensitised resistant cells to cisplatin and enhanced T cell-mediated killing. The resistant phenotype could be rescued by restoring PD-L1 expression. Our findings reveal TAB2 as a critical regulator of both chemoresistance and immune escape in CC through NF-κB pathway activation. This suggests TAB2 as a potential therapeutic target for overcoming treatment resistance in CC.

Breast cancer (BC) is one of the most common types of cancer and is caused by the complex interplay of genetic and environmental factors, such as an unhealthy lifestyle, family history of illness, reproductive factors, and ageing. However, increasing evidence has revealed that manufactured organic pollutants such as bisphenols are closely related to BC. Bisphenols exposure can promote the progression of BC through multiple complicated and variable molecular mechanisms. Reanalysis of existing data on this topic may reveal molecular markers with clinical value. In this study, we identified four key genes [keratin 14 (KRT14), keratin 5 (KRT5), acyl-CoA synthetase long chain family member 1 (ACSL1) and matrix metallopeptidase 1 (MMP1)] related to both bisphenols exposure and BC by employing the Comparative Toxicogenomics Database (CTD) and The Cancer Genome Atlas Cervical Cancer (TCGA-CESC) dataset; notably, KRT14 expression exhibited the most significant difference between tumour and normal tissues. Further analysis of the functions and biological processes associated with KRT14 and related regulatory molecules revealed that bisphenols exposure induces BC-promoting characteristics and aggressive behaviour-related signaling pathways, such as the steroid biosynthesis, Forkhead box (FOXO) and prolactin signaling pathways. To confirm the expression and biological effects of KRT14, we conducted relevant experiments. In vitro studies revealed that bisphenols such as bisphenol A (BPA) exposure significantly affected the proliferation, migration, and invasion of MCF-7 cells by inhibiting KRT14 expression. Similarly, we also observed a decrease in KRT14 expression in BPA induced abnormal breast tissue in mice. In summary, our study revealed potential genes and pathways associated with bisphenols exposure in BC.

Schizophrenia (SCZ) has limited treatment options, often with significant side effects. Cannabidiol (CBD), a non-euphoric phytocannabinoid, has shown potential as a novel therapeutic option in SCZ due to antipsychotic-like, anti-inflammatory, and antioxidant properties. We compared the therapeutic effects of CBD and risperidone (RISP) in a rat model of SCZ induced by sub-chronic ketamine (KET), focusing on inflammatory and oxidative stress, and behavioral phenotypes.

Breast cancer cells are characterized by heightened autophagy, which impairs tumor-associated antigen presentation and represents a significant barrier to the antitumor immunity. In this study, a PD-L1-targeting autophagy modulator (PFC@CQ) is fabricated to activate the photoimmunotherapy against breast cancer. Specifically, the hydrophobic photosensitizer protoporphyrin IX (PpIX) is covalently linked to the hydrophobic peptide FFVLK and a PD-L1-targeting peptide sequence CLQKTPKQC, resulting in the formation of an amphiphilic photosensitizer-peptide conjugate (PpIX-FFVLK-CLQKTPKQC, called PFC), which is capable of encapsulating the autophagy inhibitor chloroquine (CQ). PFC@CQ can not only facilitate the targeted drug codelivery to PD-L1-overexpressing breast cancer cells, but also effectively disrupt their immune evasion by blocking PD-1/PD-L1 pathway. Upon light irradiation, the photodynamic therapy (PDT) of PFC@CQ induces tumor cell destruction and immunogenic cell death (ICD), causing the release of damage-associated molecular patterns (DAMPs). Simultaneously, PFC@CQ can inhibit autophagy pathway to mediate the upregulation of MHC-I, thereby enhancing antigen presentation. This cascade immunomodulation promotes the dendritic cell maturation and CD8+ T cell activation, leading to a synergistic suppression of both primary and metastatic tumors. This work introduces an innovative autophagy modulation strategy with potent immunomodulatory capability, demonstrating a potential to trigger systemic antitumor immune responses through local treatment.

Serotonin acts in an autocrine/paracrine manner within the mammary epithelium regulating cell homeostasis during lactation and cell turnover during involution after milk stasis. However, the presence and role of mammary serotonin during the pubertal developmental stage is unknown in the bovine. Here, we characterized the serotonin receptor profile and serotonin immunolocalization in bovine mammary tissue at eight developmental stages (i.e., birth, weaning, puberty, six months gestation, early lactation, mid-lactation, early dry and late dry, n = 6/stage). Further, we investigated the effects of 5-HTP (serotonin precursor), 17β-estradiol (E2), and ICI 182780 (ERα antagonist) either alone or in various combinations (i.e., 5-HTP +  E2, 5-HTP + ICI, E2 + ICI or 5-HTP + E2 +  ICI) on cultured bovine mammary epithelial cells (MAC-T). Serotonin receptor gene expression is highly dynamic throughout mammary development, particularly highly expressed in the puberty stage expressing 12 out of the 13 serotonin receptors evaluated (5-HTR1A, -1B, -1D, -1F, -2A, -2B, -2C, -3B, -4, -5a, -6, and -7), relative to the birth stage. Following a 24-hour incubation, all treatments except ICI increased MAC-T cell proliferation. Incubation with 5-HTP +  ICI resulted in a downregulation of ESR1, ESR2, GPER1 and AREG, relative to CON. Incubation with 5-HTP and E2 alone downregulated the expression of TPH1, 5-HTR1A and 5-HTR1B, relative to CON. Overall, our data indicates serotonin is present in the juvenile developing mammary tissue and the expression of various receptors is observed suggesting an active involvement at this early stage. Additionally, serotonin might indirectly regulate mammary epithelial cell proliferation alone and concurrently with E2 during puberty through the modulation of E2 signaling genes and 5-HTR1A and -1B.

This study aimed to investigate the relationship between tumor necrosis factor alpha-induced protein (TNFAIP6/TSG-6) and astrocytes in cerebral ischemia/reperfusion (I/R) injury.

This study aims to investigate the effect and mechanism of photodynamic therapy (PDT) combined with cisplatin on human lung adenocarcinoma A549 cells transplanted tumors in nude mice, and to provide a theoretical basis for clinical PDT. Construction of a nude mouse lung cancer transplantation tumor model using the human lung adenocarcinoma A549 cell line, and the mice were randomly divided into four groups: the control group, the cisplatin alone group, the PDT alone group, and the cisplatin combined PDT group. The apoptosis of tumor cells in the four groups was observed and compared by the TUNEL method, and the mRNA expression levels of apoptosis-related genes Bax, caspase-3 and Survivin, as well as the expression levels of the corresponding proteins, were detected by the real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and the protein immunoblotting technique (Western blot) respectively. The results showed that photodynamic force combined with cisplatin was effective in inhibiting tumor growth, and its effect was superior to that of cisplatin or PDT alone. This may be related to the promotion of apoptosis, specifically through the up-regulation of Bax and caspase-3, and the down-regulation of Survivin gene expression, thus inhibiting cell proliferation.

Inadequate angiogenesis of endometriotic implants stimulated by the inflammatory microenvironment in the uterine region leads to the development of gynecological diseases, which significantly reduce the fertility and vitality of young women. Angiogenic processes are controlled by factors whose activities are regulated at the gene level by reactive oxygen species (ROS), hypoxia-induced factors (HIFs), and zinc-finger proteins (ZnFs) or posttranscriptionally via non-coding RNAs. The cooperation of these factors is responsible for the manifestation of pathological stimuli in the form of endometriosis of the body of the uterus, ovaries, or peritoneum, from which endometrioid carcinoma can develop. Molecules that can control gene expression by their intercalation to target DNA sequence, such as [Zn(neo)(nif)2], could prevent the hyperactivation of pro-angiogenic pathways (decrease HIF-1α, VEGF-A, TGF-β1, COX2, and ANG2/ANG1), reduce the formation of ROS, and reduce the risk of uterine neoplasticity. The NSAID-metal complex [Zn(neo)(nif)2] shows an ability to intercalate into ZNF3-7 target DNA sequence at a higher rate, which could explain its effect on genes regulated by this transcription factor. In addition, [Zn(neo)(nif)2] affects ROS production and Ca2+ level, possibly pointing to mitochondrial dysfunction as a potential cause for the described apoptosis.

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery is the primary treatment for localized MPNST with a 61.9% overall survival rate, metastatic disease is often fatal due to resistance to systemic therapies which underscores the urgent need for effective treatments. MPNSTs frequently harbor inactivating driver mutations in the PRC2 epigenetic repressor complex suggesting epigenetic therapies may represent a specific vulnerability in these tumors. Here, we investigate the role of the LSD1-HDAC1-CoREST (LHC) repressor complex in mediating MPNST tumor growth and progression. Our findings demonstrate that the LHC small molecule inhibitor, corin, induces apoptosis and significantly inhibits proliferation in MPNST cells. Transcriptomic analysis of corin-treated MPNST cells demonstrates specific increases in genes associated with axonogenesis and neuronal differentiation as well as altered extracellular matrix; additionally, corin treatment is shown to inhibit MPNST invasion in vitro. These results underscore the critical role of the LHC complex in facilitating MPNST growth and progression and suggest that targeting the LHC complex represents a promising therapeutic approach for this aggressive malignancy.

Although tsRNA has been demonstrated to modulate various physiological processes analogous to miRNA, the potential regulatory functions and mechanisms of tsRNAs related to the pharmacological effects of small molecule drugs remain unclear. Herein, it is shown that eurycomalactone (ELT), a natural product, can reversibly switch hepatocellular carcinoma (HCC) PLC/PRF/5 and HUH7 cells into a quiescent state. This quiescence is characterized by cell proliferation inhibition without cytotoxicity, cell cycle arrest at the G0/G1 phase, and cell reactivation following the removal of ELT. Given the established role of β-catenin activity in mediating cancer cellular quiescence or proliferation, a notable reduction in total, cytoplasmic, and nuclear β-catenin expression, along with its downstream targets Survivin, c-myc, and Cyclin D1, was observed in ELT-treated cells. Subsequently, two new tsRNAs, namely 5'tRFAla and 5'tiRNAAla, which match well with the mRNAs of two pivotal upstream regulators (DVL2 and DVL3) of β-catenin based on bioinformatics analyses, were detected to be significantly decreased in ELT-treated PLC/PRF/5 cells using Arraystar small RNA microarray analyses. Consistently, the concentrations of the DVL2 and DVL3 proteins were also found to be reduced by ELT. The mimic of 5'tRFAla could increase the relative expression of DVL2 and DVL3 mRNA and rescue their decrease induced by ELT, while the mimic of 5'tiRNAAla could not. It therefore seems that ELT could down-regulate the expression of 5'tRFAla, leading to the suppression of DVL2 and DVL3 mRNA translation, consequently inhibiting the β-catenin signaling pathway and reversibly switching HCC cells into a quiescent state. Conclusively, our findings imply that tsRNAs, like miRNAs, might activate the translation of their matched mRNAs in non-dividing cells and provide a possible potential for repressing tumor cell growth, although further evidence is still needed.

Colospheroids contain colon cancer stem cells (CSCs) that cause colorectal cancer metastasis (mCRC). Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the U.S. Little is known about the role of mitochondria in the survival and metastatic ability of CSCs. In this study, we investigate the effect of andrographolide (AGP) and melatonin (MLT) on mitochondrial dynamics (including fusion and fission) and the expression of mitochondrial ribosomal proteins (MRPs). Our results show that AGP and MLT synergistically reduce the total active mitochondrial mass, downregulate fusion and fission proteins, reduce OXPHOS proteins, and lead to CSC growth inhibition via Nrf2 and KEAP1 signaling. Microarray revealed 4389 differentially expressed mRNAs in the AGP and MLT combination compared to the control. Results exhibiting a three-fold induction/reduction were validated by qRT-PCR and immunoblot. MRPS6, a mitochondrial ribosomal (Mitoribosome) small subunit protein, was dramatically downregulated by AGP + MLT treatment compared to control. MRPS6 inhibition by siRNA reduced mCRC cell viability. Molecular docking-based protein-ligand interactions showed that AGP has direct physical interaction with MRPS6 and increases the binding affinity of MLT to MRPS6. This drug combination downregulated genes in the NRF2 (NFE2L2) pathway in CSCs. MRPS6 may be directly linked to CSC proliferation and could be a therapeutic target for this population. Functionally, MRPS6 knockdown significantly reduced colony formation, with enhanced suppression in AGP + MLT-treated cells. In xenograft models, the AGP-MLT combination synergistically decreased MRPS6 expression and increased apoptosis, as evidenced by TUNEL assays, demonstrating the therapeutic potential of targeting MRPS6 in CRC.

Parkinson's disease (PD) is one of the most common progressive neurodegenerative pathologies that leads to dopaminergic deficiency and motor manifestations. Alpha-synuclein aggregation is a characteristic hallmark of PD pathogenesis. These aggregates facilitate the formation of Lewy bodies and degeneration. The epidemiological evidence demonstrates a definitive association of diabetes with PD risk. Considering this, many antidiabetic agents such as GLP-1 agonists and DPP-4 inhibitors are being explored as alternative PD therapeutics. This study evaluated the neuroprotective effect of the DPP-4 inhibitor sitagliptin mediated by the PI3K/AKT and Nrf2 pathways in PD models. In silico studies were conducted to determine the binding affinity, stability, and ADMET properties of DPP-4 inhibitors with target proteins. Sitagliptin (15 mg/kg p.o.) was administered in rotenone (30 mg/kg p.o. for 28 days)-induced and MPTP/P (25 mg/kg i.p. MPTP and 100 mg/kg probenecid i.p. twice a week for 5 weeks)-induced PD mouse (C57/BL6) models. Neurobehavioral assessments were carried out throughout the study. Biochemical (GSH, MDA), molecular estimations (AKT, Nrf2, PI3K, GSK-3β, GLP1, CREB, BDNF, NF-κB, alpha-synuclein), histopathological studies, and immunohistochemistry were carried out at the end of the study. The in silico studies demonstrate better binding, stability, and ADMET profile of sitagliptin with both target proteins. Sitagliptin restored cognitive and motor deficits in both rotenone- and MPTP/P-induced mouse models. There was upregulation of PI3K, AKT, Nrf2, CREB, and BDNF levels and downregulation of GSK-3β, NF-κB, and alpha-synuclein levels in both models after treatment with sitagliptin. However, GLP1 levels were not significantly restored, indicating a GLP1-independent mechanism. It also restored histopathological alterations and TH+ neuronal loss induced by rotenone and MPTP/P. These findings demonstrate that sitagliptin exhibits neuroprotective action mediated by upregulation of the PI3K/AKT and Nrf2 pathways in rotenone and MPTP/P mouse models of PD.

Type 2 diabetes (T2D) is a crucial risk factor for both colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, so far, there was no study that has investigated common drugs against HCC and CRC during their co-occurrence with T2D patients. Consequently, patients often require multiple disease-specific multiple drugs, which can lead toxicities and adverse effects to the patients due to drug-drug interactions. This study aimed to identify common genomic biomarkers (cGBs) and associated pathogenetic mechanisms underlying CRC, HCC, and T2D to uncover potential common therapeutic compounds against these three diseases. Firstly, we identified 86 common differentially expressed genes (cDEGs) capable of separating each of CRC, HCC and T2D patients from control groups based on transcriptomic profiling. Of these cDEGs, 37 genes were upregulated and 49 were downregulated. Genetic association studies based on average of Log2 fold-change (aLog2FC) of cDEGs suggested a genetic association among CRC, HCC and T2D. Subsequently, six top-ranked cDEGs (MYC, MMP9, THBS1, IL6, CXCL1, and SPP1) were identified as common genomic biomarkers (cGBs) through protein-protein interaction (PPI) network analysis. Further analysis of these cGBs with GO-terms and KEGG pathways revealed shared pathogenetic mechanisms of three diseases, including specific biological processes, molecular functions, cellular components and signaling pathways. The gene co-regulatory network analysis identified two transcription factors (FOXC1 and GATA2) and three miRNAs (hsa-mir-195-5p, hsa-mir-124a-3p, and hsa-mir-34a-5p) as crucial transcriptional and post-transcriptional regulators of the cGBs. Finally, cGBs-guided seven candidate drugs (Digitoxin, Camptosar, AMG-900, Imatinib, Irinotecan, Midostaurin, and Linsitinib) as the common treatment against T2D, CRC and HCC were identified through molecular docking, cross-validation, and ADME/T (Absorption-Distribution-Metabolism-Excretion-Toxicity) analysis. Most of these findings received support by the literature review of diseases specific individual studies. Thus, this study offers valuable insights for researchers and clinicians to improve the diagnosis and treatment of CRC and/or HCC patients during the co-occurrence of T2D.

A well-developed root system is a key factor in improving crop quality, as it can absorb water, nourish and resist stress. A series of arylthiourea derivatives were synthesized and their biological activities were evaluated in this study. The results indicate that compound A2 significantly promotes rice root growth, exhibiting effects more than twice those of the naphthylacetic acid (NAA). Additionally, A2 enhances dry matter accumulation and increases chlorophyll content, thereby improving the disease resistance of rice. Preliminary mechanistic studies suggest that compound A2 mimics auxin-like activity, similar to NAA, A2 interacts with SER438 and PHE82, demonstrating strong binding affinity to the auxin receptor TIR1. Moreover, compound A2 upregulates the auxin-responsive gene ARF, promoting cell elongation and accelerating lateral root development, leading to a larger root system in rice. Compound A2 may have application potential as an auxin receptor agonist, providing a molecular basis for the design of root growth regulators.

Non-small cell lung cancer (NSCLC) is a common cause of cancer-related deaths worldwide, and its incidence has been increasing in recent years. While targeted therapies like osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor, have brought about notable improvements in patient outcomes for advanced NSCLC, the challenge of acquired drug resistance persists. Here, we found that cellular mesenchymal-epithelial transition factor (c-Met) was highly expressed in osimertinib-resistant cells, and depletion of c-Met markedly inhibited the growth of osimertinib-resistant cells ex vivo and in vivo, suggesting that c-Met is a potential target to address osimertinib resistance. Through a screening process using a natural product compound library, we identified piperlongumine as a potent inhibitor to overcome osimertinib resistance. Furthermore, the combined treatment of piperlongumine and osimertinib exhibited robust antitumor effects in resistant cells, partially restoring their sensitivity to osimertinib. Additionally, we discovered that piperlongumine could enhance the interaction between E3 ligase RNF4 and Sp1, inhibit the phosphorylation of Sp1 at Thr739, facilitate the ubiquitination and degradation of Sp1, lead to c-Met destabilization, and trigger intrinsic apoptosis in resistant cells. In summary, our study sheds light on the potential of piperlongumine in overcoming osimertinib resistance, offering new strategies and perspectives for the clinical management of drug-resistant NSCLC.

The causes of death in patients with advanced esophageal cancer are multifactorial, with tumor metastasis being one of the important factors. Histone acetylation promotes the migration of esophageal squamous cell carcinoma (ESCC) cells, while the histone deacetylase inhibitor (HDACi) shows complex effects on tumor functions.

Glycolysis provides growth advantages and leads to drug resistance in colorectal cancer (CRC) cells. SIRT1, an NAD+-dependent deacetylase, regulates various cellular processes, and its upregulation results in antitumor effects. This study investigated the role of SIRT1 in metabolic reprogramming and oxaliplatin resistance in CRC cells.

Cascading regulation of signaling pathways plays a crucial role in insect growth, development, and adaptation. However, how insects employ signaling cascades to regulate detoxification gene expression and enhance resistance is not well understood. In the current study, we investigated the MAPK signaling pathway in mediating nitenpyram resistance in Nilaparvata lugens. qRT-PCR and western-blot analyses revealed that both transcription and protein levels of NlJNK and NlERK were upregulated in the nitenpyram resistant strain, and these changes can be induced by exposure to nitenpyram. Moreover, the expression of P450 genes including NlCYP6ER1, NlCYP302A1, and NlCYP6AY1, which were closely associated with nitenpyram resistance, was significantly decreased following the silencing of NlJNK and NlERK or inhibitor treatments. Further studies showed that NlERK-NlJNK comediated transcription factors NlCREB and NlAP-1 to regulate P450 gene expression. These findings highlight the critical role of the MAPK pathway in N. lugens resistance and offer the potential targets for the insecticide resistance management.