As antibiotic resistance escalates into a global health crisis, novel therapeutic approaches against infectious diseases are in urgent need. Pseudomonas aeruginosa, an adaptable opportunistic pathogen, poses substantial challenges in treating a range of infections. The quorum-sensing (QS) system plays a pivotal role in orchestrating the production of a large set of virulence factors in a cell density-dependent manner, and the anti-virulence strategy targeting QS may show huge potential. Here, we present a comprehensive investigation into the potential of the synthesized compound 3-(benzo[d][1,3]dioxol-4-yl)oxazolidin-2-one (OZDO, C10H9NO4) as a QS inhibitor to curb the virulence of P. aeruginosa. By employing an integrated approach encompassing in silico screening, in vitro and in vivo functional identification, we elucidated the multifaceted effects of OZDO. Molecular docking predicted that OZDO interfered with three core regulatory proteins of P. aeruginosa QS system. Notably, OZDO exhibited significant inhibition on the production of pyocyanin, rhamnolipid and extracellular proteases, biofilm formation, and cell motilities of P. aeruginosa. Transcriptomic analysis and quantitative real-time PCR displayed the down-regulation of QS-controlled genes in OZDO-treated PAO1, reaffirming the QS-inhibition activity of OZDO. In vivo assessments using a Caenorhabditis elegans-infection model demonstrated OZDO mitigated P. aeruginosa pathogenicity, particularly against the hypervirulent strain PA14. Moreover, OZDO in combination with polymyxin B and aztreonam presented a promising avenue for innovative anti-infective therapy. Our study sheds light on the multifaceted potential of OZDO as an anti-virulence agent and its significance in combating P. aeruginosa-associated infections.

Light is an essential environmental factor that facilitates the robust upward growth of post-germinative seedlings emerging from buried seeds that is partly mediated by the photoreceptors. Salinity stress hampers plant growth and development and reduces yield. However, the involvement and regulatory role of photoreceptors and light signaling factors to salt stress are largely unknown. Here, we report that mutants of the phytochrome B (phyB) photoreceptor showed reduced sensitivity to salt-inhibited hypocotyl elongation in darkness, and that PHYTOCHROME-INTERACTING FACTOR 3 (PIF3) acts downstream of phyB in regulating this process in Arabidopsis thaliana. We also show that SALT OVERLY SENSITIVE 2 (SOS2) regulates phyB protein accumulation under salt stress in darkness. Surprisingly, salt treatment induces phyB nuclear body formation in darkness. Moreover, we found that the phosphorylation at residue Ser-86 of phyB is essential for its function, and the scaffold protein 14-3-3κ is involved in the regulation of phyB under salt stress in darkness. Taken together, our study reveals a regulatory role of the phyB-PIF3 module in mediating post-germination growth in darkness in response to salt stress.

Psilocybin, a psychedelic compound found in specific hallucinogenic mushrooms, is known to induce changes in visual perception and experience in humans. However, there is little knowledge of the molecular mechanisms through which psilocybin affects vision-associated regions in the brain, such as the visual cortex. The current study determined both psilocybin-induced and experience-dependent changes (exposure to light) in visual cortex gene expression in mice. Of great interest, psilocybin induced robust gene expression changes in the visual cortex that closely mirror light-induced gene expression changes, even when the mice are kept in the dark. These gene expression changes correspond to specific molecular pathways, including synaptic functioning, and represent genes expressed in specific subtypes of neurons. In addition, exposure to both psilocybin and light induced synergetic changes in genes involved in epigenetic programming. Overall, the study determined that psilocybin induces robust changes in gene expression in the visual cortex that may have functional consequences in visual perception both in the absence and in synergy with visual experience.

Ovarian cancer is a gynecological malignancy with the highest recurrence and mortality rates. Although niraparib can effectively affect its progression, the challenge of drug resistance remains. Herein, niraparib-resistant ovarian cancer cell lines were constructed to identify the abnormally activated enhancers and associated target genes via RNA in situ conformation sequencing. Notably, the target gene RAD23A was markedly upregulated in niraparib-resistant cells, and inhibiting RAD23A restored their sensitivity. Additionally, abnormal activation of glycolysis in niraparib-resistant cells induced lactate accumulation, which promoted the lactylation of histone H4K12 lysine residues. Correlation analysis showed that key glycolysis enzymes such as pyruvate kinase M and lactate dehydrogenase A were significantly positively correlated with RAD23A expression in ovarian cancer. Additionally, H4K12la activated the super-enhancer (SE) of niraparib and RAD23A expression via MYC transcription factor, thereby enhancing the DNA damage repair ability and promoting the drug resistance of ovarian cancer cells. Overall, the findings of this study indicate that lactic acid accumulation leads to lactylation of histone H4K12la, thereby upregulating SE-mediated abnormal RAD23A expression and promoting niraparib resistance in ovarian cancer cells, suggesting RAD23A as a potential therapeutic target for niraparib-resistant ovarian cancer.

The complete dormancy release determines the quality of bud break, flowering and fruiting. While in tree peony (Paeonia suffruticosa Andr.), the insufficient accumulation of cold temperatures results in incomplete dormancy release and poor flowering quality.

Breast cancer cells have the propensity to metastasize to bone, resulting in altered growth, chemoresistance, and causing skeletal failures, often leading to death in patients. There is a scarcity of effective therapeutics for bone metastasized breast cancer due to the lack of accurate drug screening metastasis models. We utilize a unique 3D in vitro nano clay-based scaffold model as a testbed for bone metastatic breast cancer for drug screening applications. Rhodiola crenulata, a Tibetan plant-based extract, has been previously explored for primary-site breast cancer. However, its effect on bone metastasized breast cancer cells is unknown. In the present study, we evaluated the cytotoxicity of R. crenulata extract on bone metastatic breast cancer using testbeds and compared the results with 2D cultured cells. We observed that R. crenulata induced apoptosis in bone metastasized breast cancer cells grown on a 3D in vitro testbed by upregulating pro-apoptotic proteins, p53, and caspase-9. Alternatively, we observed that bone cells remain unaffected by the treatment of R. crenulata. For the first time, we demonstrated the anticancer capabilities of R. crenulata against bone metastasis of breast cancer. R. crenulata is a robust therapeutic candidate for bone metastasis, shown to induce death in bone metastatic breast cancer while unaffecting healthy bone.

Studies have demonstrated that sialylation changes play a vital part in lung adenocarcinoma (LUAD), yet the specific mechanism is uncertain. Hence, in the present research, we screened sialylation-related biomarkers in LUAD using the bioinformatic strategy, predicted the drugs and performed relevant experiments to explore their role in regulating LUAD. The TCGA-LUAD, GSE31210, and GSE13213 datasets were combined to form LUAD ensemble. The sialylation-related genes (SRGs) linked with LUAD prognosis were determined by univariate Cox regression analysis, and their expressions and mutations in LUAD were analyzed in GSCA database. Then, depending on the consistent clustering of prognostic SRGs, LUAD patients were divided into sialylation-related subgroups, followed by the investigation of survival, immunity, and clinical characteristics in the subgroups. LASSO regression analysis was further employed to identify prognostic gene signatures and to build a sialylation-related model to predict the prognosis of LUAD patients. The gene signature were validated using RT-qPCR and used for predicting target medicines using molecular docking to further investigate the potential therapies for LUAD patients. A total of 26 SRGs in LUAD ensemble were associated with prognosis, and LUAD samples were classified into two sialylation-related subgroups based on these SRGs. Intergroup comparisons revealed that patients in Cluster A had greater survival rates, as well as higher immune infiltration. The risk prognostic model built based on 6 prognostic gene signature was able to effectively predict the survival of LUAD patients. Finally, the experimental findings indicated that Troxerutin exhibits a strong binding energy to the sialylation-related gene EGLN3, which could greatly reduce the growth of LUAD by inhibiting the expression of EGLN3, thus limiting the capacity of LUAD cells in the proliferation, migration, and invasion. Troxerutin could target and lower the expression of sialylation-related gene EGLN3, reducing LUAD cells' ability to proliferate, migrate, and invade, making it an essential reference for LUAD prevention and treatment.

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) represents a critical global health challenge, making the SaeRS two-component system (TCS), a key regulator of S. aureus virulence, an ideal target for novel therapeutic approaches. In this study, virtual screening and thermal shift assays identified Baohuoside I (BI), a flavonol glycoside, as a potent inhibitor of the SaeR response regulator. BI significantly attenuated S. aureus pathogenicity without bactericidal effects, suppressing the expression of key virulence factors, such as hemolysin A (Hla) and Panton-Valentine leukocidin (PVL), while modulating immune evasion pathways. Additionally, BI disrupted biofilm formation, promoting the development of porous, less structured biofilms. Biochemical assays, including EMSA, CETSA, fluorescence quenching, and SPR, confirmed strong binding interactions between SaeR and BI. In vivo, BI demonstrated therapeutic efficacy in Galleria mellonella and rat MRSA models. These findings establish BI as a promising lead for nonbactericidal therapies to combat MRSA infections and mitigate resistance.

Feeding low crude protein (LCP) diets supplemented with crystalline amino acids improves environmental and welfare parameters of broilers. However, increased body fat contents in broilers fed LCP diets have become a concern. Black soldier fly larvae oil (BSFLO), rich in lauric acid, has been reported to inhibit lipogenesis and reduce body fat. A 3 × 2 factorial experiment was conducted to evaluate the effect of BSFLO on performance, blood biochemistry, carcass quality, fat metabolism gene expression, and litter quality in broilers fed protein-reduced diets. A total of 288 broilers were divided into 6 treatments: three CP levels (200, 185, or 170 g/kg; high [HCP], medium [MCP], or low [LCP]) and two oil sources (BSFLO and Crude Palm Oil [CPO]), with 6 replicate pens of 8 birds each. Results showed a 15 g/kg CP reduction had no effect on body weight and feed intake (P > 0.05) but increased FCR (P = 0.001). A 30 g/kg CP significantly reduced the body weight and feed intake with inferior FCR (P < 0.05). However, negative effect of low CP diets on FCR was mitigated by BSFLO (P = 0.008). Reducing CP by 30 g/kg increased fat pads (P = 0.033), whereas BSFLO reduced fat pads (P = 0.049) at all three CP levels. Protein-reduced diets increased blood cholesterol (P = 0.002), HDL (P < 0.001), and LDL (P = 0.002). BSFLO decreased blood triglyceride (P = 0.026) and cholesterol (P < 0.001). Reducing 30 g/kg CP increased meat cooking loss (P = 0.035), while BSFLO decreased cooking loss (P < 0.001). BSFLO increased meat protein (P < 0.001) and decreased cholesterol (P = 0.003). The inclusion of BSFLO in protein-reduced diet down-regulated the gene expression of FAS, ACC, SREBP-1, and HMGR in broilers (P < 0.001). Reducing CP levels decreased litter pH (P = 0.011), nitrogen (P < 0.001), ammonia (P < 0.001) and moisture (P = 0.018). The study concludes that BSFLO reduced body fat by down-regulating the lipogenesis gene expression. In addition, BSFLO enhanced feed efficiency in broilers fed protein-reduced diet.

The development of resistance to chemotherapy in the case of aggressive glioblastoma multiforme (GBM) presents a significant treatment challenge. Dysregulation of the Notch signalling pathway promotes tumour proliferation in GBM cells. This study was that targeting the Notch signalling pathway could be a potential therapeutic approach for GBM. Initially, temozolomide-(TMZ)-resistant GBM cells were generated, and the effect of Notch1 on the expression of multiple resistance proteins within these cells was investigated. Subsequently, the expression of Notch-1 in GBM cells was reduced using siRNA. Results revealed a significant reduction in TMZ sensitivity in TMZ-resistant GBM cells, accompanied by a substantial increase in the expression of major vault protein-(MVP), O6-methylguanine-DNA-methyltransferase-(MGMT), and ATP-binding-cassette transporter-G2-(ABCG2). Furthermore, TMZ-resistant U87-R and U251-R cells exhibited higher proliferation rates compared to their parental control cells (U87 and U251). Additionally, we observed that downregulating Notch-1 signalling inhibited the proliferation of TMZ-resistant U87-R and U251-R cells. This downregulation led to the inactivation of MGMT, ABCG2, and MVP. Importantly, it increased chemosensitivity to TMZ, particularly by downregulating MVP expression. Consequently, Notch1 could serve as a potential therapeutic target for GBM cells and may be effective in preventing TMZ resistance by targeting MVP, as well as MGMT and ABCG2 in GBM cells.

Triple-negative breast cancer (TNBC) poses a significant challenge due to its high mortality rates, primarily attributed to resistance against chemotherapy regimens containing taxanes like paclitaxel. Thus, developing combinatorial strategies to override resistance is a pressing need. By taking advantage of a library screening with various kinase inhibitors, we found that the small-molecule inhibitor enzastaurin targeting protein kinase C (PKC) could overcome resistance in TNBC cells. Mechanistically, dual treatment with paclitaxel and enzastaurin resulted in efficient mitotic arrest and subsequent cell death by restoring AURKB expression. Further analysis revealed that the GCN2-p-eIF2α axis was responsible for the posttranscriptional accumulation of AURKB upon combinatorial treatment. Finally, we confirmed that combinatorial regimens synergistically suppressed tumour growth in vivo in mouse models. Moreover, the efficiency of dual treatment was largely determined by AURKB, implying that AURKB could be a potential predictive marker for stratifying patients who may benefit from the combinatorial treatment. Collectively, our study not only unravels a novel underlying mechanism for paclitaxel resistance in TNBC but also provides a new potential combinatorial therapeutic strategy in the clinic.

Humans are regularly exposed to environmental substances through inhaled air. Some chemicals or particles are respiratory sensitizers that can cause adverse respiratory health effects by triggering amplified immune responses. Understanding the process of respiratory sensitization and identifying potential sensitizers have been challenging due to the complexity of the underlying mechanisms.

Chloroquine (CQ) is a 4-aminoquinoline that has historically been used as an anti-malarial drug. It has also been used to treat several autoimmune diseases, cancers, and viral infections. Most of the effects of CQ are mediated through its ability to accumulate in acidic vacuoles and increase their pH. However, at high doses, CQ is known to have various toxic effects, including ocular, retinal, neuromuscular, renal, and cardiac toxicities. The host responses involved in counteracting CQ toxicity remain poorly characterized. Here, using the Caenorhabditis elegans model, we characterize the host pathways that protect against CQ toxicity. Transcriptomics studies reveal that CQ exposure results in the upregulation of innate immune response and endoplasmic reticulum (ER) unfolded protein response (UPR) pathways. An analysis of multiple immune pathway mutants shows that different immune pathways defend against CQ toxicity. Intriguingly, some of these pathways, which converge to defend against pathogenic bacteria, operate independently to protect against CQ toxicity. Finally, we demonstrate that the ER-UPR pathways also play a crucial role in counteracting CQ toxicity.

Breast cancer is a prominent health issue among oncological diseases in emerging nations. The study sought to assess the significant function of amygdalin as a protective and chemotherapeutical substance in combating this lethal condition, either independently or in conjunction with tamoxifen therapy. Breast cancer in mice was induced by 7,12-Dimethylbenz(a)anthracene (DMBA). Mice were divided into six groups, 15 mice in each group. (i) control group, (ii) carcinogenic group, (iii) tamoxifen-treated group, (iv) Amygdalin-treated group, (v) (Amygdalin + tamoxifen) group, (vi) Amygdalin protective group. Results revealed that DMBA-induced breast cancer caused a significant increase in biochemical parameters such as CEA, CA15.3, CA125, PRL, E2, urea, creatinine, ALT, AST, and ALP and a substantial increase in gene expression of TNF-α and BcL-2. In contrast, amygdalin administrations alone or in co-administration with tamoxifen could ameliorate breast cancer by declining TNF-α, BcL-2 and attenuating the biochemical parameters. Amygdalin administrations showed a significant increase in SOD and GPx antioxidants and upregulation of Caspase-3 and P53 in breast tissue. Moreover, flow cytometric analysis revealed that amygdalin administrations were correlated with CD20 and CD44 and promoted the cell cycle and apoptosis in carcinogenic mice. Indeed, the above results were confirmed by the histopathological examinations, which showed that the DMBA group had proliferated microductular carcinoma with marked mononuclear inflammatory cell infiltration, which decreased by the Amygdalin administrations. In conclusion, amygdalin administration may be effective in preventing breast cancer and exhibiting chemotherapeutic properties.

Ovarian carcinoma is one of the fatal gynecological cancers due to the lack of clinical symptoms at earlier stages of disease leading to metastasis and lower survival rates. Hence, an in-depth exploration of the mechanisms of metastasis facilitates the development of novel-targeted therapeutic strategies to treat the disease. Research studies have reported that three predominant Matrix metalloproteinases (MMPs), namely, MMP14, MMP2 and MMP9 can induce the migration of ovarian cancer cells, Epithelial-Mesenchymal transition, breakdown of extracellular matrix, upregulation of expression of transcription factors etc. in the microenvironment of ovarian tumors. In our current research, these predominant MMPs were used as target proteins and docked with potential anti-cancerous phyto-nutraceuticals present in Allium ascalonicum species. Allium ascalonicum, commonly referred to as Shallots is being used in various cuisines worldwide and is still largely unexploited for its anti-cancer properties. Docking results, revealed three potential phyto-nutraceuticals, of which, 1-[[3,5-bis(phenylmethoxy)phenyl]methyl]-6-methoxy-2-methyl-3,4-dihydro-1H-isoquinoline, an isoquinoline alkaloid was considered the best, since it exhibits significant binding affinity when compared to that of the standard drug, Melphalan. Molecular dynamic simulation studies exhibited that MMP2 is highly flexible and can form more stable interactions. Furthermore, simulation studies of finest interaction pose of the target MMPs with the best phyto-nutraceutical, revealed stable interactions and occurrence of conformational changes. The results, also suggested that, the best phyto-nutraceutical of Allium ascalonicum is a novel isoquinoline alkaloid, with favorable bioavailability scores that interact with target MMPs to control the progression and metastasis of ovarian cancer, proposing the prospect of formulating it into sustainable medications for treating metastasized Ovarian Cancer.

Ovarian cancer ranks first lethally among gynecological malignancies. Platinum-based chemotherapy constitutes the first-line therapeutic regime. However, primary or acquired resistance seriously affects the survival rate of patients with ovarian cancer. Serine hydroxy methyltransferase (SHMT) catalyzes conversion of serine to glycine and is responsible for production of S-adenosylmethionine (SAM) for methylation. There are cytosolic SHMT1 and mitochondrial SHMT2 in human. Alternative promoter usage is a proteome-expanding mechanism that allows multiple pre-mRNAs to be transcribed from a single gene. The current study demonstrated that cisplatin-sensitive and cisplatin-resistant ovarian cancer cells expressed discrete SHMT2 isoforms, which was ascribed to the selective utilization of SHMT2 alternative promoters. SHMT2 isoforms exerted somewhat paradoxical roles in ovarian cancer cells, with tumor-suppressive role of isoform 1, and tumor-promotive role of isoform 3. In addition, the current study demonstrated that SHMT2 alternative promoter usage mediated by HIF1α and TFE3 might represent adaptive response of ovarian cancer cells to metabolic stress. Collectively, regulation of SHMT2 isoform expression via alternative promoter usage by transcription factors HIF1α and TFE3 provides a novel basis and potential drug targets for the clinical treatment of platin-resistant ovarian cancer.

De novo purine biosynthesis (DNPS) was previously shown to be aberrantly activated in many cancers. However, the activity of DNPS pathway and its underlying regulatory mechanism in hepatoblastoma (HB) remain poorly understood. Herein, we discovered that the expression of PPAT, the rate-limiting enzyme in DNPS, was markedly upregulated in HB, leading to an augmented purine flux via DNPS, thereby promoting both HB cell proliferation and migration. Furthermore, we found that activated mutant β-catenin, a dominant driver of HB, transcriptionally activated PPAT expression, hence stimulating DNPS and constituting a druggable metabolic vulnerability in HB. Consistently, pharmacological targeting using a DNPS inhibitor lometrexol or genetic repressing the enhanced DNPS markedly blocked HB progression in vitro and in vivo. Our findings suggest that HB patients harboring activated β-catenin mutations and consequent DNPS upregulation, may be treated efficaciously with DNPS enzyme inhibitors like lometrexol. These novel findings bear major therapeutic implications for targeted precision medicine of HB.

Psychiatric disorders and antipsychotics are associated with impaired neuroplasticity, while physical exercise has been reported to enhance neuroplasticity and improve cognitive and affective processes. Therefore, this study hypothesizes that voluntary exercise can enhance synaptic plasticity in juvenile rats disrupted by risperidone, a commonly prescribed antipsychotic for pediatric patients.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC are still not fully elucidated. Here, we demonstrate that BARD1 is overexpressed in PDAC and its genetic inhibition suppresses c-Myc and disrupts c-Myc dependent transcriptional program. Mechanistically, BARD1 stabilizes c-Myc through ubiquitin-proteasome system by regulating FBXW7. Importantly, targeting BARD1 using either siRNAs or CRISPR/Cas9 deletion blocks PDAC growth in vitro and in vivo, without any signs of toxicity to mice. Using a focused drug library of 477 DNA damage response compounds, we also found that BARD1 inhibition enhances therapeutic efficacy of several clinically relevant agents (fold changes ≥4), including PARPi, in HRR proficient PDAC cells. These data uncover BARD1 as an attractive therapeutic target for HRR proficient PDAC.

Aging interventions have progressed in recent years due to the growing curiosity about how lifestyle impacts longevity. This study assessed the effects of SRW Laboratories' Cel System nutraceutical range on epigenetic methylation patterns, inflammation, physical performance, body composition, and epigenetic biomarkers of aging. A 1-year study was conducted with 51 individuals, collecting data at baseline, 3 months, 6 months, and 12 months. Participants were encouraged to walk 10 minutes and practice 5 minutes of mindfulness daily. Significant improvements in muscle strength, body function, and body composition metrics were observed. Epigenetic clock analysis showed a decrease in biological age with significant reductions in stem cell division rates. Immune cell subset analysis indicated significant changes, with increases in eosinophils and CD8T cells and decreases in B memory, CD4T memory, and T-regulatory cells. Predicted epigenetic biomarker proxies (EBPs) showed significant changes in retinol/TTHY, a regulator of cell growth, proliferation, and differentiation, and deoxycholic acid glucuronide levels, a metabolite of deoxycholic acid generated in the liver. Gene ontology analysis revealed significant CpG methylation changes in genes involved in critical biological processes related to aging, such as oxidative stress-induced premature senescence, pyrimidine deoxyribonucleotide metabolic process, TRAIL binding, hyaluronan biosynthetic process, neurotransmitter loading into synaptic vesicles, pore complex assembly, collagen biosynthetic process, protein phosphatase 2A binding activity, and activation of transcription factor binding. Our findings suggest that the Cel System supplement range may effectively reduce biological age and improve health metrics, warranting further investigation into its mechanistic pathways and long-term efficacy.