Staphylococcus aureus and its drug-resistant mutants are mentioned among the WHO's high-priority list of pathogens. Antibiotics like fluoroquinolones and cephalosporins are used to treat multidrug-resistant S. aureus infections. However, a higher expression of efflux pumps (NorA, NorB, and AbcA) induces multidrug resistance. The master regulator, MgrA, regulates the expression of most of these efflux pumps in S. aureus. The phosphorylation status of MgrA is determined by the cellular PknB/RsbU ratio, where PknB, a serine-threonine kinase, and RsbU, a serine-threonine phosphatase, are critical for MgrA functioning.

Lenalidomide (LEN) is a mainstay for treating multiple myeloma (MM), but its efficacy is often limited by resistance. We investigated the interaction between aldo-keto reductase family 1 member C3 (AKR1C3) and Yin Yang 1 (YY1) and their roles in LEN resistance. We induced LEN-resistant MM cell lines (H929R and U266R). Loss- or gain-of-function assays of AKR1C3 and YY1 were used to analyse the half maximal inhibitory concentration (IC50) values, cell senescence, DNA damage, and glycolytic activity under LEN treatment. Chromatin immunoprecipitation was used to determine the interaction between YY1 and AKR1C3. As results, AKR1C3 and YY1 were upregulated in H929R and U266R cells. AKR1C3 silencing decreased the LEN's IC50, slowed cell growth, enhanced senescence and DNA damage, reduced metabolic reprogramming. YY1 activated the transcription of AKR1C3 by binding to its promoter region. Similarly, silencing YY1 enhanced LEN sensitivity, suppressed glycolysis, and was counteracted by AKR1C3 overexpression. Mechanistically, YY1-AKR1C3 activated the Hedgehog pathway; fluticasone reversed the effects of AKR1C3 silencing on LEN resistance and glycolysis in H929R and U266R cells. Overall, YY1 activates AKR1C3 transcription and the Hedgehog pathway to increase LEN resistance and glycolytic activity in MM cells.

Breast cancer is the second leading cause of cancer deaths among women. Recent studies emphasize the significant role of folate metabolic pathways in cancer progression. The Reduced Folate Carrier (RFC), a folate transporter in cell membranes, plays an essential role in transporting folate receptor-dependent drugs. Curcumin, a bioactive compound with anticancer and anti-inflammatory effects, is hindered by low stability and a short half-life. Niosomes are versatile nanoparticles that can deliver both hydrophilic and hydrophobic drugs.

 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.

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.

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.

Sweet whey (SW), a by-product of cheese production, has potential immunomodulatory properties that could be beneficial in preventing inflammation-related diseases. This study investigated the effects of SW derived from bovine, caprine, ovine, or an ovine/caprine mixture of milk on inflammation-related gene expression in THP-1-derived macrophages, both with and without LPS stimulation. Cells were treated with SW-D-P3 (a fraction smaller than 3 kDa produced by in vitro digestion), and the expression of inflammation-related genes was assessed using quantitative PCR. Results showed that the expression of TLR2 and ICAM1 was attenuated in non-LPS-stimulated macrophages treated with SW-D-P3, regardless of animal origin. Moreover, the expression of TLR4, IL1B, and IL6 was decreased and the expression of an NF-κB subunit RELA and CXCL8 was elevated in a subset of samples treated with SW-D-P3, depending on the milk source. In LPS-challenged cells, the expression of CXCL8 was upregulated and the expression of IRF5 and TNFRSF1A was downregulated in SW-D-P3-treated cells, regardless of animal origin. On the other hand, a number of inflammation-related genes were differentially expressed depending on the animal origin of the samples. Moreover, the higher IL10 expression observed in cells treated with ovine/caprine SW-D-P3 compared to those treated with SW-D-P3 of bovine, caprine, or ovine origin suggests an anti-inflammatory response, in which alternatively activated macrophages (M2 polarization phenotype) may participate. Overall, these findings suggest that incorporating SW into the food industry, either as a standalone ingredient or supplement, may help to prevent inflammation-related diseases.

1'-Acetoxychavicol acetate (ACA) is a natural compound derived from rhizomes of the Zingiberaceae family that suppresses the nuclear factor κB (NF-κB) signaling pathway; however, the underlying mechanisms remain unclear. Therefore, the present study investigated the molecular mechanisms by which ACA inhibits the NF-κB signaling pathway in human lung adenocarcinoma A549 cells. The results obtained showed ACA decreased tumor necrosis factor (TNF)-α-induced intercellular adhesion molecule-1 (ICAM-1) expression in A549 cells. It also inhibited TNF-α-induced ICAM-1 mRNA expression and ICAM-1 promoter-driven and NF-κB-responsive luciferase reporter activities. Furthermore, the TNF-α-induced degradation of the inhibitor of NF-κB α protein in the NF-κB signaling pathway was suppressed by ACA. Although ACA did not affect TNF receptor 1, TNF receptor-associated death domain, or receptor-interacting protein kinase 1 protein expression, it selectively downregulated TNF receptor-associated factor 2 (TRAF2) protein expression. The proteasome inhibitor MG-132, but not inhibitors of caspases or lysosomal degradation, attenuated ACA-induced reductions in TRAF2 expression. ACA also downregulated TRAF2 protein expression in human fibrosarcoma HT-1080 cells. This is the first study to demonstrate that ACA selectively downregulates TRAF2 protein expression.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, affecting an increasing number of older adults. Despite extensive research, a definitive cure remains elusive. Eucommia ulmoides Oliv. leaves (EUOL) have been reported to exhibit protective effects on neurodegenerative diseases, however, their efficacy, key active constituents, and pharmacological mechanisms are not yet understood. This study aims to explore the optimal constituents of EUOL regarding anti-PD activity and its underlying mechanisms. Using a zebrafish PD model, we found that the 30% ethanol fraction extract (EF) of EUOL significantly relieved MPTP-induced locomotor impairments, increased the length of dopaminergic neurons, inhibited the loss of neuronal vasculature, and regulated the misexpression of autophagy-related genes (α-syn, lc3b, p62, and atg7). Assays of key regulators involved in PD further verified the potential of the 30% EF against PD in the cellular PD model. Reverse phase protein array (RPPA) analysis revealed that 30% EF exerted anti-PD activity by activating 4E-BP1, which was confirmed by Western blotting. Phytochemical analysis indicated that cryptochlorogenic acid, chlorogenic acid, asperuloside, caffeic acid, and asperulosidic acid are the main components of the 30% EF. Molecular docking and surface plasmon resonance (SPR) indicated that the main components of the 30% EF exhibited favorable binding interactions with 4E-BP1, further highlighting the roles of 4E-BP1 in this process. Accordingly, these components were observed to ameliorate PD-like behaviors in the zebrafish model. Overall, this study revealed that the 30% EF is the key active constituent of EUOL, which had considerable ameliorative effects on PD by up-regulating 4E-BP1. This suggests that EUOL could serve as a promising candidate for the development of novel functional foods aimed at supporting PD treatment.

The prolyl-hydroxylase inhibitor (PHI), used effectively in several countries for the treatment of renal anemia, activates the multifunctional hypoxia-inducible factors (HIFs). While hypoxic conditions in tumors are known to affect the response to radiation therapy, the effect of PHI on the radiation response of cancer cells has not been determined. Hypoxic pretreatment increased the radiation sensitivity of A549 lung adenocarcinoma cells, whereas hypoxic culture after irradiation decreased the radiation sensitivity of HSC2 oral squamous cell carcinoma cells. Treatment of PC9 lung adenocarcinoma and HSC2 cells with the PHI FG-4592 significantly increased radiation resistance, whereas A549 and TIG3 lung fibroblast cells tended to be sensitized, suggesting cell type-specific differential effects of PHI. Quantitative RT-PCR analyses revealed that the basal and radiation-inducible expressions of DEC2, BAX, and BCL2 may be related to PHI-mediated radiation responses. Knock-down experiments showed that silencing of DEC2 sensitized both A549 and PC9 cells under PHI-treated conditions. On the other hand, silencing of p53, which regulates BAX/BCL2, desensitized A549 cells expressing wild-type p53, but not PC9 cells, with mutant-type p53, to irradiation, regardless of whether PHI was treated or not. Taken together, PHI modifies radiation responses in a cell type-specific manner, possibly through DEC2 signaling.

Methamphetamine (METH) use disorder (MUD) is a public health catastrophe. Herein, we used a METH self-administration model to assess behavioral responses to the dopamine receptor D1 (DRD1) antagonist, SCH23390. Differential gene expression was measured in the dorsal striatum after a 30-day withdrawal from METH. SCH23390 administration reduced METH taking in all animals. Shock Resistant (SR) rats showed greater incubation of METH seeking, which was correlated with increased Creb1, Cbp, and JunD mRNA expression. Cytoplasmic polyadenylation element binding protein 4 (Cpeb4) mRNA levels were increased in shock-sensitive (SS) rats. SS rats also showed increased protein levels for cleavage and polyadenylation specificity factor (CPSF) and germ line development 2 (GLD2) that are CPEB4-interacting proteins. Interestingly, GLD2-regulated GLUN2A mRNA and its protein showed increased expression in the shock-sensitive rats. Taken together, these observations identified CPEB4-regulated molecular mechanisms acting via NMDA GLUN2A receptors as potential targets for the treatment of METH use disorder.