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[Display omitted] Neuropathic pain is chronic pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain, with a high incidence and complex pathogenesis, is one of the most significant areas of clinical medicine and basic research. Currently, prescribed treatments are still unsatisfactory or have limited effectiveness. A medicinal preparation is required that relieves the neuropathic pain and prolongs action time, which has not yet been discovered. In this study, MIL-101 (Fe) was employed as a drug carrier to regulate the release of diclofenac sodium, thereby achieving the effect of analgesia and sustained release. The release curves demonstrated that diclofenac sodium could be continuously released from MIL-101 (Fe) for more than 48 h. There was no toxicity in vitro and in vivo, and the safety of MIL-101 (Fe) was confirmed by hematoxylin and eosin as well as ELISA tests in vivo. The results of behavioral testing, pharmacokinetics, and RNA sequencing analysis showed that MIL-101 (Fe) loaded with diclofenac sodium could enhance the mechanical withdrawal threshold and alleviate cold allodynia induced by Spared Nerve Injury, prolonging the work time by three days. The results indicated that MIL-101 (Fe) exhibited excellent biocompatibility, while the MIL-101 (Fe)-DS demonstrated analgesic and controlled-release properties. These findings provide a scientific foundation for the clinical management of neuropathic pain and the development of a novel formulation. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a debilitating psychiatric disorder which is common and endangers human physical and mental health. Studies have shown that hesperidin could improve the symptoms of depression with unclear mechanisms. In this study, hesperidin was administered to chronic unpredictable mild stress (CUMS) depressed mice before behavioral test, network pharmacology analysis, RNA expression microarray analysis, pathway validation and molecular docking experiments. we found that hesperidin intervention could significantly improve the depressive symptoms and downregulate the expression level of pyroptosis pathway including caspase 1 (Casp1), interleukin 18 (IL18), interleukin-1β (IL-1β) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). In addition, we found that hesperidin could possibly bind to NLRP3. Our study demonstrated that hesperidin had huge potential as anti-depressive neuroprotectant, and may play a role in treating MDD by regulating NLRP3-mediated pyroptosis. [ABSTRACT FROM AUTHOR]

Fresh lotus seeds are gaining favor with consumers for their crunchy texture and natural sweetness. However, the intricacies of sugar accumulation in lotus seeds remain elusive, which greatly hinders the quality improvement of fresh lotus seeds. This study endeavors to elucidate this mechanism by identifying and characterizing the sucrose synthase (SUS) gene family in lotus. Comprising five distinct members, namely NnSUS1 to NnSUS5 , each gene within this family features a C-terminal glycosyl transferase1 (GT1) domain. Among them, NnSUS1 is the predominately expressed gene, showing high transcript abundance in the floral organs and cotyledons. NnSUS1 was continuously up-regulated from 6 to 18 days after pollination (DAP) in lotus cotyledons. Furthermore, NnSUS1 demonstrates co-expression relationships with numerous genes involved in starch and sucrose metabolism. To investigate the function of NnSUS1 , a transient overexpression system was established in lotus cotyledons, which confirmed the gene's contribution to sugar accumulation. Specifically, transient overexpression of NnSUS1 in seed cotyledons leads to a significant increase in the levels of total soluble sugar, including sucrose and fructose. These findings provide valuable theoretical insights for improving sugar content in lotus seeds through molecular breeding methods. • Five sucrose synthase (SUS) genes were identified and characterized in lotus. • NnSUS1 is the predominately expressed gene in lotus. • A transient overexpression system was successfully established in cotyledon. • NnSUS1 plays a positive role in sugar accumulation in seed cotyledons. [ABSTRACT FROM AUTHOR]

Abstract: Deregulations of erythroid differentiation may lead to erythroleukemia and other hemoglobinopathies, yet the molecular mechanisms underlying these events are not fully understood. Here, we found that KAP-1-associated complexes contribute to the regulation of the β-globin locus, the key events of erythroid differentiation. We show that RNAi-mediated knockdown of KAP-1 in mouse erythroleukemia (MEL) cells increases expression of the Ey and β-major globin genes during hexamethylenebisacetamide (HMBA) induced differentiation process. This indicates that at least part of KAP-1-associated complexes negatively regulates β-globin gene expression during definitive erythroid differentiation. ChIP-PCR analysis revealed that one or more KAP-1-associated complexes are targeted to the promoter region of the Ey and beta-major globin genes. Since KAP-1 is only a scaffold molecule, there must be some transcriptional regulators allowing its targeted recruitment to the β-globin locus. To further discover these novel regulators, proteins interacting with KAP-1 were isolated by endogenous immunoprecipitation and identified by LC-ESI–MS/MS. Among the proteins identified, MafK and Zfp445 were studied further. We found that KAP-1 may contribute to the repression of Ey and β-major globin gene transcription through recruitment to the promoters of these two genes, mediated by the interaction of KAP-1 with either Zfp445 or MafK, respectively. [Copyright &y& Elsevier]

Papillary and non-papillary are two histological patterns of bladder carcinogenesis and are considered as dual-track oncogenic pathways, which have different genetic alterations. The TCGA-bladder cancer (BLCA) database contains clinicopathological, genomic and survival data from over 400 muscle-invasive bladder cancer patients. In this study, using data from this database, we performed a systematic screening of gene expression to identify the protein-coding gene that might have prognostic value in papillary and non-papillary muscle-invasive bladder cancer (MIBC). The data of patients with primary MIBC in TCGA-BLCA was acquired from the UCSC Xena project (http://xena.ucsc.edu) for re-analysis. By setting |log2 fold change|≥2 and adjusted p value <0.01 as the screening criteria, we found 751 significantly dysregulated genes, including 183 overexpressed and 568 downregulated genes. HMMR was identified as a potential prognostic marker with unique expression. Multivariate analysis showed that its expression was an independent prognostic indicator of shorter progression-free survival (PFS) (HR: 1.400, 95%CI: 1.021–1.920, p = 0.037) in the papillary subtype. ENST00000393915.8 and ENST00000358715.3, two transcripts that contain all 18 exons and encode the full length of HMMR , were significantly upregulated in cancer tissues compared with normal bladder tissues. None of the 17 CpG sites in its DNA locus was relevant to HMMR expression. 26/403 (6.5%) MIBC cases had HMMR gene-level amplification, which was associated with upregulated HMMR expression compared with the copy-neutral and deletion groups. Gene set enrichment analysis (GSEA) in papillary MIBC found that the high HMMR expression group was associated with upregulated genes enriched in multiple gene sets with well-established role in BC development, including G2M checkpoint, E2 F Targets, Myc Targets V1, Myc Targets V2 and Glycolysis. Based on these findings, we infer that HMMR expression might be a specific prognostic marker in terms of PFS in papillary MIBC. DNA amplification might be an important mechanism of its elevation. [ABSTRACT FROM AUTHOR]

Originating in the subtropics, cucumbers require warm weather and plenty of light, low light inhibits the growth of cucumbers. For cucumbers to efficiently absorb light energy in low light, chlorophyll synthesis is necessary. Oxygenase for chlorophyllate is encoded by CsCAO. RNA interference (RNAi) was used to reduce CsCAO expression in cucumber, reduced chlorophyll b content and Fv/Fm (maximal photochemical efficiency of photosystem II) were found in RNAi- CsCAO lines. The Arabidopsis Atcao mutant lacks chlorophyll b and has a low Fv/Fm, but overexpressing CsCAO restored the mutant's phenotype. CsCAO gene expression was found to be upregulated in the presence of low light. The Y1H screening assay revealed that CsHsfA6b and CsBLH4 were potential CsCAO expression regulators. The results of the Y1H, LUC/REN, and EMSA assays confirmed that only CsBLH4 can bind to the CsCAO promoter. Furthermore, like Atcao , the Atblh4 mutant had low chlorophyll b content and Fv/Fm. CsCAO overexpression in the Atblh4 mutant increased the content of chlorophyll b and Fv/Fm, especially under low light conditions. CsBLH4 targeting CsCAO was found to positively regulate chlorophyll b synthesis and photosynthetic capacity in cucumber under low light conditions in our study. • Low light promoted the accumulation of chlorophyll b by up-regulating the transcription level of CsCAO. • It clarified the regulatory mechanism of BLH family member involved in chlorophyll b synthesis. • The synthesis of chlorophyll plays an important role in the response of cucumber to low light stress. [ABSTRACT FROM AUTHOR]

• By inhibiting SLC7A11/xCT with the inhibitor sulfasalazine and nanoreactors with tetrasulfide bond (-s-s-s-s-)- as the backbone, tumor cell glutathione synthesis is suppressed and its consumption is promoted. • Decreased glutathione content inhibits GPX4 synthesis, promotes intracellular lipid peroxide accumulation, and induces ferroptosis in tumor cells. • The photosensitizer DVDMS produces ROS under ultrasound, which, together with Fe3+, promotes lipid peroxide generation. • Targeted delivery of USP39 shRNA can efficiently silence USP39 gene expression under ultrasound stimulation, inhibiting cell proliferation and selectively inducing autophagy-dependent ferroptosis. The promotion of cellular ferroptosis through ultrasound (US)-assisted Fenton chemistry has emerged as a promising strategy for tumor therapy. To enhance the therapeutic effect, we designed a GSH-responsive ultrasound-driven nanoreactor for RNA interference (RNAi)-intensified ferroptosis in synergistic sono-chemodynamic therapy. Our nanoreactor comprises Fe3+/tetrasulfide bond (-s-s-s-s-) enriched dendritic organosilica encapsulating USP39 shRNA, along with co-loading of sinophoryrin sodium (DVDMS) and sulfasalazine (SAS). Hyaluronic acid surface functionalization ensures high tumor accumulation for active targeting of tumor cells. Upon internalization into tumor cells, the nanoreactor degrades upon the triggering of intracellular overproduced GSH. Ultrasound-triggered release of DVDMS generates large amounts of ROS, synergizing with Fe-catalyzed Fenton chemistry. The simultaneous depletion of glutathione peroxidase 4 and GSH by SAS and Fe3+ weakens the ROS-scavenging system, leading to tumoral redox dyshomeostasis via oxidative stress amplification. This results in the accumulation of lipid peroxide in tumor cells, efficiently inducing ferroptosis. Additionally, USP39 shRNA effectively silences the expression of the USP39 gene in cells, inhibiting tumor cell proliferation, while promoting ATG5 gene expression to intensify ferroptosis. Our work provides a promising nanoreactor for high-efficiency synergistic tumor therapy via RNAi-intensified ferroptosis, highlighting the potential of sono-chemodynamic therapy in cancer treatment. [ABSTRACT FROM AUTHOR]

Adenylate cyclase 3 ( AC3 ) is an important component of the cyclic adenosine 3′,5′-monophosphate (cAMP) signaling pathway and converts adenosine triphosphate into cAMP. Male mice with AC3 deletion ( AC3 −/− ) are sterile. However, the mechanical mechanism remains unclear. By TUNEL staining, we found that cell apoptosis in the testicular tissues of AC3 −/− mice increased significantly compared with that in the wild-type ( AC3 +/+ ) mice. Differentially expressed genes regulated by AC3 in the testicular tissues were identified by gene chip hybridization. We observed that the expression of 693 genes was altered in the testicular tissues of AC3 −/− mice, including 330 up-regulated and 363 down-regulated gene expression with fold changes higher than 2 (≥ 2) as the standards. Furthermore, part of these differentially expressed genes was verified by the real-time fluorescence quantification PCR and immunofluorescent staining. The expression levels of the genes related to olfactory receptors, cell apoptosis, transcriptional activity, defensive reaction, cell adhesion, cell death, and immunoreactions were significantly altered in the testicular tissues of AC3 −/− mice compared with AC3 +/+ mice. In addition, the corresponding Ca 2 + , cAMP, and cell adhesion signaling pathways, as well as the signaling pathways related to axon guidance and cell interaction, were altered significantly in the AC3 −/− mice. These data would help elucidate the general understanding of the mechanisms underlying the sterility in AC3 −/− male mice. [ABSTRACT FROM AUTHOR]

Special AT-rich sequence binding protein 1 (SATB1) plays important role in the regulation of chromatin structure and gene expression. Recent studies have indicated oncogenic role of SATB1. However, the function of SATB1 in prostate cancer progression and metastasis remains unclear. In this study SATB1 expression vector or siRNA was employed to modulate the expression level of SATB1 in prostate cancer cells and xenograft tumor in nude mouse model. Immunohistochemical analysis was performed on clinical prostate cancer samples. Silencing SATB1 inhibited the growth of DU-145 cells subcutaneous tumor in nude mice, while SATB1 overexpression promoted the growth of LNCaP cells subcutaneous tumor in nude mice. Immunohistochemical and Western blot analysis of the xenografts showed that silencing SATB1 led to decreased expression of vimentin and MMP2 and increased expression of E-cadherin, while SATB1 overexpression led to increased expression of vimentin and MMP2 and decreased expression of E-cadherin. Furthermore, SATB1, vimentin and MMP2 expression was increased significantly while E-cadherin expression was reduced significantly in clinical samples of prostate carcinoma with metastasis compared to prostate carcinoma without metastasis and benign prostate hyperplasia. Taken together, these findings suggest that the modulation of epithelial–mesenchymal transition by SATB1 may contribute to prostate cancer metastasis. [ABSTRACT FROM AUTHOR]

Seed germination is important for early plant morphogenesis as well as abiotic stress tolerance, and is mainly controlled by the phytohormones abscisic acid (ABA) and gibberellic acid (GA). Our previous studies identified a salt-tolerant tomato cultivar, LA2711, which is also a fast-germinating genotype, compared to its salt-sensitive counterpart, ZS-5. In an effort to further clarify the mechanism underlying this phenomenon, we compared the dynamic levels of ABA and GA 4 , the transcript abundance of genes involved in their biosynthesis and catabolism as well as signal transduction between the two cultivars. In addition, we tested seed germination sensitivity to ABA and GAs. Our results revealed that insensitivity of seed germination to exogenous ABA and low ABA content in seeds are the physiological mechanisms conferring faster germination rates of LA2711 seeds. SlCYP707A2 , which encodes an ABA catabolic enzyme, may play a decisive role in the fast germination rate of LA2711, as it showed a significantly higher level of expression in LA2711 than ZS-5 at most time points tested during germination. The current results will enable us to gain insight into the mechanism(s) regarding seed germination of tomato and the role of fast germination in stress tolerance. [ABSTRACT FROM AUTHOR]

Cucumber (Cucumis sativus L.) is a high water-demanding and drought-susceptible vegetable crop. Basic leucine zipper (bZIP) transcription factors (TFs) have been linked to drought stress response in plants. Here we characterized a G subfamily gene in cucumber, CsbZIP50 , which was strongly induced by drought stress and an exogenous abscisic acid (ABA) treatment. Under drought stress, CsbZIP50 -overexpressing plants exhibited enhanced drought tolerance compared with wild-type plants, as indicated by the higher antioxidant enzyme activities but lower reactive oxygen species (ROS) and malondialdehyde contents. In addition, overexpression of CsbZIP50 enhanced cucumber's sensitivity to exogenously applied ABA, and up-regulated the expression of its stress-related genes. Moreover, we found that CsbZIP50 activated CsRD29 expression by directly binding to the G-box/ABRE cis-acting element in its promoter, both in vitro and in vivo. Yeast two-hybrid, luciferase complementation imaging, and pull-down assays showed that CsbZIP50 physically interacted with two IQ domain-containing proteins, CsIQD1 and CsIQD4, both of which promoted the ability of CsbZIP50 to activate the expression of CsRD29. Taken together, our results show that CsbZIP50 enhances drought stress tolerance in cucumber by regulating drought-responsive gene expression and ROS levels. • CsbZIP50 is a G subfamily of the bZIP TF, which was induced by drought stress and exogenous ABA treatment. • Expression of CsbZIP50 positively regulates drought tolerance by improving stomata closure and ROS scavenging. • CsbZIP50 targeted CsRD29A and the expression activation effect was enhanced by interacting with CsIQD1 and CsIQD4. [ABSTRACT FROM AUTHOR]

Abstract: The response and adaptation of plants to different environmental stresses are of great interest as they provide the key to understanding the mechanisms underlying stress tolerance. In this study, the changing patterns of four endogenous hormones and various physiological and biochemical parameters of both a salt-tolerant (LA2711) and a salt-sensitive (ZS-5) tomato cultivar were examined under salt stress and non-stress conditions. Additionally, the transcription of key genes in the abscisic acid (ABA) biosynthesis and metabolism were analyzed at different time points. The results indicated that gene expression responsible for ABA biosynthesis and metabolism coincided with the hormone level, and SlNCED1 and SlCYP707A3 may play major roles in the process. LA2711 performed superior to ZS-5 on various parameters, including seed germination, Na+ compartmentation, selective absorption of K+, and antioxidant enzymes activity. The difference in salt tolerance between the two genotypes could be attributed to the different levels of ABA due to differences in gene expression of key genes in ABA biosynthesis and metabolism. Although gibberellin, cytokinin and auxin were involved, our results indicated that ABA signaling plays a major role in tomato salt tolerance. As compared to ZS-5, LA2711 had a higher capability to selectively absorb and redistribute K+ and a higher tolerance to Na+ in young leaves, which may be the main physiological mechanisms of salt tolerance. [Copyright &y& Elsevier]

Abstract: Background: Recent researches document that an oncogenic role of USP22 activation may contribute to progression and predict the prognosis. We have reported that USP22 mediates cell survival and proliferation by promoting the expression of BMI-1 and upregulation of activated AKT pathway in colon cancer cells. However, little is known about its mechanisms in non-small-cell lung cancer (NSCLC). Here the authors investigated the significance of activation of USP22 and potential targets BMI-1, PTEN and phospho-AKT (p-AKT) in NSCLC. Methods: Expression levels of USP22, BMI-1, PTEN and p-AKT in samples from 114 patients with NSCLC were evaluated immunohistochemically using the tissue microarray method. Clinical significance was analyzed by multivariate Cox regression analysis, Kaplan–Meier curves and the log-rank test. Results: Immunohistochemically, USP22, BMI-1, p-AKT and PTEN were positive in 66.66%, 78.07%, 71.92% and 43.85% of NSCLC samples, respectively. Statistical correlation analysis showed USP22 to be significantly correlated with BMI-1 (r =0.315, P =0.001), p-AKT (r =0.271, P =0.003), and PTEN (r =−0.384, P <0.0001). NSCLCs with positive expression of USP22, BMI-1, p-AKT, and negative expression of PTEN were significantly correlated to tumor size (P =0.0240), differentiation (P =0.0457), pT classification (P =0.0077), pN classification (P =0.0064), and AJCC stage (P =0.0363) and poor overall survival (P <0.001). Multivariate Cox proportional hazards model analysis showed that the combined 4 markers was the independent prognostic indicator of overall survival (P <0.001; HR, 5.974; 95% CI, 3.307–10.791). Conclusions: The simultaneous targeting of USP22, and its downstream signal transduction molecules seem highly informative in stratification of the cancer into subgroups with distinct likelihood of therapy failure, which contribute to make decision process regarding the individualized therapy selection and optimization. [Copyright &y& Elsevier]