Design, synthesis, and evaluation of benzodioxolane compounds for antitumor activity.

This study reports the design, synthesis, and comprehensive biological evaluation of 13 benzodioxolane derivatives, derived from the core structure of piperine, a natural product with established antitumor properties. Piperine, primarily found in black pepper, has been noted for its diverse pharmacological activities, including anti-inflammatory, antioxidant, and anticancer effects. Leveraging piperine's antitumor potential, we aimed to enhance its efficacy through structural modifications. Among the synthesized compounds, HJ1 emerged as the most potent, exhibiting a 4-fold and 10-fold increase in inhibitory effects on HeLa and MDA-MB-231 cell lines, respectively, compared to piperine. Furthermore, HJ1 demonstrated a favorable safety profile, characterized by significantly lower cytotoxicity towards the human normal cell line 293T. Mechanistic investigations revealed that HJ1 markedly inhibited clonogenicity, migration, and adhesion of HeLa cells. In vivo studies utilizing the chick embryo chorioallantoic membrane (CAM) model substantiated the robust antitumor activity of HJ1, evidenced by its ability to suppress tumor angiogenesis and reduce tumor weight. These results suggest that HJ1 holds significant promise as a lead compound for the development of novel antitumor therapies.

Dysfunction of Nrf2-regulated cellular defence system and JNK activation induced by high dose of fly Ash particles are associated with pulmonary injury in mouse lungs.

The mechanisms of the exposure to fine particulate matter (PM) as a risk factor for pulmonary injury are not fully understood. The transcription factor, NF-E2-related factor 2 (Nrf2), plays a key role in protection lung against PM insult and cancer chemoprevention. In this study, F3-S fly ash particles from a municipal waste incinerator were evaluated as a PM model. We found that F3-S triggered hierarchical oxidative stress responses involving the prolonged activation of the cytoprotective Nrf2 transcriptional program via Keap1 Cys151 modification, and c-Jun NH2-terminal kinase (JNK) phosphorylation at higher doses. In mouse lungs exposed to fly ash particles at a low dose (10-20 mg/kg), Nrf2 signalling was upregulated, while in those exposed to a high fly ash particle dose (40 mg/kg), there was significant activation of JNK, and this correlated with Nrf2 phosphorylation and the downregulation of antioxidant response element (ARE)-driven genes. The JNK inhibitor, SP600125, reversed Nrf2 phosphorylation, and downregulation of detoxifying enzymes. Silencing JNK expression in mouse lungs using adenoviral shRNA inhibited JNK activation and Nrf2 phosphorylation, promoted ARE-driven gene expression, and reduced pulmonary injury. Furthermore, we found that the 452-515 amino acid region within the Neh1 domain of Nrf2 was required for its interaction with P-JNK. We demonstrated that Nrf2 was an important P-JNK target in fly ash-induced pulmonary toxicity. JNK phosphorylated Nrf2, leading to a dysfunction of the Nrf2-mediated defence system.

c-Jun NH2 -Terminal Protein Kinase Phosphorylates the Nrf2-ECH Homology 6 Domain of Nuclear Factor Erythroid 2-Related Factor 2 and Downregulates Cytoprotective Genes in Acetaminophen-Induced Liver Injury in Mice.

BACKGROUND AND AIMS: Acetaminophen (APAP) overdose induces severe liver injury and hepatic failure. While the activation of c-Jun NH2 -terminal kinase (JNK) has been implicated as a mechanism in APAP-induced liver injury, the hepatic defense system controlled by nuclear factor erythroid 2-related factor 2 (Nrf2) plays a central role in the mitigation of APAP toxicity. However, the link between the two signaling pathways in APAP-induced liver injury (AILI) remains unclear. APPROACH AND RESULTS: In this study, we demonstrated that the activation of JNK in mouse liver following exposure to APAP was correlated with the phosphorylation of Nrf2 and down-regulation of the antioxidant response element (ARE)-driven genes, NAD(P)H:quinone dehydrogenase 1, glutathione S-transferase α3, glutathione S-transferase M1, glutathione S-transferase M5, and aldo-keto reductase 1C. The JNK inhibitor, SP600125, or knockdown of JNK by infection of adenovirus expressing JNK small interfering RNA, ameliorated the APAP induced liver toxicity, and inhibited the phosphorylation of Nrf2 and down-regulation of detoxifying enzymes by stabilizing the transcription factor. Mechanistically, JNK antagonized Nrf2- and ARE-driven gene expression in a Kelch-like ECH-associated protein 1-independent manner. Biochemical analysis revealed that phosphorylated JNK (P-JNK) directly interacted with the Nrf2-ECH homology (Neh) 1 domain of Nrf2 and phosphorylated the serine-aspartate-serine motif 1 (SDS1) region in the Neh6 domain of Nrf2. CONCLUSIONS: Mass spectrometric analysis identified serine 335 in the SDS1 region of mNrf2 as the major phosphorylation site for modulation of Nrf2 ubiquitylation by P-JNK. This study demonstrates that Nrf2 is a target of P-JNK in AILI. Our finding may provide a strategy for the treatment of AILI.

Transcriptome analysis of potential candidate genes and molecular pathways in colitis-associated colorectal cancer of Mkp-1-deficient mice.

BACKGROUND: The nuclear phosphatase mitogen-activate protein kinase phosphatase-1 (MKP-1) is a key negative regulator of the innate immune response through the regulation of the biosynthesis of proinflammatory cytokines. In colorectal cancer (CRC), which is induced mainly by chronic inflammation, Mkp-1 overexpression was found in addition to disturbances in Mkp-1 functions, which may play a role in cancer development in different types of tumors. However, the potential molecular mechanisms by which Mkp-1 influences CRC development is not clear. Here, we performed global gene expression profiling of Mkp-1 KO mice using RNA sequencing (RNA-seq) to explore the role of Mkp-1 in CRC progression using transcriptome analysis. METHODS: Azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models were used to examine the most dramatic molecular and signaling changes that occur during different phases of CRC development in wild-type mice and Mkp-1 KO mice. Comprehensive bioinformatics analyses were used to elucidate the molecular processes regulated by Mkp-1. Differentially expressed genes (DEGs) were identified and functionally analyzed by Gene Ontology (GO), Kyoto Enrichment of Genes and Genomes (KEGG). Then, protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape software. RESULTS: Persistent DEGs were different in adenoma and carcinoma stage (238 & 251, respectively) and in WT and MKp-1 KO mice (221& 196, respectively). Mkp-1 KO modulated key molecular processes typically activated in cancer, in particular, cell adhesion, ion transport, extracellular matrix organization, response to drug, response to hypoxia, and response to toxic substance. It was obvious that these pathways are closely associated with cancer development and metastasis. From the PPI network analyses, nine hub genes associated with CRC were identified. CONCLUSION: These findings suggest that MKp-1 and its hub genes may play a critical role in cancer development, prognosis, and determining treatment outcomes. We provide clues to build a potential link between Mkp-1 and colitis-associated tumorigenesis and identify areas requiring further investigation.

Transcriptomic profiling identifies a critical role of Nrf2 in regulating the inflammatory response to fly ash particles in mouse lung.

Exposure to combustion-derived nanoparticles is recognized as a major health hazard, but the molecular responses are still insufficiently described. The transcription factor erythroid 2-related factor 2 (Nrf2, also known as NFE2L2) is a master regulator of the pulmonary defense system against insults by particulate matter. However, its downstream molecular processes are not fully characterized. In the current study, BALB/c wild-type (WT) and Nrf2-/- mice were exposed by intranasal administration to fly ash particles (F3-S; 20 mg/kg BW), which were collected from a municipal waste incinerator in China, for three consecutive days. Using a comparative transcriptomics approach, the pulmonary global gene expression profiles to F3-S exposure were characterized for both genotypes. The preponderance of the differentially-expressed genes (DEGs) in WT mice induced by the fly ash particles, was related to inflammation. Functional enrichment and molecular pathway mapping of the DEGs specific to Nrf2-/- mice exposed to the particles revealed that all of the top 10 perturbed molecular pathways were associated with the inflammatory response. Our study identified a transcriptional signature related to the initial pulmonary injury in mouse upon fly ash exposure, and suggests an anti-inflammatory role of Nrf2 in protecting the lung against such exposure.

Comparative transcriptome analysis reveals Dusp1 as a critical regulator of inflammatory response to fly ash particle exposure in mouse.

Exposure to outdoor concentrations of fine particulate matter (PM2.5) is a leading global health concern. Waste incineration emission has been recognized as a potential major contributor of ambient PM2.5. Respiratory inflammation is a central feature induced by PM2.5 exposure by inhalation. However, the molecular mechanisms are not fully understood. Dual-specificity phosphatase 1 (Dusp1) plays an instrumental role in the regulation of airway inflammation. In this study, fly ash particles (20 mg/kg BW) collected from a municipal waste incinerator in China were given to BALB/c wild-type (WT) and Dusp1-/- mice by intranasal administration daily for three consecutive days. While these particles induced mild inflammation in both genotypes, a significantly higher level of serum interleukin-6 (665 pg/ml) was measured in Dusp1-/- mice challenged with fly ash particles than in their WT counterparts. Genome-wide transcriptome profiling of pulmonary coding genes in response to the exposure were performed in both genotypes by RNA sequencing. We identified 487 differentially-expressed genes (DEGs) in fly ash-challenged Dusp1-/- mice versus their WT counterparts with a log2fold-change >1.5 and p < 0.05. Functional enrichment and molecular pathway mapping of the DEGs specific to Dusp1-/- mice exposed to the particles revealed that the top 10 perturbed molecular pathways were associated with the immune response. Our study demonstrates the anti-inflammatory role of Dusp1 in protecting the lung against insults by fly ash particles, suggesting that Dusp1 might be a therapeutic target for the treatment of PM2.5-induced respiratory diseases.

Using Nrf2/antioxidant response element-dependent signaling to assess the toxicity potential of fly ash particles.

Epidemiological studies have demonstrated an association between ambient particulate pollution and adverse health effects in humans. The antioxidant-responsive element (ARE) cytoprotective system mediated by the transcription factor NF-E2 p45-related factor 2 (Nrf2) serves as a primary defense against the oxidative stress triggered by particulate matter. In this study, using a cell-based ARE-reporter assay, the fine fractions of the fly ash collected from the municipal solid waste incinerators at four cities in China were examined for their ability to activate Nrf2/ARE signaling. We found that, at a non-lethal dose, all the fly ash samples were able to activate the ARE-reporter gene in a dose- and redox-dependent manner, and this was correlated with their cytotoxicity and their ability to induce DNA damage. Study of the kinetics revealed that fly ash particles elicited a prolonged activation of the ARE-reporter activity. Upon exposure to the particles, the ARE-luciferase activity significantly increased in 2 h, reached a peak at 24 h, and remained high level at 72 h. This was in contrast to the transient activation of the ARE-reporter gene triggered by the Nrf2 activators tert-butylhydroquinone and sulforaphane, while ARE-luciferase activity dropped to the basal level at 72 h from the peak at 24 h. These results demonstrate the robustness of using cell-based ARE-reporter assays to evaluate the oxidative potential of fly ash. Our novel findings suggest that the sustained activation of the Nrf2/ARE signaling pathway induced by fly ash particles perturbs cellular redox homeostasis, which in turn contributes to toxicity.

Nrf2 signaling pathway: Pivotal roles in inflammation.

Inflammation is the most common feature of many chronic diseases and complications, while playing critical roles in carcinogenesis. Several studies have demonstrated that Nrf2 contributes to the anti-inflammatory process by orchestrating the recruitment of inflammatory cells and regulating gene expression through the antioxidant response element (ARE). The Keap1 (Kelch-like ECH-associated protein)/Nrf2 (NF-E2 p45-related factor 2)/ARE signaling pathway mainly regulates anti-inflammatory gene expression and inhibits the progression of inflammation. Therefore, the identification of new Nrf2-dependent anti-inflammatory phytochemicals has become a key point in drug discovery. In this review, we discuss the members of the Keap1/Nrf2/ARE signal pathway and its downstream genes, the effects of this pathway on animal models of inflammatory diseases, and crosstalk with the NF-κB pathway. In addition we also discuss about the regulation of NLRP3 inflammasome by Nrf2. Besides this, we summarize the current scenario of the development of anti-inflammatory phytochemicals and others that mediate the Nrf2/ARE signaling pathway.

Theoretical study on the gas adsorption capacity and selectivity of CPM-200-In/Mg and CPM-200-In/Mg-X (-X = -NH2, -OH, -N, -F).

The adsorption capacities of a heterometallic metal-organic framework (CPM-200-In/Mg) to VOCs (HCHO, C2H4, CH4, C2H2, C3H8, C2H6, C2H3Cl, C2H2Cl2, CH2Cl2 and CHCl3) and some inorganic gas molecules (HCN, SO2, NO, CO2, CO, H2S and NH3), as well as its selectivity in ternary mixture systems of natural gas and post-combustion flue gas are theoretically explored at the grand canonical Monte Carlo (GCMC) and density functional theory (DFT) levels. It is shown that CPM-200-In/Mg is suitable for the adsorption of VOCs, particularly for HCHO (up to 0.39 g g-1 at 298 K and 1 bar), and the adsorption capacities of some inorganic gas molecules such as SO2, H2S and CO2 match well with the sequence of their polarizability (SO2 > H2S > CO2). The large adsorption capacities of HCN and HCHO in the framework result from the strong interaction between adsorbates and metal centers, based on analyzing the radial distribution functions (RDF). Comparing C2H4 and CH4 molecules interacting with CPM-200-In/Mg by VDW interaction, we speculate that the high adsorption capacities of their chlorine derivatives in the framework could be due to the existence of halogen bonding or strong electrostatic and VDW interactions. It is found that the basic groups, including -NH2, -N and -OH, can effectively improve both the adsorption capacities and selectivity of CPM-200-In/Mg for harmful gases. Note that the adsorption capacity of CPM-200-In/Mg-NH2 (site 2) (245 cm3 g-1) for CO2 exceeded that of MOF-74-Mg (228 cm3 g-1) at 273 K and 1 bar and that for HCHO can reach 0.41 g g-1, which is almost twice that of 438-MOF and nearly 45 times of that in active carbon. Moreover, for natural gas mixtures, the decarburization and desulfurization abilities of CPM-200-In/Mg-NH2 (site 2) have exceeded those of the MOF-74 series, while for post-combustion flue gas mixtures, the desulfurization ability of CPM-200-In/Mg-NH2 (site 2) is still comparable to those of the MOF-74 series at 303 K and 4 MPa. We hope that the current theoretical study could guide experimental research in the future.

Modulation of NRF2 signaling pathway by nuclear receptors: implications for cancer.

Nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also known as Nfe2l2) plays a critical role in regulating cellular defense against electrophilic and oxidative stress by activating the expression of an array of antioxidant response element-dependent genes. On one hand, NRF2 activators have been used in clinical trials for cancer prevention and the treatment of diseases associated with oxidative stress; on the other hand, constitutive activation of NRF2 in many types of tumors contributes to the survival and growth of cancer cells, as well as resistance to anticancer therapy. In this review, we provide an overview of the NRF2 signaling pathway and discuss its role in carcinogenesis. We also introduce the inhibition of NRF2 by nuclear receptors. Further, we address the biological significance of regulation of the NRF2 signaling pathway by nuclear receptors in health and disease. Finally, we discuss the possible impact of NRF2 inhibition by nuclear receptors on cancer therapy.

Butylated hydroxyanisole induces distinct expression patterns of Nrf2 and detoxification enzymes in the liver and small intestine of C57BL/6 mice.

Butylated hydroxyanisole (BHA) is widely used as an antioxidant and preservative in food, food packaging and medicines. Its chemopreventive properties are attributing to its ability to activate the transcription factor NF-E2 p45-related factor 2 (Nrf2), which directs central genetic programs of detoxification and protection against oxidative stress. This study was to investigate the histological changes of Nrf2 and its regulated phase II enzymes Nqo1, AKR1B8, and Ho-1 in wild-type (WT) and Nrf2(-/-) mice induced by BHA. The mice were given a 200mg/kg oral dose of BHA daily for three days. Immunohistochemistry revealed that, in the liver from WT mice, BHA increased Nqo1 staining in hepatocytes, predominately in the pericentral region. In contrast, the induction of AKR1B8 appeared mostly in hepatocytes in the periportal region. The basal and inducible Ho-1 was located almost exclusively in Kupffer cells. In the small intestine from WT mice, the inducible expression patterns of Nqo1 and AKR1B8 were nearly identical to that of Nrf2, with more intense staining in the villus than that the crypt. Conversely, Keap1 was more highly expressed in the crypt, where the proliferative cells reside. Our study demonstrates that BHA elicited differential expression patterns of phase II-detoxifying enzymes in the liver and small intestine from WT but not Nrf2(-/-) mice, demonstrating a cell type specific response to BHA in vivo.

Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is over-expressed in many types of tumor, promotes tumor growth, and confers resistance to anticancer therapy. Hence, Nrf2 is regarded as a novel therapeutic target in cancer. Previously, we reported that luteolin is a strong inhibitor of Nrf2 in vitro. Here, we showed that luteolin reduced the constitutive expression of NAD(P)H quinone oxidoreductase 1 in mouse liver in a time- and dose-dependent manner. Further, luteolin inhibited the expression of antioxidant enzymes and glutathione transferases, decreasing the reduced glutathione in the liver of wild-type mice under both constitutive and butylated hydroxyanisole-induced conditions. In contrast, such distinct responses were not detected in Nrf2(-/-) mice. In addition, oral administration of luteolin, either alone or combined with intraperitoneal injection of the cytotoxic drug cisplatin, greatly inhibited the growth of xenograft tumors from non-small-cell lung cancer (NSCLC) cell line A549 cells grown subcutaneously in athymic nude mice. Cell proliferation, the expression of Nrf2, and antioxidant enzymes were all reduced in tumor xenograft tissues. Furthermore, luteolin enhanced the anti-cancer effect of cisplatin. Together, our findings demonstrated that luteolin inhibits the Nrf2 pathway in vivo and can serve as an adjuvant in the chemotherapy of NSCLC.

Aberrant estrogen receptor alpha expression correlates with hepatocellular carcinoma metastasis and its mechanisms.

BACKGROUND/AIMS: Metastasis one of the obstacles before poor prognosis of hepatocellular carcinoma (HCC) is improved. Estrogen receptor alpha (ERalpha) plays an important role in the development and progression of HCC. However, the molecular mechanism of ERalpha in mediating HCC metastasis is still unclear. The aim of the present study was to detect aberrant ERalpha expression in HCC and elucidate its possible mechanisms in HCC metastasis. METHODOLOGY: We detected expression of ERalpha, phospho-estrogen receptor alpha (p-ERalpha), nuclear factor kappa B (NF-kappaB) p65 and Matrix metalloproteinase-9 (MMP-9) between HCC tissues with portal vein tumor thrombus (PVTT) and those without PVTT by immunohistochemical method. Moreover, the expression of above parameters was also determined in HCC cells of different metastatic potential by using immunocytochemical and reverse transcriptase-polymerase chain reaction (RT-PCR) methods. RESULTS: The expression of ERalpha and p-ERalpha was lower in HCC with PVTT than those without PVTT. Meanwhile, the expression pattern of above parameters was also similar in HCC cells of different metastatic potential, whereas, the expression of NF-kappaB p65 and MMP-9 was higher in HCC with PVTT than those without PVTT. The expression of NF-kappaB p65 and MMP-9 in HCC cells was also analogous to the tissues. CONCLUSIONS: These results demonstrated that expression of ERalpha, p-ERalpha, NF-kappaB p65 and MMP-9 correlated with invasion and metastasis in HCC. The mechanism of HCC metastasis may mediate through cross-talk between the NF-KB and ER signaling pathways. Meanwhile, ERa regulated MMP-9 through NF-kappaB indirectly.

Effects of exogenous melatonin on the osmotic regulation and antioxidant capacity of Ginkgo biloba seedlings under salt stress.

We investigated the effects of exogenous melatonin on the osmotic regulation and antioxidant capacity of 4-year-old Ginkgo biloba seedlings under salt stress. There were three treatments, with low (50 mmol·L-1), medium (100 mmol·L-1), and high (200 mmol·L-1) NaCl stress. Leaves were sprayed and the soil was watered with melatonin solution (0, 0.02, 0.1, 0.5 mmol·L-1). The results showed that saline stress significantly inhibited the osmoregulation and antioxidant capacities of G. biloba seedlings. Application of exogenous melatonin at appropriate concentrations (0.02, 0.1 mmol·L-1) under salt stress could promote plant growth, reduce the rate of electrolyte leakage, decrease the content of flavonoids and malonic dialdehyde, and enhance peroxidase and superoxide dismutase activities in leaves. High concentration (0.5 mmol·L-1) of exogenous melatonin would aggravate the oxidative and osmotic stresses. The 0.02 and 0.1 mmol·L-1 exogenous melatonin alleviated osmotic stress and oxidative stress in G. biloba seedlings under salt stress, while the 0.02 mmol·L-1 exogenous melatonin treatment had the best effect on NaCl stress alleviation. Ground diameter, branch width, branch length, electrolyte leakage rate, superoxide dismutase activity, and flavonoids content could be used as the key indices for rapid identification of the degree of salt stress in G. biloba seedlings.

Design, synthesis and biological evaluation of piperine derivatives as potent antitumor agents.

A series of piperine derivatives were designed and successfully synthesized. The antitumor activities of these compounds against 293 T human normal cells, as well as MDA-MB-231 (breast) and Hela (cervical) cancer cell lines, were assessed through the MTT assay. Notably, compound H7 exhibited moderate activity, displaying reduced toxicity towards non-tumor 293 T cells while potently enhancing the antiproliferative effects in Hela and MDA-MB-231 cells. The IC50 values were determined to be 147.45 ± 6.05 µM, 11.86 ± 0.32 µM, and 10.50 ± 3.74 µM for the respective cell lines. In subsequent mechanistic investigations, compound H7 demonstrated a dose-dependent inhibition of clone formation, migration, and adhesion in Hela cells. At a concentration of 15 µM, its inhibitory effect on Hela cell function surpassed that of both piperine and 5-Fu. Furthermore, compound H7 exhibited promising antitumor activity in vivo, as evidenced by significant inhibition of tumor angiogenesis and reduction in tumor weight in a chicken embryo model. These findings provide a valuable scientific foundation for the development of novel and efficacious antitumor agents, particularly highlighting the potential of compound H7 as a therapeutic candidate for cervical cancer and breast cancer.

Electrophilic tuning of the chemoprotective natural product sulforaphane.

Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate derived from cruciferous vegetables, is a highly potent inducer of phase 2 cytoprotective enzymes and can protect against electrophiles including carcinogens, oxidative stress, and inflammation. The mechanism of action of sulforaphane is believed to involve modifications of critical cysteine residues of Keap1, which lead to stabilization of Nrf2 to activate the antioxidant response element of phase 2 enzymes. However, the dithiocarbamate functional group formed by a reversible reaction between isothiocyanate of sulforaphane and sulfhydryl nucleophiles of Keap1 is kinetically labile, and such modification in intact cells has not yet been demonstrated. Here we designed sulforaphane analogs with replacement of the reactive isothiocyanate by the more gentle electrophilic sulfoxythiocarbamate group that also selectively targets cysteine residues in proteins but forms stable thiocarbamate adducts. Twenty-four sulfoxythiocarbamate analogs were synthesized that retain the structural features important for high potency in sulforaphane analogs: the sulfoxide or keto group and its appropriate distance to electrophilic functional group. Evaluation in various cell lines including hepatoma cells, retinal pigment epithelial cells, and keratinocytes as well as in mouse skin shows that these analogs maintain high potency and efficacy for phase 2 enzyme induction as well as the inhibitory effect on lipopolysaccharide-induced nitric oxide formation like sulforaphane. We further show in living cells that a sulfoxythiocarbamate analog can label Keap1 on several key cysteine residues as well as other cellular proteins offering new insights into the mechanism of chemoprotection.

NRF2 has a splicing regulatory function involving the survival of motor neuron (SMN) in non-small cell lung cancer.

The nuclear factor erythroid 2-like 2 (NFE2L2; NRF2) signaling pathway is frequently deregulated in human cancers. The critical functions of NRF2, other than its transcriptional activation, in cancers remain largely unknown. Here, we uncovered a previously unrecognized role of NRF2 in the regulation of RNA splicing. Global splicing analysis revealed that NRF2 knockdown in non-small cell lung cancer (NSCLC) A549 cells altered 839 alternative splicing (AS) events in 485 genes. Mechanistic studies demonstrated that NRF2 transcriptionally regulated SMN mRNA expression by binding to two antioxidant response elements in the SMN1 promoter. Post-transcriptionally, NRF2 was physically associated with the SMN protein. The Neh2 domain of NRF2, as well as the YG box and the region encoded by exon 7 of SMN, were required for their interaction. NRF2 formed a complex with SMN and Gemin2 in nuclear gems and Cajal bodies. Furthermore, the NRF2-SMN interaction regulated RNA splicing by expressing SMN in NRF2-knockout HeLa cells, reverting some of the altered RNA splicing. Moreover, SMN overexpression was significantly associated with alterations in the NRF2 pathway in patients with lung squamous cell carcinoma from The Cancer Genome Atlas. Taken together, our findings suggest a novel therapeutic strategy for cancers involving an aberrant NRF2 pathway.

Survey and analysis of willingness to use mobile medical services and influencing factors of TB patients treated at home.

INTRODUCTION: The objective of this study was to investigate the willingness of patients with tuberculosis (TB) to use mobile medical services (mHealth) and its influencing factors, so as to provide theoretical guidance for optimizing the TB mobile medical platform and improve the willingness of patients to use mHealth. METHODOLOGY: In this cross-sectional study, convenience sampling method was used to investigate patients with TB from the outpatient clinics of two TB specialized hospitals (Beijing Thoracic Tumor and Tuberculosis Hospital and Tuberculosis Prevention and Treatment Hospital of Shaanxi Province) from January to June 2021 using a self-designed questionnaire. RESULTS: Out of 231 patients, only 90 (38.96%) were aware of mHealth services, and 63 (27.27%) had used mHealth services. Among the 63 patients who had used mHealth services, the proportion of mobile medical forms based on WeChat platform was 74.89%. Patients' willingness to use mHealth was scored (11.49 ± 2.53). Univariate analysis showed that the scores of patients' willingness to use mHealth differed by gender and the different ways of affording healthcare (p < 0.05). Regression analysis showed that the influencing factors of willingness to use mHealth in patients with TB included attitude towards use (0.750), health beliefs (0.091) and social impact (0.169) (adjusted R2 = 0.781, p < 0.001). CONCLUSIONS: Patients' awareness of the advantages of the new medical model needs to be improved. Optimized design can improve the willingness of patients to use mHealth services and improve the role of mHealth in patient management.

Newly synthesized bis-benzimidazole derivatives exerting anti-tumor activity through induction of apoptosis and autophagy.

In this study, a new series of bis-benzimidazole derivatives were designed and synthesized. Most of these new compounds showed significant anti-tumor activity in vitro compared to Hoechst 33258. Among them, the most potent compound 8 had the IC(50) values of 0.56µM for HL60 (Human promyelocytic leukemia cells) tumor cell line and 0.58µM for U937 (Human leukemic monocyte lymphoma cells) tumor cell line. Subsequent toxicity study on human peripheral blood mononuclear cells (PBMC) showed that compound 8 exhibited less toxicity than 5-FU. We also found that apoptosis and autophagy were simultaneously induced by compound 8 in HL60 cells, and inhibition of autophagy by 3-MA decreased compound 8-induced apoptosis, indicating that they acted in synergy to exert tumor cell death.