Search results for: TLR4/NF-κB pathway

Authors: Hanan M. Hassan, Laila Abouzeid, Lamya H. Al-Wahaibi, George S. G. Shehatou, Ali A. El-Emam

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Cancer is a major public health problem and the second leading cause of death worldwide. In 2020, cancer diagnosis and treatment have been negatively affected by the coronavirus 2019 (COVID-19) pandemic. During the quarantine, because of the limited access to healthcare and avoiding exposure to COVID-19 as a contagious disease; patients of cancer suffered deferments in follow-up and treatment regimens leading to substantial worsening of disease, death, and increased healthcare costs. Thus, this study is designed to investigate the molecular mechanisms by which adamantne derivatives attenuate hepatocllular carcinoma experimentally and theoretically. There is a close association between increased resistance to anticancer drugs and defective apoptosis that considered a causative factor for oncogenesis. Cancer cells use different molecular pathways to inhibit apoptosis, BAX and Bcl-2 proteins have essential roles in the progression or inhibition of intrinsic apoptotic pathways triggered by mitochondrial dysfunction. Therefore, their balance ratio can promote the cellular apoptotic fate. In this study, the in vitro cytotoxic effects of seven synthetic adamantyl isothiorea derivatives were evaluated against five human tumor cell lines by MTT assay. Compounds 5 and 6 showed the best results, mostly against hepatocellular carcinoma (HCC). Hence, in vivo studies were performed in male Sprague-Dawley (SD) rats in which experimental hepatocellular carcinoma was induced with thioacetamide (TAA) (200 mg/kg, i.p., twice weekly) for 16 weeks. The most promising compounds, 5 and 6, were administered to treat liver cancer rats at a dose of 10 mg/kg/day for an additional two weeks, and the effects were compared with doxorubicin (DR), the anticancer drug. Hepatocellular carcinoma was evidenced by a dramatic increase in liver indices, oxidative stress markers, and immunohistochemical studies that were accompanied by a plethora of inflammatory mediators and alterations in the apoptotic cascade. Our results showed that treatment with adamantane derivatives 5 and 6 significantly suppressed fibrosis, inflammation, and other histopathological insults resulting in the diminished formation of hepatocyte tumorigenesis. Moreover, administration of the tested compounds resulted in amelioration of EGFR protein expression, upregulation of BAX, and lessening down of Bcl-2 levels that prove their role as apoptosis inducers. Also, the docking simulations performed for adamantane showed good fit and binding to the EGFR protein through hydrogen bond formation with conservative amino acids, which gives a shred of strong evidence for its hepatoprotective effect. In most analyses, the effects of compound 6 were more comparable to DR than compound 5. Our findings suggest that adamantane derivatives 5 and 6 are shown to have cytotoxic activity against HCC in vitro and in vivo, by more than one mechanism, possibly by inhibiting the TLR4-MyD88-NF-κB pathway and targeting EGFR signaling.

Keywords: adamantane, EGFR, HCC, apoptosis

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Authors: Zhaoguo Liu, Cunsi Shen, Yin Lu

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Growing evidence has shown that menthol has potent anticancer activity in various human cancers. However, its effect on skin cancer remains largely unknown. In the present study, we investigated the chemopreventive potential of menthol against 7, 12-dimethylbenz[a] anthracene(DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin tumorigenesis in ICR mice. Our results showed that menthol significantly inhibited TPA-induced inflammatory responses and pro-inflammatory cytokine release. We also found that menthol treatment significantly inhibited TPA-induced lipid peroxidation (LPO), mouse UDP-glucumno-syltransferase (UGT), mouse NADH Dehydrogenase, Quinone 1 (NQO1) release. Furthermore, we found menthol treatment significantly inhibited the tumor incidence and number of tumors (P < 0.001). Interestingly, we observed that menthol treatment significantly inhibited TPA-induced altered activity of NF-κB in skin tumor. Consistently, menthol-treated tumors also showed significantly suppressed the Ras-Raf-ERK signaling pathway. Thus, our results suggest that menthol inhibits DMBA/TPA-induced skin tumorigenesis by attenuating the Ras and inhibiting NF-κB activity via inhibition of inflammation responses and pro-inflammatory cytokine release.

Keywords: DMBA/TPA, NF-κB, Ras-Raf-ERK, skin tumorigenesis

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Authors: Wei Xiao, Gangzhi Cai, Xingliang Qin, Hongyan Ren, Zaidong Hua, Zhe Zhu, Hongwei Xiao, Ximin Zheng, Jie Yao, Yanzhen Bi

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Myostatin (MSTN) is the master regulator of double muscling phenotype with overgrown muscle and decreased fatness in animals, but its action mode to regulate fat deposition remains to be elucidated. In this study a swin-specific pathway through which MSTN acts to regulate the fat deposition was deciphered. Deep sequenincing of the mRNA and miRNA of fat tissues of MSTN knockout (KO) and wildtype (WT) pigs discovered the positive correlation of myocyte enhancer factor 2C (MEF2C) and fat-inhibiting miR222 expression, and the inverse correlation of miR222 and stearoyl-CoA desaturase 5 (SCD5) expression. SCD5 is rodent-absent and expressed only in pig, sheep and cattle. Fatty acid spectrum of fat tissues revealed a lower percentage of oleoyl-CoA (18:1) and palmitoleyl CoA (16:1) in MSTN KO pigs, which are the catalyzing products of SCD5-mediated desaturation of steroyl CoA (18:0) and palmitoyl CoA (16:0). Blood metrics demonstrated a 45% decline of triglyceride (TG) content in MSTN KO pigs. In light of these observations we hypothesized that MSTN might act through MEF2C/miR222/SCD5 pathway to regulate desaturation of fatty acid as well as triglyceride synthesis in pigs. To this end, real-time PCR and Western blotting were carried out to detect the expression of the three genes stated above. These experiments showed that MEF2C expression was up-regulated by nearly 2-fold, miR222 up-regulated by nearly 3-fold and SCD5 down-regulated by nearly 50% in MSTN KO pigs. These data were consistent with the expression change in deep sequencing analysis. Dual luciferase reporter was then used to confirm the regulation of MEF2C upon the promoter of miR222. Ecotopic expression of MEF2C in preadipocyte cells enhanced miR222 expression by 3.48-fold. CHIP-PCR identified a putative binding site of MEF2C on -2077 to -2066 region of miR222 promoter. Electrophoretic mobility shift assay (EMSA) demonstrated the interaction of MEF2C and miR222 promoter in vitro. These data indicated that MEF2C transcriptionally regulates the expression of miR222. Next, the regulation of miR222 on SCD5 mRNA as well as its physiological consequences were examined. Dual luciferase reporter testing revealed the translational inhibition of miR222 upon the 3´ UTR (untranslated region) of SCD5 in preadipocyte cells. Transfection of miR222 mimics and inhibitors resulted in the down-regulation and up-regulation of SCD5 in preadipocyte cells respectively, consistent with the results from reporter testing. RNA interference of SCD5 in preadipocyte cells caused 26.2% reduction of TG, in agreement with the results of TG content in MSTN KO pigs. In summary, the results above supported the existence of a molecular pathway that MSTN signals through MEF2C/miR222/SCD5 to regulate the fat deposition in pigs. This swine-specific pathway offers potential molecular markers for the development and breeding of a new pig line with optimised fatty acid composition. This would benefit human health by decreasing the takeup of saturated fatty acid.

Keywords: fat deposition, MEF2C, miR222, myostatin, SCD5, pig

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Authors: Dong-Cheol Jeong, Jookyung Lee, Yu Hyeon Ro, Changsik Song

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The design and synthesis of photo-active polymeric systems are important in regard to solar energy harvesting and utilization. In this study, we synthesized photo-active polymer, thin films, and polymer gel via iterative self-assembly using reversible metal-terpyridine (M-tpy) interactions. The photocurrent generated in the polymeric thin films with Zn(II) was much higher than those of other films. Apparent diffusion rate constant (kapp) was measured for the electron hopping process via potential-step chronoamperometry. As a result, the kapp for the polymeric thin films with Zn(II) was almost two times larger than those with other metal ions. We found that the anodic photocurrents increased with the inclusion of the multi-walled carbon nanotube (MWNT) layer. Inclusion of MWNTs can provide efficient electron transfer pathways. In addition, polymer gel based on interactions between terpyridine and metal ions was shown the photocatalytic activity. Interestingly, in the Mg-terpyridine gel, the reaction rate of benzylamine to imine photo-oxidative coupling was faster than Fe-terpyridine gel because the Mg-terpyridine gel has two steps electron transfer pathway but Fe-terpyridine gel has three steps electron transfer pathway.

Keywords: terpyridine, photocatalyst, self-assebly, metal-ligand

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Authors: Chia-Ju Peng, Shih-Jui Chen

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This paper proposes a method to discriminate electroencephalogram (EEG) signals between different concentration states using empirical mode decomposition (EMD). Brain-computer interface (BCI), also called brain-machine interface, is a direct communication pathway between the brain and an external device without the inherent pathway such as the peripheral nervous system or skeletal muscles. Attention level is a common index as a control signal of BCI systems. The EEG signals acquired from people paying attention or in relaxation, respectively, are decomposed into a set of intrinsic mode functions (IMF) by EMD. Fast Fourier transform (FFT) analysis is then applied to each IMF to obtain the frequency spectrums. By observing power spectrums of IMFs, the proposed method has the better identification of EEG attention level than the original EEG signals between different concentration states. The band power of IMF3 is the most obvious especially in β wave, which corresponds to fully awake and generally alert. The signal processing method and results of this experiment paves a new way for BCI robotic system using the attention-level control strategy. The integrated signal processing method reveals appropriate information for discrimination of the attention and relaxation, contributing to a more enhanced BCI performance.

Keywords: biomedical engineering, brain computer interface, electroencephalography, rehabilitation

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Authors: Akash Bera, Suraj Singh, Jacinta Dsouza, Ramakrishna V. Hosur, Pushpa Mishra

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Ultraviolet C (UVC) radiation induces apoptosis in mammalian cells and it is suggested that the mechanism by which this occurs is the mitochondrial pathway of apoptosis through the release of cytochrome c from the mitochondria into the cytosol. The Bcl-2 family of proteins pro-and anti-apoptotic is the regulators of the mitochondrial pathway of apoptosis. Upon UVC irradiation, the proliferation of apoptosis is enhanced through the downregulation of the anti-apoptotic protein Bcl-xl and up-regulation of Bax. Although the participation of the Bcl-2 family of proteins in apoptosis appears responsive to UVC radiation, to the author's best knowledge, it is unknown how the structure and, effectively, the function of these proteins are directly impacted by UVC exposure. In this background, we present here a structural rationale for the effect of UVC irradiation in restoring apoptosis using two of the relevant proteins, namely, Bid-FL and Bcl-xl ΔC, whose solution structures have been reported previously. Using a variety of biophysical tools such as circular dichroism, fluorescence and NMR spectroscopy, we show that following UVC irradiation, the structures of Bcl-xlΔC and Bid-FL are irreversibly altered. Bcl-xLΔC is found to be more sensitive to UV exposure than Bid-FL. From the NMR data, dramatic structural perturbations (α-helix to β-sheet) are seen to occur in the BH3 binding region, a crucial segment of Bcl-xlΔC which impacts the efficacy of its interactions with pro-apoptotic tBid. These results explain the regulation of apoptosis by UVC irradiation. Our results on irradiation dosage dependence of the structural changes have therapeutic potential for the treatment of cancer.

Keywords: Bid, Bcl-xl, UVC, apoptosis

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Authors: Mohamed A. Dkhil, Denis Delic, Saleh Al-Quraishy

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Coccidiosis causes considerable economic loss in the poultry industry. The current study aimed to investigate the response of goblet cells as well as the induced tissue damage during Eimeria papilata infection. Mice were infected with sporulated E. papillata oocyts. On day 5 post-infection, the fecal output was determined. Also, the jejunum was prepared for the histological, histochemical and molecular studies. Our results revealed that the intestinal coccidian infection with E. papillata induced a marked goblet cell hypoplasia and depleted mucus secretion. Also, the infection was able to alter the jejuna architecture and increased the apoptotic cells inside the villi. In addition, the real time PCR results indicated that, the inflammatory cytokines TNF-α, iNOS, IFN-y and IL-1β were significantly up-regulated. In contrast, the mRNA expression patterns of IL-6 in response to E. papillata infection did not differ significantly between control and infected mice. Moreover, the mRNA expression of TLR4 was significantly up-regulated, whereas the expression of MUC2 is significantly down-regulated upon infection. Further studies are required to understand the regulatory mechanisms of goblet cells related genes.

Keywords: goblet cells, Eimeria papillata, mice, jejunum

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Authors: Jyothi Nagraj, Sudeshna Mukherjee, Rajdeep Chowdhury

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Autophagy has recently been linked with cancer cell survival post drug insult contributing to acquisition of resistance. However, the molecular signaling governing autophagic survival response is poorly explored. In our study, in osteosarcoma (OS) cells cisplatin shock was found to activate both MAPK and autophagy signaling. An activation of JNK and autophagy acted as pro-survival strategy, while ERK1/2 triggered apoptotic signals upon cisplatin stress. An increased sensitivity of the cells to cisplatin was obtained with simultaneous inhibition of both autophagy and JNK pathway. Furthermore, we observed that the autophagic stimulation upon drug stress regulates other developmentally active signaling pathways like the Hippo pathway in OS cells. Cisplatin resistant cells were thereafter developed by repetitive drug exposure followed by clonal selection. Basal levels of autophagy were found to be high in resistant cells to. However, the signaling mechanism leading to autophagic up-regulation and its regulatory effect differed in OS cells upon attaining drug resistance. Our results provide valuable clues to regulatory dynamics of autophagy that can be considered for development of improved therapeutic strategy against resistant type cancers.

Keywords: JNK, autophagy, drug resistance, cancer

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Authors: Shiva Shakori Poshteh

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Lung cancer is a highly prevalent and devastating disease, representing a significant global health concern with profound implications for healthcare systems and society. Its high incidence, mortality rates, and late-stage diagnosis contribute to its formidable nature. To address these challenges, nanoparticle-based drug delivery has emerged as a promising therapeutic strategy. Curcumin (CUR), a natural compound derived from turmeric, has garnered attention as a potential nanomedicine for lung cancer treatment. Nanoparticle formulations of CUR offer several advantages, including improved drug delivery efficiency, enhanced stability, controlled release kinetics, and targeted delivery to lung cancer cells. CUR exhibits a diverse array of effects on cancer cells. It induces apoptosis by upregulating pro-apoptotic proteins, such as Bax and Bak, and downregulating anti-apoptotic proteins, such as Bcl-2. Additionally, CUR inhibits cell proliferation by modulating key signaling pathways involved in cancer progression. It suppresses the PI3K/Akt pathway, crucial for cell survival and growth, and attenuates the mTOR pathway, which regulates protein synthesis and cell proliferation. CUR also interferes with the MAPK pathway, which controls cell proliferation and survival, and modulates the Wnt/β-catenin pathway, which plays a role in cell proliferation and tumor development. Moreover, CUR exhibits potent antioxidant activity, reducing oxidative stress and protecting cells from DNA damage. Utilizing CUR as a standalone treatment is limited by poor bioavailability, lack of targeting, and degradation susceptibility. Nanoparticle-based delivery systems can overcome these challenges. They enhance CUR’s bioavailability, protect it from degradation, and improve absorption. Further, Nanoparticles enable targeted delivery to lung cancer cells through surface modifications or ligand-based targeting, ensuring sustained release of CUR to prolong therapeutic effects, reduce administration frequency, and facilitate penetration through the tumor microenvironment, thereby enhancing CUR’s access to cancer cells. Thus, nanoparticle-based CUR delivery systems promise to improve lung cancer treatment outcomes. This article provides an overview of lung cancer, explores CUR nanoparticles as a treatment approach, discusses the benefits and challenges of nanoparticle-based drug delivery, and highlights prospects for CUR nanoparticles in lung cancer treatment. Future research aims to optimize these delivery systems for improved efficacy and patient prognosis in lung cancer.

Keywords: lung cancer, curcumin, nanomedicine, nanoparticle-based drug delivery

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Authors: Azhar Jabareen, Mahmoud Huleihel

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BRCA-1 is a multifunctional tumor suppressor, whose expression is activated by the estrogen (E2)-liganded ERα receptor. The activated ERα is a transcriptional factor which activates various genes either by direct binding to the DNA at E2-responsive elements (EREs) and indirectly associated with a range of alternative non-ERE elements. Interference with BRCA-1 expression and/or functions leads to high risk of breast or/and ovarian cancer. Our lab investigated the involvement of Human T-cell leukemia Virus Type 1 (HTLV-1) in breast cancer, since HTLV-1 Tax was found to strongly inhibit BRCA-1 expression. In addition, long exposure of 12-O-tetradecanoylphorbol-13-acetate (TPA), which is one of the stress-inducing agents activated the HTLV-1 promoter. So here the involvement of TPA in breast cancer had been examined by testing the effect of TPA on BRCA-1 and ERE expression. The results showed that TPA activated both BRCA-1 and ERE expression. In the 12 hours TPA activated the tow promoters more than others time, and after 24 hours the level of the tow promoters was decreased. Tax inhibited BRCA-1 expression but did not succeed to inhibit the effect of TPA. Then the activation of the two promoters was not through ERα pathway because TPA had no effect on ERα binding to the two promoters of the BRCA-1 and ERE. Also, the activation was not via nuclear factor kappa B (NF-κB) pathway because when the inhibitory of NF-κB had been added to the TPA, it still activated the tow promoters. However, it seems that 53BP1 may be involved in TPA activation of these promoters because ectopic high expression of 53BP1 significantly reduced the TPA activity. In addition, in the presence of Bisindolylmaleimide-I (BI)- the inhibitor of Protein Kinase C (PKC)- there was no activation for the two promoters, so the PKC is agonized BRCA-1 and ERE activation.

Keywords: BRCA-1, ERE, HTLV-1, TPA

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Authors: Jma Hannan, Prawej Ansari, Yasser H. A. Abdel-Wahab, Peter R. Flatt

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Spirulina platensis (SP, Blue-green algae) have been accepted as a supplement for the treatment of pre and post-diabetes. The present study investigated the effects of butanol fraction from ethanol extract of S. platensis on insulin release from BRIN BD11 cells, isolated mouse islets, and perfused rat pancreas, as well as glucose homeostasis in type 2 diabetic rats and their molecular pathways. In a dose-dependent manner, S. platensis increased insulin release from mouse islets and pancreatic β-cells. The extract also elevated insulin release in perfused rat pancreas. Glucose, isobutylmethylxanthine, tolbutamide, and a depolarizing concentration of KCl significantly potentiated insulin release from BRIN BD11 cells. The effect of diazoxide and verapamil, as well as the absence of extracellular Ca2+ showed a reduction in insulin secretion. When administered orally together with glucose (2.5g/kg bw), S. platensis extract improved fasting and postprandial blood glucose in type 2 diabetes. These data suggest that the anti-diabetic activity of S. platensis is partly mediated by insulin secretion via the KATP channel-dependent pathway/the intracellular cAMP pathway.

Keywords: Insulin, glucose, S. platensis, type 2 diabetes, medicinal plants

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Authors: Nouha Bouayed Abdelmoula, Rim Louati, Nawel Abdellaoui, Balkiss Abdelmoula, Oldez Kaabi, Walid Smaoui, Samir Aloulou

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Background and Aims: Cardiofaciocutaneous syndrome (CFC) is an autosomal dominant disorder with the vast majority of cases arising by a new mutation of BRAF, MEK1, MEK2, or rarely, KRAS genes. Here, we report a rare Tunisian case of CFC syndrome for whom we identify SOS1 mutation. Methods: Genomic DNA was obtained from peripheral blood collected in an EDTA tube and extracted from leukocytes using the phenol/chloroform method according to standard protocols. High resolution melting (HRM) analysis for screening of mutations in the entire coding sequence of PTPN11 was conducted first. Then, HRM assays to look for hot spot mutations coding regions of the other genes of the RAS-MAPK pathway (RAt Sarcoma viral oncogene homolog Mitogen-Activated Protein Kinases Pathway): SOS1, SHOC2, KRAS, RAF1, KRAS, NRAS, CBL, BRAF, MEK1, MEK2, HRAS, and RIT1, were applied. Results: Heterozygous SOS1 point mutation clustered in exon 10, which encodes for the PH domain of SOS1, was identified: c.1655 G > A. The patient was a 9-year-old female born from a consanguineous couple. She exhibited pulmonic valvular stenosis as congenital heart disease. She had facial features and other malformations of Noonan syndrome, including macrocephaly, hypertelorism, ptosis, downslanting palpebral fissures, sparse eyebrows, a short and broad nose with upturned tip, low-set ears, high forehead commonly associated with bitemporal narrowing and prominent supraorbital ridges, short and/or webbed neck and short stature. However, the phenotype is also suggestive of CFC syndrome with the presence of more severe ectodermal abnormalities, including curly hair, keloid scars, hyperkeratotic skin, deep plantar creases, and delayed permanent dentition with agenesis of the right maxillary first molar. Moreover, the familial history of the patient revealed recurrent brain malignancies in the paternal family and epileptic disease in the maternal family. Conclusions: This case report of an overlapping RASopathy associated with SOS1 mutation and familial history of brain tumorigenesis is exceptional. The evidence suggests that RASopathies are truly cancer-prone syndromes, but the magnitude of the cancer risk and the types of cancer partially overlap.

Keywords: cardiofaciocutaneous syndrome, CFC, SOS1, brain cancer, germline mutation

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Authors: Hager Elsheikh, Juliane Glaubitz, Frank Ulrich Weiss, Matthias Sendler

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Aim: Acute pancreatitis (AP) and chronic pancreatitis (CP) are both accompanied by a prominent immune response which influences the course of disease. Whereas during AP the pro-inflammatory immune response dominates, during CP a fibroinflammatory response regulates organ remodeling. The transcription factor signal transducer and activator of transcription 6 (STAT6) is a crucial part of the Type 2 immune response. Here we investigate the role of STAT6 in a mouse model of AP and CP. Material and Methods: AP was induced by hourly repetitive i.p. injections of caerulein (50µg/kg/bodyweight) in C57Bl/6 J and STAT6-/- mice. CP was induced by repetitive caerulein injections 6 times a day, 3 days a week over 4 weeks. Disease severity was evaluated by serum amylase/lipase measurement, H&E staining of pancreas. Pancreatic infiltrate was characterized by immunofluorescent labeling of CD68, CD206, CCR2, CD4 and CD8. Pancreas fibrosis was evaluated by Azan blue staining. qRT-PCR was performed of Arg1, Nos2, Il6, Il1b, Col3a, Socs3 and Ym1. Affymetrix chip array analyses were done to illustrate the IL4/IL13/STAT6 signaling in bone marrow derived macrophages. Results: AP severity is mitigated in STAT6-/- mice, as shown by decreased serum amylase and lipase, as well as histological damage. CP mice surprisingly showed only slightly reduced fibrosis of the pancreas. Also staining of CD206 a classical marker of alternatively activated macrophages showed no decrease of M2-like polarization in the absence of STAT6. In contrast, transcription profile analysis in BMDM showed complete blockade of the IL4/IL13 pathway in STAT6-/- animals. Conclusion: STAT6 signaling pathway is protective during AP and mitigates the pancreatic damage. During chronic pancreatitis the IL4/IL13 – STAT6 axisis involved in organ fibrogenesis. Notably, fibrosis is not dependent on a single signaling pathway, and alternative macrophage activation is also complex and involves different subclasses (M2a, M2b, M2c and M2d) which could be independent of the IL4/IL13 STAT6 axis.

Keywords: chronic pancreatitis, macrophages, IL4/IL13, Type immune response

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Authors: Chaiwat Boonkaewwan, Anutian Suklek, Jatuporn Rattanasrisomporn, Autchara Kayan

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Toll-like receptors (TLR) are conserved microbial sensing receptors located on cell surface that are able to detect different pathogens. The aim of the present study is to examine the expression of TLR gene in peripheral blood mononuclear cell of Betong (KU line) chicken. Blood samples were collected from healthy 12 Betong (KU line) chicken. PBMCs were isolated and maintained in RPMI1640 with 10% FBS, penicillin and streptomycin. Cell viability was determined by trypan blue dye exclusion test. The expression of TLRs gene was investigated by polymerase chain reaction (PCR) technique. Results showed that PBMCs viability from Betong (KU line) chicken was 95.38 ± 1.06%. From the study of TLRs gene expression, results indicated that there are expressions of TLR1.1 TLR1.2 TLR2.1 TLR2.2 TLR3 TLR4 TLR5 TLR 7 TLR15 and TLR21 in PBMCs of Betong (KU line) chicken. In conclusion, PBMCs isolated from blood of Betong (KU line) chicken had a high cell viability ( > 95%). The expression of TLRs in chicken was all found in PBMCs, which indicated that PBMC isolated from the blood of Betong (KU line) chicken can be used as an in vitro immune responses study.

Keywords: toll-like receptor, Betong (KU line) chicken, peripheral blood mononuclear cells

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Authors: Nandhana Vivek, Bhaskar Gogoi, Ayyavu Mahesh

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Breast cancer metastasis plays a key role in cancer progression and fatality. The present study examines the potential causes of metastasis in breast cancer by investigating the novel interactions between genes and their pathways. The gene expression profile of GSE99394, GSE1246464, and GSE103865 was downloaded from the GEO data repository to analyze the differentially expressed genes (DEGs). Protein-protein interactions, target factor interactions, pathways and gene relationships, and functional enrichment networks were investigated. The proliferation pathway was shown to be highly expressed in breast cancer progression and metastasis in all three datasets. Gene Ontology analysis revealed 11 DEGs as gene targets to control breast cancer metastasis: LYN, DLGAP5, CXCR4, CDC6, NANOG, IFI30, TXP2, AGTR1, MKI67, and FTH1. Upon studying the function, genomic and proteomic data, and pathway involvement of the target genes, DLGAP5 proved to be a promising candidate due to it being highly differentially expressed in all datasets. The study takes a unique perspective on the avenues through which DLGAP5 promotes metastasis. The current investigation helps pave the way in understanding the role DLGAP5 plays in metastasis, which leads to an increased incidence of death among breast cancer patients.

Keywords: genomics, metastasis, microarray, cancer

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Authors: Connick K, Lalor R, Murphy A, O’Neill S. M., Rabab S. Zalat, Eman E. El Shanawany

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Cryptosporidium parvum is an opportunistic intracellular parasite that causes mild to severe diarrhea in human and animal populations and is an important zoonotic disease globally. In immunocompromised hosts, infection Canbe life-threatening as no effective treatments are currently available to control infection. To increase our understanding of the mechanisms that play a role in host-parasite interactions at the level of the immune response, we investigated the effects of Cryptosporidium parvum antigen (CPA) on bone marrow-derived (DCS). Herein we examined cytokine secretion and cell surface marker expression on DCs exposed to CPA. We also measured cytokine production in CD4+ cells co-cultured with CPA primed DCs in the presence of anti-CD3. CPA induced a significant increase in the production of interleukin(IL)-12p40, IL-10, IL-6, and TNF-α by DCs and enhanced the expression of the cell surface markers TLR4, CD80, CD86, and MHC11. CPA primed DC co-cultured in the presence of anti-CD3 with CD4+ T-cells inhibited the secretion of Th2 associated cytokines, notably IL-5 and IL-13, with no effects on the secretions of interferon (IFN)-γ, IL-2, IL-17, and IL-10. These findings support studies in the literature that CPA can induce the full maturation of DCs that subsequently initiate Th1 immune responses critical to the resolution of C. parvum infection.

Keywords: cryptosporidium parvum, dendritic cells, IL-12 p70, cell surface marker

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Authors: S. K. Ashiquer Rahman

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The paper concentrates on the importance of Sustainable Campus Strategies, emphasizing the significance of mobilizing Innovative technological tools for constructing effectiveness of higher education strategy and institutional cooperation for sustainable campus at the university level and preparing the university’s authority to face the upcoming higher education strategy and institutional cooperation difficulties to the Sustainable Campus Plan. Within a framework of Sustainable Campus Strategies and institutional cooperation, the paper discusses the significance of a set of reference points that will lead to operational activities for multi-stakeholder multi-criteria evaluation of Higher Education and Research Institutions relative to the Sustainable Campus criteria and potential action plan for the University’s Strategy and Institutional Cooperation. It makes mention of the emergence of the effectiveness of Higher Education Strategy and Institutional Cooperation as well as the necessity of mobilizing innovative technological methods and tools for constructing the effectiveness of this Process. The paper outlines the conceptual framing of a Sustainable Campus Strategy, Institutional Cooperation and Action Plan for a sustainable campus. Optimistically, these will be a milestone in higher education, a pathway to meet the imminent Sustainable Campus Strategy and Institutional Cooperation of the completive world, and be able to manage the required criteria for a Sustainable University.

Keywords: higher education strategy, institutional cooperation, sustainable campus, multi-criteria evaluation, innovative method and tools

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Authors: Richard White, Anne Drabble, Maureen O’Neill

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The University of the Sunshine Coast (USC) offers secondary school students in the final two years of school (Years 11 and 12, 16 – 18 years of age) an opportunity to participate in a program which provides an accelerated pathway to tertiary studies. Whilst still at secondary school, the students undertake two first year university subjects that are required subjects in USC undergraduate degree programs. The program is called Integrated Learning Pathway (ILP) and offers a range of disciplines, including business, design, drama, education, and engineering. Between 2010 and 2014, 38% of secondary students who participated in an ILP program commenced undergraduate studies at USC following completion of secondary school studies. The research reported here considers “before and after” literacy and numeracy competencies of students to determine what impact participation in the ILP program has had on their academic skills. Qualitative and quantitative data has been gathered via numeracy and literacy testing of the students, and a survey asking the students to self-evaluate their numeracy and literacy skills, and reflect on their views of these academic skills. The research will enable improved targeting of teaching strategies so that students will acquire not only course-specific learning outcomes but also collateral academic skills. This enhancement of academic skills will improve undergraduate experience and improve student retention.

Keywords: academic skills enhancement, accelerated pathways, improved teaching, student retention

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Authors: Mingxi Zhou, Jiří Kubásek, Iva Mozgová

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In Arabidopsis thaliana, histone 3 lysine 27 tri-methylation catalysed byPRC2 is playing essential functions in the regulation of plant development, growth, and reproduction[1-2]. Despite numerous studies related to the role of PRC2 in developmental control, how PRC2 works in the operational control in plants is unknown. In the present, the evidence that PRC2 probably participates in the regulation of retrograde singalling pathway in Arabidopsisis found. Firstly, we observed that the rosette size and biomass in PRC2-depletion mutants (clf-29 and swn-3) is significantly higher than WTunder medium light condition (ML: 125 µmol m⁻² s⁻²), while under medium high light condition (MHL: 300 µmol m⁻² s-2), the increase was reverse. Under ML condition, the photosynthesis related parameters determined by fluorCam did not show significant differences between WT and mutants, while the pigments concentration increased in the leaf of PRC2-depletion mutants, especially in swn. The dynamic of light-responsive genes and circadian clock genes expression by RT-qPCRwithin 24 hours in the mutants were comparable to WT. However, we observed upregulation of photosynthesis-associated nuclear genes in the PRC2-depletion mutants under chloroplast damaging condition (treated by lincomycin), corresponding to the so-called genome uncoupled (gun) phenotype. Here, we will present our results describing these phenotypes and our suggestion and outlook for studying the involvement of PRC2 in chloroplast-to-nucleus retrograde signalling.

Keywords: PRC2, retrograde signalling, light acclimation, photosyntheis

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Authors: Rassoli Aisa, Abrishami Movahhed Arezu, Faturaee Nasser, Seddighi Amir Saeed, Shafigh Mohammad

Abstract:

Cardiovascular diseases are one of the most common causes of mortality in developed countries. Coronary artery abnormalities and carotid artery stenosis, also known as silent death, are among these diseases. One of the treatment methods for these diseases is to create a deviatory pathway to conduct blood into the heart through a bypass surgery. The saphenous vein is usually used in this surgery to create the deviatory pathway. Unfortunately, a re-surgery will be necessary after some years due to ignoring the disagreement of mechanical properties of graft tissue and/or applied prostheses with those of host tissue. The objective of the present study is to clarify the viscoelastic behavior of human saphenous tissue. The stress relaxation tests in circumferential and longitudinal direction were done in this vein by exerting 20% and 50% strains. Considering the stress relaxation curves obtained from stress relaxation tests and the coefficients of the standard solid model, it was demonstrated that the saphenous vein has a non-linear viscoelastic behavior. Thereafter, the fitting with Fung’s quasilinear viscoelastic (QLV) model was performed based on stress relaxation time curves. Finally, the coefficients of Fung’s QLV model, which models the behavior of saphenous tissue very well, were presented.

Keywords: Viscoelastic behavior, stress relaxation test, uniaxial tensile test, Fung’s quasilinear viscoelastic (QLV) model, strain rate

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Authors: Ozlem Oral, Emre Taskin, Aysel Yuce, Serap Dokmeci, Devrim Gozuacik

Abstract:

Autophagy is an evolutionary conserved lysosome-dependent catabolic pathway, responsible for the degradation of long-lived proteins, abnormal aggregates and damaged organelles which cannot be degraded by the ubiquitin-proteasome system. Lysosomes degrade the substrates through the activity of lysosomal hydrolases and lysosomal membrane-bound proteins. Mutations in the coding region of these proteins cause malfunctional lysosomes, which contributes to the pathogenesis of lysosomal storage diseases. Gaucher disease is a lysosomal storage disease resulting from the mutation of a lysosomal membrane-associated glycoprotein called glucocerebrosidase and its cofactor saposin C. The disease leads to intracellular accumulation of glucosylceramide and other glycolipids. Because of the essential role of lysosomes in autophagic degradation, Gaucher disease may directly be linked to this pathway. In this study, we investigated the expression of autophagy and/or lysosome-related genes and proteins in fibroblast cells isolated from patients with different mutations. We carried out confocal microscopy analysis and examined autophagic flux by utilizing the differential pH sensitivities of RFP and GFP in mRFP-GFP-LC3 probe. We also evaluated lysosomal pH by active lysosome staining and lysosomal enzyme activity. Beside lysosomes, we also performed proteasomal activity and cell death analysis in patient samples. Our data showed significant attenuation in the expression of key autophagy-related genes and accumulation of their proteins in mutant cells. We found decreased the ability of autophagosomes to fuse with lysosomes, associated with elevated lysosomal pH and reduced lysosomal enzyme activity. Proteasomal degradation and cell death analysis showed reduced proteolytic activity of the proteasome, which consequently leads to increased susceptibility to cell death. Our data indicate that the major degradation pathways are affected by multifunctional lysosomes in mutant patient cells and may underlie in the mechanism of clinical severity of Gaucher patients. (This project is supported by TUBITAK-3501-National Young Researchers Career Development Program, Project No: 112T130).

Keywords: autophagy, Gaucher's disease, glucocerebrosidase, mutant fibroblasts

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Authors: Ayesha Waqar Khan, Mariam Altaf, Jamil Ahmad, Shaheen Shahzad

Abstract:

Kidney fibrosis is an anticipated outcome of possibly all types of progressive chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) signaling pathway is responsible for production of matrix-producing fibroblasts and myofibroblasts in diseased kidney. In this study, a discrete model of TGF-beta (transforming growth factor) and CTGF (connective tissue growth factor) was constructed using Rene Thomas formalism to investigate renal fibrosis turn over. The kinetic logic proposed by Rene Thomas is a renowned approach for modeling of Biological Regulatory Networks (BRNs). This modeling approach uses a set of constraints which represents the dynamics of the BRN thus analyzing the pathway and predicting critical trajectories that lead to a normal or diseased state. The molecular connection between TGF-beta, Smad 2/3 (transcription factor) phosphorylation and CTGF is modeled using GenoTech. The order of BRN is CTGF, TGF-B, and SMAD3 respectively. The predicted cycle depicts activation of TGF-B (TGF-β) via cleavage of its own pro-domain (0,1,0) and presentation to TGFR-II receptor phosphorylating SMAD3 (Smad2/3) in the state (0,1,1). Later TGF-B is turned off (0,0,1) thereby activating SMAD3 that further stimulates the expression of CTGF in the state (1,0,1) and itself turns off in (1,0,0). Elevated CTGF expression reactivates TGF-B (1,1,0) and the cycle continues. The predicted model has generated one cycle and two steady states. Cyclic behavior in this study represents the diseased state in which all three proteins contribute to renal fibrosis. The proposed model is in accordance with the experimental findings of the existing diseased state. Extended cycle results in enhanced CTGF expression through Smad2/3 and Smad4 translocation in the nucleus. The results suggest that the system converges towards organ fibrogenesis if CTGF remains constructively active along with Smad2/3 and Smad 4 that plays an important role in kidney fibrosis. Therefore, modeling regulatory pathways of kidney fibrosis will escort to the progress of therapeutic tools and real-world useful applications such as predictive and preventive medicine.

Keywords: CTGF, renal fibrosis signaling pathway, system biology, qualitative modeling

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Authors: Farnaz Yusuf, Naseem A. Gaur

Abstract:

The increase in environmental concerns, rapid depletion of fossil fuel reserves and intense interest in achieving energy security has led to a global research effort towards developing renewable sources of fuels. Second generation biofuels have attracted more attention recently as the use of lignocellulosic biomass can reduce fossil fuel dependence and is environment-friendly. Xylose is the main pentose and second most abundant sugar after glucose in lignocelluloses. Saccharomyces cerevisiae does not readily uptake and use pentose sugars. For an economically feasible biofuel production, both hexose and pentose sugars must be fermented to ethanol. Therefore, it is important to develop S. cerevisiae host platforms with more efficient xylose utilization. This work aims to construct a xylose fermenting yeast strains with engineered oxido-reductative pathway for xylose metabolism. Engineered strain was further improved by adaptive evolutionary engineering approach. The engineered strain is able to grow on xylose as sole carbon source with the maximum ethanol yield of 0.39g/g xylose and productivity of 0.139g/l/h at 96 hours. The further improvement in strain development involves over expression of pentose phosphate pathway and protein engineering of xylose reductase/xylitol dehydrogenase to change their cofactor specificity in order to reduce xylitol accumulation.

Keywords: biofuel, lignocellulosic biomass, saccharomyces cerevisiae, xylose

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Authors: Mansi Srivastava, Uzma Saqib, Adnan Naim, Anjali Roy, Dongfang Liu, Deepak Bhatnagar, Ravinder Ravinder, Mirza S. Baig

Abstract:

Macrophages polarize to proinflammatory M1 or anti-inflammatory M2 states with distinct physiological functions. This transition within the M1 to M2 phenotypes decides the nature, duration, and severity of an inflammatory response. However, inspite of a substantial understanding of the fate of these phenotypes, the underlying molecular mechanisms are not well understood. We have investigated the role of Neuronal nitric oxide synthase (NOS1) mediated regulation of Activator protein 1 (AP-1) transcription factor in macrophages as a critical effector of macrophage phenotypic change. Activator protein 1 (AP-1) is a group of dimeric transcription factors composed of jun, Fos, and ATF family proteins. We determined that NOS1-derived nitric oxide (NO) facilitate Fos and jun interaction which induces IL12 & IL23 expression. Pharmacological inhibition of NOS1 inhibits Fos and jun interaction but increases ATF2 and Fos dimerization. Switching of Fos and jun dimer to ATF2 and jun dimerization switches phenotype from IL–12high IL-23high IL-10low to IL–12low IL-23lowIL-10high phenotype, respectively. Together, these findings highlight a key role of the TLR4-NOS1-AP1 signaling axis in regulating macrophage polarization.

Keywords: inflammation, macrophage, lipopolysaccharide (LPS), proinflammatory cytokines, activator protein 1 (AP-1), neuronal nitric oxide synthase (NOS1)

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Authors: Ankan Roy, Niharika, Samir Kumar Patra

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Anomalous nexus of complex topological assemblies and spatiotemporal epigenetic choreography at chromosomal territory may forms the most sophisticated regulatory layer of gene expression in cancer. Colon cancer is one of the leading malignant neoplasms of the lower gastrointestinal tract worldwide. There is still a paucity of information about the complex molecular mechanisms of colonic cancerogenesis. Bioinformatics prediction and analysis helps to identify essential genes and significant pathways for monitoring and conquering this deadly disease. The present study investigates and explores potential hub genes as biomarkers and effective therapeutic targets for colon cancer treatment. Colon cancer patient sample containing gene expression profile datasets, such as GSE44076, GSE20916, and GSE37364 were downloaded from Gene Expression Omnibus (GEO) database and thoroughly screened using the GEO2R tool and Funrich software to find out common 2 differentially expressed genes (DEGs). Other approaches, including Gene Ontology (GO) and KEGG pathway analysis, Protein-Protein Interaction (PPI) network construction and hub gene investigation, Overall Survival (OS) analysis, gene correlation analysis, methylation pattern analysis, and hub gene-Transcription factors regulatory network construction, were performed and validated using various bioinformatics tool. Initially, we identified 166 DEGs, including 68 up-regulated and 98 down-regulated genes. Up-regulated genes are mainly associated with the Cytokine-cytokine receptor interaction, IL17 signaling pathway, ECM-receptor interaction, Focal adhesion and PI3K-Akt pathway. Downregulated genes are enriched in metabolic pathways, retinol metabolism, Steroid hormone biosynthesis, and bile secretion. From the protein-protein interaction network, thirty hub genes with high connectivity are selected using the MCODE and cytoHubba plugin. Survival analysis, expression validation, correlation analysis, and methylation pattern analysis were further verified using TCGA data. Finally, we predicted COL1A1, COL1A2, COL4A1, SPP1, SPARC, and THBS2 as potential master regulators in colonic cancerogenesis. Moreover, our experimental data highlights that disruption of lipid raft and RAS/MAPK signaling cascade affects this gene hub at mRNA level. We identified COL1A1, COL1A2, COL4A1, SPP1, SPARC, and THBS2 as determinant hub genes in colon cancer progression. They can be considered as biomarkers for diagnosis and promising therapeutic targets in colon cancer treatment. Additionally, our experimental data advertise that signaling pathway act as connecting link between membrane hub and gene hub.

Keywords: hub genes, colon cancer, DNA methylation, epigenetic engineering, bioinformatic predictions

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Authors: Hakam Alkhateeb

Abstract:

Oleuropein, the main constituent of leaves and fruits of the olive tree, has been demonstrated to exert beneficial effects on parameters relevant to the normal homeostatic mechanisms of glucose regulation in rat skeletal muscle. However, the antidiabetic effect of oleuropein, to our knowledge, has not been examined. Therefore, in this study, we examined whether oleuropein ameliorated palmitate-induced insulin resistance in skeletal muscle. To examine this question, insulin resistance was rapidly induced by incubating (12h) soleus muscle with a high concentration of palmitate(2mM). Subsequently, we attempted to restore insulin sensitivity by incubating (12h) muscles with oleuropien (1.5mM), while maintaining high concentrations of palmitate. Palmitate treatment for 12 h reduced insulin-stimulated glucose transport, GLUT4 translocationandAS160 phosphorylation. Oleuropein treatment (12 h) fully restoredinsulin-stimulated glucose transport, GLUT4translocationandAS160 phosphorylation. Inhibition of PI3K phosphorylation with wortmannin (1µM)did not affect the oleuropein-induced improvements in insulin-stimulated glucose transport, GLUT4 translocation, and AS160 phosphorylation. These results suggested that the improvements in these parameters cannot account for activating PI3K pathway. Taken altogether, it appears that oleuropein, through activation of another pathway like activated protein kinase (AMPK), may provide a possible strategy by which they ameliorate palmitate-induced insulin resistance in skeletal muscles.

Keywords: AS160, diabetes, GLUT4, oleuropein

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Authors: Maryam Zahedifard, Fadhil Lafta Faraj, Maryam Hajrezaie, Nazia Abdul Majid, Mahmood Ameen Abdulla, Hapipah Mohd Ali

Abstract:

In the current study, we prepared two new quinazoline schiff bases through condensation reaction of 2-aminobenzhydrazide with 5-bromosalicylaldehyde and 3-methoxy-5-bromosalicylaldehyde. The chemical structures of both newly synthesized compounds (1 and 2) were confirmed by FT-IR and X-ray crystallography studies. The cytotoxic effect of compounds was investigated against MCF-7 human breast cancer cells. MTT results showed that (1) and (2) decreased the viability of MCF-7 cells in a time-dependent manner, exhibiting an IC50 value of 3.23 ± 0.28 µg/mL and 3.41 ± 0.34 µg/mL, respectively, after a 72-hours treatment period. In contrast, they did not show significant anti-proliferative effect towards MCF-10A normal breast cells and WRL-68 normal liver cells. We found a perturbation in mitochondrial membrane potential and increased cytochrome c release from the mitochondria to the cytosol, suggesting an activation of apoptosis by compounds, which was confirmed by activation of the initiator caspase-9 and the executioner caspases-3/7. (1) was also able to trigger extrinsic pathway via activation of caspase-8 and inhibition of NF-κB translocation. The acute toxicity test showed no toxicity effect of the compounds in rats. Our results showed that the selected synthesized compounds are highly potent to induce apoptosis in MCF-7 cells via either intrinsic or extrinsic mitochondrial pathway.

Keywords: Quinazoline Schiff base, apoptosis, MCF-7 human breast cancer cell line, caspase, NF-κB translocation

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Authors: Ilya B. Tsyrlov, Dmitry Y. Oshchepkov

Abstract:

A computational search for dioxin response elements (DREs) in genes of proteins comprising the Ah receptor (AhR) cytosolic core complex was performed by highly efficient tool SITECON. Eventually, the following number of new DREs in 5’flanking region was detected by SITECON: one in AHR gene, five in XAP2, eight in HSP90AA1, and three in HSP90AB1 genes. Numerous DREs found in genes of AhR and AhR cytosolic complex members would shed a light on potential mechanisms of expression, the stoichiometry of unliganded AhR core complex, and its degradation vs biosynthesis dynamics resulted from treatment of target cells with the AhR most potent ligand, 2,3,7,8-TCDD. With human viruses, reduced susceptibility to TCDD of geneencoding HIV-1 P247 was justified by the only potential DRE determined in gag gene encoding HIV-1 P24 protein, whereas the regulatory region of CMV genes encoding IE gp/UL37 has five potent DRE, 1.65 kb/UL36 – six DRE, pp65 and pp71 – each has seven DRE, and pp150 – ten DRE. Also, from six to eight DRE were determined with SITECON in the regulatory region of HSV-1 IE genes encoding tegument proteins, UL36 and UL37, and of UL19 gene encoding bindingglycoprotein C (gC). So, TCDD in the low picomolar range may activate in human cells AhR: Arnt transcription pathway that triggers CMV and HSV-1 reactivation by binding to numerous promoter DRE within immediate-early (IE) genes UL37 and UL36, thus committing virus to the lytic cycle.

Keywords: dioxin response elements, Ah receptor, AhR: Arnt transcription pathway, human and viral genes

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Authors: F. Javier Benitez, Francisco J. Real, Juan Luis Acero, Francisco Casas

Abstract:

Three emerging contaminants (amitriptyline hydrochloride, methyl salicylate and 2-phenoxyethanol) frequently found in waste-waters were selected to be individually degraded in ultra-pure water by the combined advanced oxidation process constituted by UV radiation and chlorine. The influence of pH, initial chlorine concentration and nature of the contaminants was firstly explored. The trend for the reactivity of the selected compounds was deduced: amitriptyline hydrochloride > methyl salicylate > 2-phenoxyethanol. A later kinetic study was carried out and focused on the specific evaluation of the first-order rate constants and the determination of the partial contribution to the global reaction of the direct photochemical pathway and the radical pathway. A comparison between the rate constant values among photochemical experiments without and with the presence of Cl₂ reveals a clear increase in the oxidation efficiency of the combined process with respect to the photochemical reaction alone. In a second stage, the simultaneous oxidation of mixtures of the selected contaminants in several types of water (ultrapure water, surface water from a reservoir, and two secondary effluents) was also performed by the same combination UV/Cl₂ under more realistic operating conditions. The efficiency of this combined system UV/Cl₂ was compared to other oxidants such as the UV/S₂O₈^2- and UV/H₂O₂ AOPs. Results confirmed that the UV/Cl₂ system provides higher elimination efficiencies among the AOPs tested.

Keywords: emerging contaminants, UV/chlorine advanced oxidation process, amitriptyline, methyl salicylate, 2-phenoxyethanol, chlorination, photolysis

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Authors: Chengcao Sun, Cuili Yang, Shujun Li, Ruilin Xue, Yongyong Xi, Liang Wang, Dejia Li

Abstract:

Backgrounds: A few lines of evidence show that Sulforaphane (SFN) has anti-fibrosis effect in liver tissue via Nrf2-mediated inhibition of TGF-β/Smad signaling. However, its effects on muscular dystrophic fibrosis remain unknown. This work was undertaken to evaluate the effects of SFN on fibrosis in dystrophic muscle. Methods: 3-month-old male mdx mice were treated with SFN by gavage (2 mg/kg body weight per day) for 3 months. Gastrocnemius, tibial anterior and triceps brachii muscles were collected for related analysis. Fibrosis in skeletal muscles was analyzed by Sirius red staining. Histology and morphology of skeletal muscles were investigated by H&E staining. Moreover, the expressions of Nrf2, NQO1, HO-1, and TGF-β/Smad signaling pathway were detected by western blot, qRT-PCR, immunohistochemistry and immunofluorescence assays. Results: Our results demonstrated that SFN treatment significantly decreased and improved morphological features in mdx muscles. Moreover, SFN increased the expression of muscle phase II enzymes NQO1 and HO-1 and significantly decreased the expression of TGF-β1，p-smad2, p-smad3, α-SMA, fibronectin, collagen I, PAI-1, and TIMP-1 in Nrf2 dependent manner. Additionally, SFN significantly decreased the expression of CD45 and TNF-α. Conclusions: Collectively, these results show that SFN can ameliorate muscle fibrosis in mdx mice by Nrf2-induced inhibition of TGF-β/Smad signaling pathway, which indicate Nrf2 may be useful for the treatment of muscular dystrophy.

Keywords: sulforaphane, Nrf2, TGF-β/smad signaling, duchenne muscular dystrophy, fibrosis

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