Search results for: signaling

Authors: Arunava Chakrabarti

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A one-dimensional chain of magnetic atoms, representative of a quantum gas in an artificial quasi-periodic potential and modeled by the well-known Aubry-Andre function and its variants are studied in respect of its capability of working as a spin filter for arbitrary spins. The basic formulation is explained in terms of a perfectly periodic chain first, where it is shown that a definite correlation between the spin S of the incoming particles and the magnetic moment h of the substrate atoms can open up a gap in the energy spectrum. This is crucial for a spin filtering action. The simple one-dimensional chain is shown to be equivalent to a 2S+1 strand ladder network. This equivalence is exploited to work out the condition for the opening of gaps. The formulation is then applied for a one-dimensional chain with quasi-periodic variation in the site potentials, the magnetic moments and their orientations following an Aubry-Andre modulation and its variants. In addition, we show that a certain correlation between the system parameters can generate absolutely continuous bands in such systems populated by Bloch like extended wave functions only, signaling the possibility of a metal-insulator transition. This is a case of correlated disorder (a deterministic one), and the results provide a non-trivial variation to the famous Anderson localization problem. We have worked within a tight binding formalism and have presented explicit results for the spin half, spin one, three halves and spin five half particles incident on the magnetic chain to explain our scheme and the central results.

Keywords: Aubry-Andre model, correlated disorder, localization, spin filter

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Authors: Haruna Maama

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Environmental, social and governance (ESG) reporting is gaining considerable attention despite being voluntary. Meanwhile, it consumes resources to provide ESG reporting, raising a question of its value relevance. The study examined the impact of ESG reporting on the market value of listed firms in SSA. The annual and integrated reports of 276 listed sub-Sahara Africa (SSA) firms. The integrated reporting scores of the firm were analysed using a content analysis method. A multiple regression estimation technique using a GMM approach was employed for the analysis. The results revealed that ESG has a positive relationship with firms’ market value, suggesting that investors are interested in the ESG information disclosure of firms in SSA. This suggests that extensive ESG disclosures are attempts by firms to obtain the approval of powerful social, political and environmental stakeholders, especially institutional investors. Furthermore, the market value analysis evidence is consistent with signalling theory, which postulates that firms provide integrated reports as a signal to influence the behaviour of stakeholders. This finding reflects the value placed on investors' social, environmental and governance disclosures, which affirms the views that conventional investors would care about the social, environmental and governance issues of their potential or existing investee firms. Overall, the evidence is consistent with the prediction of signalling theory. In the context of this theory, integrated reporting is seen as part of firms' overall competitive strategy to influence investors' behaviour. The findings of this study make unique contributions to knowledge and practice in corporate reporting.

Keywords: environmental accounting, ESG accounting, signalling theory, sustainability reporting, sub-saharan Africa

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Authors: Neda Seyyedi, Reza Berangi

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Voice over IP (VOIP) network, also known as Internet telephony, is growing increasingly having occupied a large part of the communications market. With the growth of each technology, the related security issues become of particular importance. Taking advantage of this technology in different environments with numerous features put at our disposal, there arises an increasing need to address the security threats. Being IP-based and playing a signaling role in VOIP networks, Session Initiation Protocol (SIP) lets the invaders use weaknesses of the protocol to disable VOIP service. One of the most important threats is denial of service attack, a branch of which in this article we have discussed as flooding attacks. These attacks make server resources wasted and deprive it from delivering service to authorized users. Distributed denial of service attacks and attacks with a low rate can mislead many attack detection mechanisms. In this paper, we introduce a mechanism which not only detects distributed denial of service attacks and low rate attacks, but can also identify the attackers accurately. We detect and prevent flooding attacks in SIP protocol using Shannon (FDP-S), Renyi (FDP-R) and Tsallis (FDP-T) entropy. We conducted an experiment to compare the percentage of detection and rate of false alarm messages using any of the Shannon, Renyi and Tsallis entropy as a measure of disorder. Implementation results show that, according to the parametric nature of the Renyi and Tsallis entropy, by changing the parameters, different detection percentages and false alarm rates will be gained with the possibility to adjust the sensitivity of the detection mechanism.

Keywords: VOIP networks, flooding attacks, entropy, computer networks

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Authors: Suwattana Visetnan, Premruethai Supungul, Sureerat Tang, Ikuo Hirono, Anchalee Tassanakajon, Vichien Rimphanitchayakit

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In animals, infection by Gram-negative bacteria and certain viruses activates the Imd signaling pathway wherein the a NF-κB transcription factor, Relish, is a key regulatory protein for the synthesis of antimicrobial proteins. Infection by yellow head virus (YHV) activates the Imd pathway. To investigate the expression of genes involved in YHV infection and under the influence of PmRelish regulation, RNA interference and suppression subtractive hybridization (SSH) are employed. The genes in forward library expressed in shrimp after YHV infection and under the activity of PmRelish were obtained by subtracting the cDNAs from YHV-infected and PmRelish-knockdown shrimp with cDNAs from YHV-infected shrimp. Opposite subtraction gave a reverse library whereby an alternative set of genes under YHV infection and no PmRelish expression was obtained. Sequencing of 252 and 99 cDNA clones from the respective forward and reverse libraries were done and annotated through blast search against the GenBank sequences. Genes involved in defense and homeostasis were abundant in both libraries, 31% and 23% in the forward and reverse libraries, respectively. They were predominantly antimicrobial proteins, proteinases and proteinase inhibitors. The expression of antimicrobial protein genes, ALFPm3, crustinPm1, penaeidin3 and penaeidin5 were tested under PmRelish silencing and Gram-negative bacterium V. harveyi infection. Together with the results previously reported, the expression of penaeidin5 and also penaeidin3 but not ALFPm3 and crustinPm1 were under the regulation of PmRelish in the Imd pathway.

Keywords: relish, yellow head virus, penaeus monodon, antimicrobial proteins

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Authors: Jiahui Song

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There have been decades of research into the action potential block in nerves. To our best knowledge electrical voltages can reversibly block the conduction of action potentials across whole animal nerves. Blocking biological electrical signaling pathways can have a variety of applications in muscular and sensory incapacitation and clinical research, including urethral pressure reduction and relieving chronic pain relief from a peripheral nerve injury. The cessation ability has been used in muscle activation and fatigue reduction. Ultrashort, high-intensity electric pulses modulate the membrane conductivity to block nerve conduction through the electroporation process. Nanopore formation on the membrane surface would increase the local membrane conductivity and effectively "short-out" the trans-membrane potential of a nerve that inhibits action potential propagation. This block would be similar in concept to stopping the propagation of an air-pressure wave down a "leaky" pipe. This research focuses on a distributed electrical model with an additional time-dependent membrane conductance to calculate the poration induced by the ultrashort, high-intensity electric pulses. The changes in membrane conductivity are used to predict changes in action potential transmission. A "strength-duration (SD)" curve is generated for action potential blockage and would be used as a design guide for benchmarking safety thresholds or setting the pulse voltage and/or durations necessary for neuro-muscular incapacitation.

Keywords: action potential, ultrashort, high-intensity, nerve, strength-duration

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Authors: Zahid Rehman, TorOve Leiknes

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Quorum sensing (QS) is the process by which bacteria communicate with each other through small signaling molecules, such as N-acylhomoserine lactones (AHLs). Also, certain bacteria have the ability to degrade AHL molecules by a process referred to as quorum quenching (QQ); therefore, QQ can be used to control bacterial infections and biofilm formation. In this study, we aimed to identify new species of bacteria with QQ activities. To achieve this, sediments from Red Sea were collected either in the close vicinity of Sea grass or from area with no vegetation. From these samples, we isolated 72 bacterial strains and tested their ability to degrade/inactivate AHL molecules. Chromobacterium violaceum based bioassay was used in initial screening of isolates for QQ activity. The QQ activity of the positive isolates was further confirmed and quantified by employing liquid chromatography and mass spectrometry. These analyses showed that isolated bacterial strain could degrade AHL molecules with different acyl chain length and modifications. Sequencing of 16S-rRNA genes of positive isolates revealed that they belong to three different genera. Specifically, two isolates belong to genus Erythrobacter, four to Labrenzia and one isolate belongs to Bacterioplanes. Time course experiment showed that isolate belonging to genus Erythrobacter could degrade AHLs faster than other isolates. Furthermore, these isolates were tested for their ability to inhibit formation of biofilm and degradation of 3OXO-C12 AHLs produced by P. aeruginosa PAO1. Our results showed that isolate VG12 is better at controlling biofilm formation. This aligns with the ability of VG12 to cause at least 10-fold reduction in the amount of different AHLs tested.

Keywords: quorum sensing, biofilm, quorum quenching, anti-biofouling

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Authors: Saleh N. Maodaa

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Perinatal exposure to nicotine imbalances the redox status in newborns. This study investigated the effect of Anethum graveolens (dill) extract on oxidative stress and tissue injury in the liver and kidney of mice newborns exposed to nicotine perinatally. Pregnant mice received nicotine (0.25 mg/kg) on gestational day 12 to day 5 after birth and/or A. graveolens extract on a gestational day 1 to day 15 after birth. Newborn mice exposed to nicotine showed multiple histopathological alterations in the kidney and liver, including inflammatory cell infiltration and degenerative changes. Nicotine exposure increased hepatic and renal reactive oxygen species (ROS), lipid peroxidation, tumor necrosis factor (TNF-_), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS) (p < 0.001), and decreased antioxidant defenses (p < 0.001). A. graveolens supplementation significantly prevented liver and kidney injury, suppressed ROS generation (p < 0.001), lipid peroxidation (p < 0.001), and inflammatory response (p < 0.001), and enhanced antioxidant defenses. In addition, A. graveolens upregulated hepatic and renal Nrf2 and HO-1 mRNA and increased HO-1 activity in normal and nicotine-exposed mice. In conclusion, A. graveolens protects against perinatal nicotine-induced oxidative stress, inflammation, and tissue injury in the liver and kidney of newborn mice. A. graveolens upregulated hepatic and renal Nrf2/HO-1 signaling and enhanced antioxidant defenses in mice.

Keywords: dill, oxidative stress, cytokines, nicotine

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Authors: Jiandong Ren, Lijun Zhao, Peng Chen

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Nafamostat (NA), a synthetic broad-spectrum serine protease inhibitor, has been routinely employed for the treatment of acute pancreatitis (AP) and other inflammatory-associated diseases in some East Asia countries. Although the potent inhibitory activity against inflammation-related proteases such as thrombin, trypsin, kallikrein, plasmin, coagulation factors and complement factors is generally considered to be responsible for the anti-inflammatory effects of NA, precise target and molecular mechanism underlying the anti-inflammatory activity in the treatment of AP remain largely unknown yet. As an intracellular inflammatory signaling platform, the NOD-like receptor protein 3 (NLRP3) inflammasome is recently identified to be involved in the development of AP. In present study, we have revealed that NA alleviated pancreatic injury in a caerulein-induced AP model by inhibiting the NLRP3 inflammasome activation in pancreas. Mechanistically, NA interacted with HDAC6, a cytoplasmic deacetylase implicated in the NLRP3 inflammasome pathway, and efficiently abrogated the function of HDAC6. This property enabled NA to influence HDAC6 dependent NF-κB transcriptional activity and thus block NF-κB-driven transcriptional priming of NLRP3 inflammasome. Moreover, NA exerted the potential to interfere HDAC6-mediated intracellular transport of NLRP3, thereby leading to the failure of NLRP3 inflammasome activation. Our current work has provided valuable insight into the molecular mechanism underlying the immunomodulatory effect of NA in treatment of AP, highlighting its promising application in prevention of NLRP3 inflammasome-associated inflammatory pathological damage.

Keywords: acute pancreatitis, HDAC6, nafamostat, NLRP3 inflammasome

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Authors: Anthara Vivek, Manisha Shukla, Mahesh Narayan, Prakash Narayan

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Sickle cell disease disproportionately affects sub-Saharan Africa and certain tribal populaces in India and has consequently drawn little intertest from Pharma. In sickle cell patients, adhesion of erythrocytes or reticulocytes to one another and the vessel wall results in painful ischemic episodes with few, if any, effective treatments for vaso-occlusive crises. Identification of disease-associated adhesion markers on erythrocytes or reticulocytes might inform the use of more effective therapies against vaso-occlusive crises. Increased expression of one or more of bcam, itga4, cd44, cd47, rap1a, vcam1, or icam4 has been reported in sickle cell subjects. Using the miRNet ontology knowledgebase, peripheral blood interactomes were generated by seeding various combinations of the afore-referenced mRNA. These interactomes yielded an array of miR targets. As examples, targeting hsa-miR-155-5p can potentially neutralize the rap1a-bcam-cd44-itga4-vcam1 erythrocyte/reticulocyte adhesion interactome whereas targeting hsa-miRs-103a-3p or 107 can potentially neutralize adhesion in cells overexpressing icam4-cd47-bcam-itga4-cd36. AM3380 (MIRacle™) is an off-the shelf hsa-miR-155-5p agomiR that can potentially neutralize the rap1a-bcam-cd44-itga4-vcam1 signaling axis. Phlebotomy coupled with transcriptomics represents a potentially feasible and effective precision medicine strategy to mitigate vaso-occlusive crises in sickle cell patients.

Keywords: adhesion, interactome, precision, medicine

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Authors: Wissem Abdaoui, Nizar M. Mhaidat, Ilhem Mokhtari, Adel Gouri

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Colorectal cancer (CRC) is one of the most common tumors all over the world. Obesity, considered a risk factor of CRC, is characterized by a high level of secreted cytokines from adipose tissue. Among these inflammatory molecules, leptin is considered the key mediator for CRC cancer development and progression by activation of mitogenic and anti apoptotic signaling pathways. Gene expression can be significantly modulated by alterations in DNA methylation patterns. The aim of this study is to investigate the impact of leptin gene methylation on CRC prognosis and sensitivity to chemotherapy. The study involved 70 CRC tissue samples collected from King Abdullah University Hospital (KAUH) from which only 53 was analyzed because of bisulfate fragmentation and low yield of DNA extracted from FFPE tissues. A total of 22 blood samples were collected from healthy volunteers and enrolled as a control group. Leptin promoter methylation was analyzed by methylation specific PCR after bisulfate conversion. Results revealed that the incidence of leptin gene methylation was significantly higher in CRC patients in comparison to that of controls (P < 0.05). The correlation between patient’s demographics and leptin gene methylation was not significant (P < 0.05). However, a significant correlation between leptin gene methylation status and early cancer stages (I, II and III) was found in male but not in female (p < 0.05). Moreover, a significant correlation was found between leptin promoter methylation and early tumor localization T1-2 (p < 0.05). The correlation between epigenetic regulation of leptin and chemosensitivity was not significant. Taken together, these results suggest the possibility to use leptin gene methylation as a biomarker for the evaluation of CRC prognosis and metastasis.

Keywords: colorectal cancer, obesity, leptin, DNA methylation, disease prognosis, bisulfate conversion, chemoresistance

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Authors: Nazari Maryam, Gorji Saman

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For most competitions, athletes usually engage in a process called rapid weight loss (RWL) and subsequent rapid weight gain (RWG) in the days preceding the event. Besides the perfection of performance, weight regulation mediates a self-image of being “a real athlete” which is mentally important as a part of the pre-competition preparation. This feeling enhances the focus and commitment of the athlete. There is a large body of evidence that weight loss, particularly in combat sports, results in several health benefits. However, intentional weight loss beyond normal levels might have unknown negative special effects on the immune system. As the results show, a high prevalence (50%) of RWL is happening among combat athletes. It seems that energy deprivation and intense exercise to reach RWL results in altered blood cell distribution through modification of body composition that, in turn, changes B and T-Lymphocyte and/or CD4 T-Helper response. Moreover, it may diminish IgG antibody levels and modulate IgG glycosylation after this course. On the other hand, some studies show suppression of signaling and regulation of IgE antibody and chemokine production are responsible for immunodeficiency following a period of low-energy availability. Some researchers hypothesize that severe glutamine depletion, which occurs during exercise and calorie restriction, is responsible for this immune system weakness. However, supplementation by this amino acid is not prescribed yet. Therefore, weight loss is achieved not only through chronic strategies (body fat losses) but also through acute manipulations prior to competition should be supervised by a sports nutritionist to minimize side effects on the immune system and other body systems.

Keywords: athletes, immune system, rapid weight loss, weight loss strategies

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Authors: Bahadir Batar, Elif Serdal, Berna Erdal, Hasan Ogul

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Micro-ribonucleic acids (miRNAs) are small short non-coding ribonucleic acid molecules about 22 nucleotides long. miRNAs play a key role in response to chemotherapeutic agents. WW domain-containing oxidoreductase (WWOX) gene encodes a tumor suppressor protein. Loss or reduction of Wwox protein is observed in many breast cancer cases. WWOX protein deficiency is increased in triple-negative breast cancer (TNBC). TNBC is a heterogeneous, highly aggressive, and difficult to treat tumor type. WWOX loss contributes to resistance to cisplatin therapy in patients with TNBC. Here, the aim of the study was to investigate the potential role of miRNAs in cisplatin therapy resistance of WWOX-deficient TNBC cells. This was a cell culture study. miRNA expression profiling was analyzed by LightCycler 480 system. miRNA Set Enrichment Analysis tool was used to integrate experimental data with literature-based biological knowledge to infer a new hypothesis. Increased miR-182 and decreased miR-214 were significantly correlated with cisplatin resistance in WWOX-deficient TNBC cells. miR-182 and miR-214 may involve in cisplatin resistance of WWOX-deficient TNBC cells by deregulating the DNA repair, apoptosis, or protein kinase B signaling pathways. These data highlight the mechanism by which WWOX regulates cisplatin resistance of TNBC and the potential use of WWOX as a predictor biomarker for cisplatin resistance.

Keywords: cisplatin, microRNA, triple-negative breast cancer, WWOX

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Authors: Jin Boo Jeong

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In this study, we elucidated anti-cancer activity and potential molecular mechanism of DKC against human colorectal cancer cells. DKC-E70 suppressed the proliferation of human colorectal cancer cell lines such as HCT116, SW480, LoVo and HT-29. Although DKC-E70 decreased cyclin D1 expression in protein and mRNA level, decreased level of cyclin D1 protein by DKC-E70 occurred at the earlier time than that of cyclin D1 mRNA, which indicates that DKC-E70-mediated downregulation of cyclin D1 protein may be a consequence of the induction of degradation and transcriptional inhibition of cyclin D1. In cyclin D1 degradation, we found that cyclin D1 downregulation by DKC-E70 was attenuated in presence of MG132. In addition, DKC-E70 phosphorylated threonine-286 (T286) of cyclin D1 and T286A abolished cyclin D1 downregulation by DKC-E70. We also observed that DKC-E70-mediated T286 phosphorylation and subsequent cyclin D1 degradation was blocked in presence of the inhibitors of ERK1/2, p38 or GSK3β. In cyclin D1 transcriptional inhibition, DKC-E70 inhibited the expression of β-catenin and TCF4, and β–catenin/TCF-dependent luciferase activity. Our results suggest that DKC-E70 may downregulate cyclin D1 as one of the potential anti-cancer targets through cyclin D1 degradation by T286 phosphorylation dependent on ERK1/2, p38 or GSK3β, and cyclin D1 transcriptional inhibition through Wnt signaling. From these findings, DKC-E70 has potential to be a candidate for the development of chemoprevention or therapeutic agents for human colorectal cancer. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A3B03931713).

Keywords: anticancer, calyx of persimmon, cyclin D1, Diospyros kaki Thunb., human colorectal cancer

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Authors: Mahsa Taghavi

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In the treatment of breast cancer, tamoxifen is a regularly prescribed medication. The effect of tamoxifen on breast cancer patients' EMT pathways was studied. In this study to see if it had any effect on the cancer cells' resistance to tamoxifen and to look for specific miRNAs associated with EMT. In this work, we used continuous and integrated bioinformatics analysis to choose the optimal GEO datasets. Once we had sorted the gene expression profile, we looked at the mechanism of signaling, the ontology of genes, and the protein interaction of each gene. In the end, we used the GEPIA database to confirm the candidate genes. after that, I investigated critical miRNAs related to candidate genes. There were two gene expression profiles that were categorized into two distinct groups. Using the expression profile of genes that were lowered in the EMT pathway, the first group was examined. The second group represented the polar opposite of the first. A total of 253 genes from the first group and 302 genes from the second group were found to be common. Several genes in the first category were linked to cell death, focal adhesion, and cellular aging. Two genes in the second group were linked to cell death, focal adhesion, and cellular aging. distinct cell cycle stages were observed. Finally, proteins such as MYLK, SOCS3, and STAT5B from the first group and BIRC5, PLK1, and RAPGAP1 from the second group were selected as potential candidates linked to tamoxifen's influence on the EMT pathway. hsa-miR-1204 and hsa-miR-639 have a very close relationship with the candidates genes according to the node degrees and betweenness index. With this, the action of tamoxifen on the EMT pathway was better understood. It's important to learn more about how tamoxifen's target genes and proteins work so that we can better understand the drug.

Keywords: tamoxifen, breast cancer, bioinformatics analysis, EMT, miRNAs

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Authors: Ntalamagka N., Sanchis-Benlloch P. J., Mayoral-Serrano R., Tena-Medialdea J., García-March J. R.

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The pen shell Pinna nobilis population has declined dramatically since 2016 due to die-off events observed in the whole extent of the Mediterranean Sea associated with the protozoan Haplosporidium pinnae. As of 2019, it is considered a critically endangered species. Due to its ecological importance and its endangered status, several initiatives have been developed for its salvation and recovery. This research is an effort to understand and control its reproduction under captivity. As a limited number of Pinna nobilis individuals could be used for experimentation, the possibility of using the Pinna rudis as a model animal was explored. The molecular mechanism that regulates the reproduction of both species is unknown; consequently, transcriptomic analysis was performed to identify neuropeptides that are expressed in the key regulatory tissues of the visceral ganglia and gonads of both species. Neuropeptides form an important group of signaling peptides that regulate reproductive, behavioral and physiological functions in molluscs. In total, 17 neuropeptide precursors were identified in P. nobilis and 14 in P. rudis transcriptomes; 14 of them were identical in both species. This affinity verified the genetic similarity of these species at the reproduction level. APGWamide, buccalin, ELH and GnRH were tested in P. rudis and demonstrated their capacity to advance gonadal maturation and trigger spawning while spawning was recorded in P. nobilis after the usage of APGWamide and buccalin. The neuropeptides were administered using intramuscular injection and cholesterol implants following relative literature as well as a new method was developed for external administration without the use of anesthesia using a mathematical model. The know-how of this research will not only lead to the survival of the species but also will narrow the horizons of broodstock conditioning of other similar species.

Keywords: neuropeptides, Pinna nobilis, reproduction, transcriptomics

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Authors: Kamila Duś-Szachniewicz, Kinga M. Walaszek, Paweł Skiba, Paweł Kołodziej, Piotr Ziółkowski

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Cell adhesion is of fundamental importance in the cell communication, signaling, and motility, and its dysfunction occurs prevalently during cancer progression. The knowledge of the molecular and cellular processes involved in abnormalities in cancer cells adhesion has greatly increased, and it has been focused mainly on cellular adhesion molecules (CAMs) and tumor microenvironment. Unfortunately, most of the data regarding CAMs expression relates to study on cells maintained in standard oxygen condition of 21%, while the emerging evidence suggests that culturing cells in ambient air is far from physiological. In fact, oxygen in human tissues ranges from 1 to 11%. The aim of this study was to compare the effects of physiological lymph node normoxia (5% O2), and hyperoxia (21% O2) on the expression of cellular adhesion molecules of primary diffuse large B-cell lymphoma cells (DLBCL) isolated from 10 lymphoma patients. Quantitative RT-PCR and immunohistochemistry were used to confirm the differential expression of several CAMs, including ICAM, CD83, CD81, CD44, depending on the level of oxygen. Our findings also suggest that DLBCL cells maintained at ambient O2 (21%) exhibit reduced growth rate and migration ability compared to the cells growing in normoxia conditions. Taking into account all the observations, we emphasize the need to identify the optimal human cell culture conditions mimicking the physiological aspects of tumor growth and differentiation.

Keywords: adhesion molecules, diffuse large B-cell lymphoma, physiological normoxia, quantitative RT-PCR

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Authors: Yang Zhao, Feng Zhang, Xuanchu Duan

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Trans-differentiation of human Tenon fibroblasts (HTFs) to myo-fibroblasts and fibrosis of episcleral tissue are the most common reasons for the failure of glaucoma filtration surgery, with limited treatment options like antimetabolites which always have side-effects such as leakage of filter bulb, infection, hypotony, and endophthalmitis. Rosiglitazone, a specific thiazolidinedione is a synthetic high-affinity ligand for PPAR-r, which has been used in the treatment of type2 diabetes, and found to have pleiotropic functions against inflammatory response, cell proliferation and tissue fibrosis and to benefit to a variety of diseases in animal myocardium models, steatohepatitis models, etc. Here, in vitro we cultured primary HTFs and stimulated with TGF- β to induced myofibrogenic, then treated cells with Rosiglitazone to assess for fibrogenic response. In vivo, we used rabbit glaucoma model to establish the formation of post- trabeculectomy scarring. Then we administered subconjunctival injection with Rosiglitazone beside the filtering bleb, later protein, mRNA and immunofluorescence of fibrogenic markers are checked, and filtering bleb condition was measured. In vitro, we found Rosiglitazone could suppressed proliferation and migration of fibroblasts through macroautophagy via TGF- β /Smad signaling pathway. In vivo, on postoperative day 28, the mean number of fibroblasts in Rosiglitazone injection group was significantly the lowest and had the least collagen content and connective tissue growth factor. Rosiglitazone effectively controlled human and rabbit fibroblasts in vivo and in vitro. Its subconjunctiiva application may represent an effective, new avenue for the prevention of scarring after glaucoma surgery.

Keywords: fibrosis, glaucoma, macroautophagy, rosiglitazone

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Authors: O. H. Gebril, N. A. Meguid

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Background: Iron had been a focus of interest recently as a main exaggerating factor for oxidative stresses in the central nervous system and a link to various neurological disorders is suspected. Many studies with various techniques showed evidence of disturbed iron-related proteins in the cell in human and animal models of neurodegenerative disorders. Also, linkage to significant pathological changes had been evidenced e.g. apoptosis and cell signaling. On the other hand, the role of iron in neurodevelopmental disorders is still unclear. With increasing prevalence of autism worldwide, some changes in iron parameters and its stores were documented in many studies. This study includes Haemochromatosis HFE gene polymorphisms (p.H63D and p.C282Y) and ferroportin gene (SLC40A1) Q248H polymorphism in autism and control children. Materials and Methods: Whole genome DNA was extracted; p.H63D and p.C282Y genotyping was studied using specific sequence amplification followed by restriction enzyme digestion on a sample of autism patients (25 cases) and twenty controls. Results: The p.H63D is seen more than the C282Y among both autism and control samples, with no significant association of p.H63D or p.C282Y polymorphism and autism was revealed. Also, no association with Q248H polymorphism was evidenced. Conclusion: The study results do not prove the role of cellular iron genes polymorphisms as risk factors for neurodevelopmental disorders, and in turn highlights the specificity of cellular iron related pathways in neurodegeneration. These results demand further gene expression studies to elucidate the main pathophysiological pathways that are disturbed in autism and other neurodevelopmental disorders.

Keywords: iron, neurodevelopmental, oxidative stress, haemohromatosis, ferroportin, genes

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Authors: Suzan Ghaddar, Aline Pinon, Manuel Gallardo-villagran, Mona Diab-assaf, Bruno Therrien, Bertrand Liagre

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Colorectal cancer (CRC) is the third most common cancer and exhibits a consistently rising incidence worldwide. Despite notable advancements in CRC treatment, frequent occurrences of side effects and the development of therapy resistance persistently challenge current approaches. Eventually, innovations in focal therapies remain imperative to enhance the patient’s overall quality of life. Photodynamic therapy (PDT) emerges as a promising treatment modality, clinically used for the treatment of various cancer types. It relies on the use of photosensitive molecules called photosensitizers (PS), which are photoactivated after accumulation in cancer cells, to induce the production of reactive oxygen species (ROS) that cause cancer cell death. Among commonly used metal-based drugs in cancer therapy, ruthenium (Ru) possesses favorable attributes that demonstrate its selectivity towards cancer cells and render it suitable for anti-cancer drug design. In vitro studies using distinct arene-Ru complexes, encapsulating porphin PS, are conducted on human HCT116 and HT-29 colorectal cancer cell lines. These studies encompass the evaluation of the antiproliferative effect, ROS production, apoptosis, cell cycle progression, molecular localization, and protein expression. Preliminary results indicated that these complexes exert significant photocytotoxicity on the studied colorectal cancer cell lines, representing them as promising and potential candidates for anti- cancer agents.

Keywords: colorectal cancer, photodynamic therapy, photosensitizers, arene-ruthenium complexes, apoptosis

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Authors: Vineeta Kaushik, Manisha Goel

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Chaperones are proteins that help other proteins fold correctly, and are found in all domains of life i.e., prokaryotes, eukaryotes and archaea. Various comparative genomic studies have suggested that the archaeal protein folding machinery appears to be highly similar to that found in eukaryotes. In case of protein folding; slow rotation of peptide prolyl-imide bond is often the rate limiting step. Formation of the prolyl-imide bond during the folding of a protein requires the assistance of other proteins, termed as peptide prolyl cis-trans isomerases (PPIases). Cyclophilins constitute the class of peptide prolyl isomerases with a wide range of biological function like protein folding, signaling and chaperoning. Most of the cyclophilins exhibit PPIase enzymatic activity and play active role in substrate protein folding which classifies them as a category of molecular chaperones. Till date, there is not very much data available in the literature on archaeal cyclophilins. We aim to compare the structural and biochemical features of the cyclophilin protein from within the three domains to elucidate the features affecting their stability and enzyme activity. In the present study, we carry out in-silico analysis of the cyclophilin proteins to predict their conserved residues, sites under positive selection and compare these proteins to their bacterial and eukaryotic counterparts to predict functional divergence. We also aim to clone and express these proteins in heterologous system and study their biophysical characteristics in detail using techniques like CD and fluorescence spectroscopy. Overall we aim to understand the features contributing to the folding, stability and dynamics of the archaeal cyclophilin proteins.

Keywords: biophysical characterization, x-ray crystallography, chaperone-like activity, cyclophilin, PPIase activity

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Authors: Ishani Majumdar, Jaishree Paul

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Introduction: Ulcerative Colitis (UC) is an inflammatory disease of the colon resulting from an autoimmune response towards individual’s own microbiota. Excessive inflammation is characterized by hyper-activation of NFkB, a transcription factor regulating expression of various pro-inflammatory genes. The ubiquitin editing complex consisting of TNFAIP3, ITCH, RNF11 and TAX1BP1 maintains homeostatic levels of active NFkB through feedback inhibition and assembles in response to various stimuli that activate NFkB. TNFAIP3 deubiquitinates key signaling molecules involved in NFkB activation pathway. ITCH, RNF11 and TAX1BP1 provide substrate specificity, acting as adaptors for TNFAIP3 function. Aim: This study aimed to find expression of members of the ubiquitin editing complex at the transcript level in inflamed colon tissues of UC patients. Materials and Methods: Colonic biopsy samples were collected from 30 UC patients recruited at Department of Gastroenterology, AIIMS (New Delhi). Control group (n= 10) consisted of individuals undergoing examination for functional disorders. Real Time PCR was used to determine relative expression with GAPDH as housekeeping gene. Results: Expression of members of the ubiquitin editing complex was significantly altered during active disease. Expression of TNFAIP3 was upregulated while concomitant decrease in expression of ITCH, RNF11, TAX1BP1 was seen in UC patients. Discussion: This study reveals that increase in expression of TNFAIP3 was unable to control inflammation during active UC. Further, insufficient upregulation of ITCH, RNF11, TAX1BP1 may limit the formation of the ubiquitin complex and contribute to pathogenesis of UC.

Keywords: altered expression, inflammation, ubiquitin editing complex, ulcerative colitis

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Authors: Surbhi Aggarwal, Jaishree Paul

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Background: Role of GABA has been implicated in autoimmune diseases like multiple sclerosis, type1 diabetes and rheumatoid arthritis where they modulate the immune response but role in gut inflammation has not been defined. Ulcerative colitis (UC) and diarrhoeal predominant irritable bowel syndrome (IBS-D) both involve inflammation of gastrointestinal tract. UC is a chronic, relapsing and idiopathic inflammation of gut. IBS is a common functional gastrointestinal disorder characterised by abdominal pain, discomfort and alternating bowel habits. Mild inflammation is known to occur in IBS-D. Aim: Aim of this study was to investigate the role of GABA in UC as well as in IBS-D. Materials and methods: Blood and biopsy samples from UC, IBS-D and controls were collected. ELISA was used for measuring level of GABA in serum of UC, IBS-D and controls. RT-PCR analysis was done to determine GABAergic signal system in colon biopsy of UC, IBS-D and controls. RT-PCR was done to check the expression of proinflammatory cytokines. CurveExpert 1.4, Graphpad prism-6 software were used for data analysis. Statistical analysis was done by unpaired, two-way student`s t-test. All sets of data were represented as mean± SEM. A probability level of p < 0.05 was considered statistically significant. Results and conclusion: Significantly decreased level of GABA and altered GABAergic signal system was detected in UC and IBS-D as compared to controls. Significantly increased expression of proinflammatory cytokines was also determined in UC and IBS-D as compared to controls. Hence we conclude that insufficient level of GABA in UC and IBS-D leads to overproduction of proinflammatory cytokines which further contributes to inflammation. GABA may be used as a promising therapeutic target for treatment of gut inflammation or other inflammatory diseases.

Keywords: diarrheal predominant irritable bowel syndrome, γ-aminobutyric acid (GABA), inflammation, ulcerative colitis

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

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Backgrounds: Inflammation is widely distributed in patients with Duchenne muscular dystrophy (DMD), and ultimately leads to progressive deterioration of muscle function with the co-effects of chronic muscle damage, oxidative stress, and reduced oxidative capacity. NF-E2-related factor 2 (Nrf2) plays a critical role in defending against inflammation in different tissues via activation of phase II enzymes, heme oxygenase-1 (HO-1). However, whether Nrf2/HO-1 pathway can attenuate muscle inflammation on DMD remains unknown. The purpose of this study was to determine the anti-inflammatory effects of Sulforaphane (SFN) on DMD. Methods: 4-week-old male mdx mice were treated with SFN by gavage (2 mg/kg body weight per day) for 4 weeks. Gastrocnemius, tibial anterior and triceps brachii muscles were collected for related analysis. Immune cell infiltration in skeletal muscles was analyzed by H&E staining and immuno-histochemistry. Moreover, the expressions of inflammatory cytokines,pro-inflammatory cytokines and Nrf2/HO-1 pathway were detected by western blot, qRT-PCR, immunohistochemistry and immunofluorescence assays. Results: Our results demonstrated that SFN treatment increased the expression of muscle phase II enzymes HO-1 in Nrf2 dependent manner. Inflammation in mdx skeletal muscles was reduced by SFN treatment as indicated by decreased immune cell infiltration and lower expressions of the inflammatory cytokines CD45, pro-inflammatory cytokines tumour necrosis factor-α and interleukin-6 in the skeletal muscles of mdx mice. Conclusions: Collectively, these results show that SFN can ameliorate muscle inflammation in mdx mice by Nrf2/HO-1 pathway, which indicates Nrf2/HO-1 pathway may represent a new therapeutic target for DMD.

Keywords: sulforaphane, Nrf2, HO-1, inflammation

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Authors: Shadia Al-Bahlani, Khadija Al-Bulushi, Zuweina Al-Hadidi, Buthaina Al-Dhahl, Nadia Al-Abri

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Breast cancer is the most common cancer in women worldwide. Triple-Negative Breast Cancer (TNBC) is an aggressive type of breast cancer, which is defined by the absence of Estrogen (ER), Progesterone (PR) and human epidermal growth factor (Her-2) receptors. The calpain system plays an important role in many cellular processes including apoptosis, necrosis, cell signaling and proliferation. However, the role of calpain in cisplatin (CDDP)-induced apoptosis in TNBC cells is not fully understood. Here, TNBC (MDA-MB231) cells were treated with different concentration of CDDP (0, 20 & 40 µM) and calpain activation and apoptosis were measured by western blot and Hoechst Stain respectively. In addition, calpain modulation by either activation and/or inhibition and its effect on CDDP-induced apoptosis were assessed by the same above approaches. Our findings showed that CDDP induced endoplasmic reticulum stress and thus Calcium release and subsequently activate calpain α-fodrin cleavage indicated by the increase in GRP78 and Calmodulin protein expression and respectively in MDA-MB231 cells. It also induced apoptosis as measured by Hoechst stain and caspase-12 cleavage. Calpain activation by both Cyclopiazonic acid and Thapsigargin showed similar effect and enhanced the sensitivity of these cells to CDDP treatment. On the other hand, calpain inhibition by either specific siRNA and/or exogenous inhibitor (Calpeptin) had an adverse effect where it attenuated calpain activation and thus CDDP- induced apoptosis in these cells. Altogether, these findings suggested that calpain activation play an essential role in sensitizing the TNBC cells to CDDP-induced apoptosis. This might lead to the discovery of novel treatment to over this aggressive type of breast cancer.

Keywords: calpain, cisplatin, apoptosis, breast cancer

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Authors: Arieh Moussaieff, Bénédicte Elena-Herrmann, Yaakov Nahmias, Daniel Aberdam

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Differentiation of pluripotent stem cells is a slow process, marked by the gradual loss of pluripotency factors over days in culture. While the first few days of differentiation show minor changes in the cellular transcriptome, intracellular signaling pathways remain largely unknown. Recently, several groups demonstrated that the metabolism of pluripotent mouse and human cells is different from that of somatic cells, showing a marked increase in glycolysis previously identified in cancer as the Warburg effect. Here, we sought to identify the earliest metabolic changes induced at the first hours of differentiation. High-resolution NMR analysis identified 35 metabolites and a distinct, gradual transition in metabolism during early differentiation. Metabolic and transcriptional analyses showed the induction of glycolysis toward acetate and acetyl-coA in pluripotent cells, and an increase in cholesterol biosynthesis during early differentiation. Importantly, this metabolic pathway regulated differentiation of human and mouse embryonic stem cells. Acetate delayed differentiation preventing differentiation-induced histone de-acetylation in a dose-dependent manner. Glycolytic inhibitors upstream of acetate caused differentiation of pluripotent cells, while those downstream delayed differentiation. Our data suggests that a rapid loss of glycolysis in early differentiation down-regulates acetate and acetyl-coA production, causing a loss of histone acetylation and concomitant loss of pluripotency. It demonstrate that pluripotent stem cells utilize a novel metabolism pathway to maintain pluripotency through acetate/acetyl-coA and highlights the important role metabolism plays in pluripotency and early differentiation of stem cells.

Keywords: pluripotency, metabolomics, epigenetics, acetyl-coA

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Authors: Abazar Ghorbani, W. M. Wishwajith W. Kandegama, Seyed Mehdi Razavi, Moxian Chen

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The roles of hydrogen sulfide (H₂S) and melatonin (MT) as gasotransmitters in plants are widely recognised. Nevertheless, the precise nature of their involvement in defensive reactions remains uncertain. This study investigates the impact of the ML-H2S interaction on tomato plants exposed to vanadium (V) toxicity, focusing on synthesising secondary metabolites and V metal sequestration. The treatments applied in this study included a control (T1), V stress (T2), MT+V (T3), MT+H2S+V (T4), MT+hypotaurine (HT)+V (T5), and MT+H2S+HT+V (T6). These treatments were administered: MT (150 µM) as a foliar spray pre-treatment (3X), HT treatment (0.1 mM, an H2S scavenger) as root immersion for 12 hours as pre-treatments, and H2S (NaHS, 0.2 mM) and V (40 mg/L) treatments added to the Hoagland solution for 2 weeks. Results demonstrate that ML and H2S+ML treatments alleviate V toxicity by promoting the transcription of key genes (ANS, F3H, CHS, DFR, PAL, and CHI) involved in phenolic and anthocyanin biosynthesis. Moreover, they decreased V uptake and accumulation and enhanced the transcription of genes involved in glutathione and phytochelatin synthesis (GSH1, PCS, and ABC1), leading to V sequestration in roots and protection against V-induced damage. Additionally, ML and H2S+ML treatments optimize chlorophyll metabolism, and increase internal H2S levels, thereby promoting tomato growth under V stress. The combined treatment of ML+H2S shows superior effects compared to ML alone, suggesting synergistic/interactive effects between these two substances. Furthermore, inhibition of the beneficial impact of ML+H2S and ML treatments by HT, an H2S scavenger, underscores the significant involvement of H₂S in the signaling pathway activated by ML during V toxicity. Overall, these findings suggest that ML requires the presence of endogenous H₂S to mitigate V-induced adverse effects on tomato seedlings.

Keywords: vanadium toxicity, secondary metabolites, vanadium sequestration, h2s-melatonin crosstalk

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Authors: Radoslav Stojchevski, Leonid Poretsky, Dimiter Avtanski

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Proinflammatory cytokines play an important role in cancer initiation and progression by mediating the intracellular communication between the cancer cells and tumor microenvironment. Increased tumor growth causing reduced oxygen concentration and oxygen pressure commonly result in hypoxia. Mechanistically, hypoxia is characterized by stabilization and nuclear translocation of hypoxia-inducible factor 1 alpha (HIF-1α) followed by propagation of molecular pathway cascade involving multiple downstream targets. Cobalt(II) chloride (CoCl₂) is commonly used to mimic hypoxia in experimental conditions since it directly induces the expression of HIF-1α. The aim of the present study was to investigate the in vitro effects and the molecular mechanisms by which hypoxia regulates the cytokine secretory profile of breast cancer cells. As a model for this study, we used several breast cancer cell lines bearing various molecular characteristics and metastatic potential (MDA-MB-231 (clauding low, ER-/PR-/HER²⁻), MCF-7 (luminal A, ER⁺/PR⁺/HER²⁻), and BT-474 (liminal B, ER⁺/PR⁺/HER²⁺)). We demonstrated that breast cancer cells secrete numerous cytokines and cytokine ligands, including interleukins, chemokines, and growth factors. Treatment with CoCl₂significantly modulated the breast cancer cells' cytokine expression in a concentration- and time-dependent manner. These effects were mediated via activation of several signaling pathways (JNK/SAPK1, NF-κB, STAT5A/B, and Erk/MAPK1/2). Taken together, the present data define some of the molecular mechanisms by which hypoxia affects the breast cancer cells' cytokine secretory profile, thus contributing to the development of novel therapies for metastatic breast cancer.

Keywords: breast cancer, cytokines, cobalt(II) chloride (CoCl₂), hypoxia

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Authors: A. Maciejak, M. Kiliszek, G. Opolski, D. Tulacz, A. Segiet, K. Matlak, S. Dobrzycki, G. Sygitowicz, B. Burzynska, M. Gora

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Introduction and aims: Acute myocardial infarction (AMI) is one of the most severe cardiovascular diseases affecting millions of patients each year worldwide. An early and accurate diagnosis of AMI is essential for optimal treatment. Therefore, new approaches that can complement and improve current strategies for AMI diagnosis are urgently needed. Recent studies have revealed the presence of stable circulating myocardial-derived microRNAs (miRNAs) in human peripheral blood, suggesting that such miRNAs could serve as potential biomarkers of infarction. The present study aimed to identify differentially expressed circulating miRNAs in ST-segment elevation myocardial infarction (STEMI) patients. Materials and methods: miRNA expression profile analysis was performed using Exiqon Serum/Plasma Focus microRNA PCR panel in plasma samples of n=16 patients on the first day of AMI (admission) and in samples from the same patients collected six months after AMI. Selected miRNAs were validated by RT-qPCR using serum samples from an independent set of n=14 AMI patients. Results: The profiling study identified 46 species of plasma miRNAs that were differentially expressed (p < 0.05) on admission compared to six months after AMI. The validation in the independent group of patients confirmed that miR-133b and miR-22-5p were significantly up-regulated upon AMI. Conclusions: Our results suggest that miRNA expression profiling provides better understanding of the changes that occur in the acute phase of MI in the myocardium and could be useful in determination of the potential role of extracellular miRNAs as paracrine signaling molecules. miR-22-5p represents a novel promising biomarker for the diagnosis of acute myocardial infarction.

Keywords: acute myocardial infarction, circulating microRNAs, microRNA expression profiling, miR-22-5p

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Authors: Kamal Ameis

Abstract:

This study aims to further improve our understanding of the underlying mechanism of local injury that occurs after manual acupuncture needle manipulation, and that initiates the muscle regeneration process, which is essential for muscle maintenance and adaptation. Skeletal muscle is maintained by resident stem cells called muscle satellite cells. These cells are normally in quiescent state, but following muscle injury, they re-enter the cell cycle and execute a myogenic program resulting in muscle fiber regeneration. Our previous work in young rats demonstrated that acupuncture treatment induced injury that activated resident satellite (stem) cells, which leads to muscle regeneration. Skeletal muscle regeneration is an adaptive response to injury that requires a tightly orchestrated event between signaling pathways activated by growth factor and intrinsic regulatory program controlled by myogenic transcription factor. We identified several gene expressions uniquely important for muscle regeneration in response to acupuncture treatment at different time course using different biological techniques, including Immunocytochemistry, western blotting, and Real Time PCR. This study uses a novel but non-invasive model of injury induced by manual acupuncture to further our current understanding of regenerative mechanism of muscle stem cells. From a clinical perspective, this model of injury induced by manual acupuncture may be easily translatable into a clinical tool that can be used as an alternative to physical exercise for patients challenged by bed rest or forced inactivity. Finally, the knowledge gained from this research could be useful for studies of the local effects of various modalities of induced injury, such as the traditional method of healing by cupping (hijamah), which may enhanced muscle stem cells and muscle fiber regeneration.

Keywords: acupuncture, injury, regeneration, muscle stem cells

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Authors: Gina Leisching, Ray-Dean Pietersen, Carel Van Heerden, Paul Van Helden, Ian Wiid, Bienyameen Baker

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The distinguishing factors that characterize the host response to infection with virulent Mycobacterium tuberculosis (M.tb) are largely confounding. We present an infection study with two genetically closely related M.tb strains that have vastly different pathogenic characteristics. The early host response to infection with these detergent-free cultured strains was analyzed through RNAseq in an attempt to provide information on the subtleties which may ultimately contribute to the virulent phenotype. Murine bone marrow-derived macrophages (BMDMs) were infected with either a hyper- (R5527) or hypovirulent (R1507) Beijing M. tuberculosis clinical isolate. RNAseq revealed 69 differentially expressed host genes in BMDMs during comparison of these two transcriptomes. Pathway analysis revealed activation of the stress-induced and growth inhibitory Gadd45 signaling pathway in hypervirulent infected BMDMs. Upstream regulators of interferon activation such as and IRF3 and IRF7 were predicted to be upregulated in hypovirulent-infected BMDMs. Additional analysis of the host immune response through ELISA and qPCR included the use of human THP-1 macrophages where a robust proinflammatory response was observed after infection with the hypervirulent strain. RNAseq revealed two early-response genes (IER3 and SAA3) and two host-defence genes (OASL1 and SLPI) that were significantly upregulated by the hypervirulent strain. The role of these genes under M.tb infection conditions are largely unknown but here we provide validation of their presence with use of qPCR and Western blot. Further analysis into their biological role under infection with virulent M.tb is required.

Keywords: host-response, Mycobacterium tuberculosis, RNAseq, virulence

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