Search results for: signalling pathway

Authors: Yee-Seul So, Guiseppe Ianiri, Alex Idnurm, Yong-Sun Bahn

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Tor1 is a serine/threonine protein kinase that is widely conserved across eukaryotic species. Tor1 was first identified in Saccharomyces cerevisiae as a target of rapamycin (TOR). The TOR pathway has been implicated in regulating cellular responses to nutrients, proliferation, translation, transcription, autophagy, and ribosome biogenesis. Here we identified two homologues of S. cerevisiae Tor proteins, CNAG_06642 (Tor1) and CNAG_05220 (Tlk1, TOR-like kinase 1), in Cryptococcus neoformans causing a life-threatening fungal meningoencephalitis. Both Tor1 and Tlk1 have rapamycin-binding (RB) domains but Tlk1 has truncated RB form. To study the TOR-signaling pathway in the fungal pathogen, we attempt to construct the tor1Δ and tlk1Δ mutants and phenotypically analyze them. Although we failed to construct the tor1Δ mutant, we successfully construct the tlk1Δ mutant. The tlk1Δ mutant does not exhibit any discernable phenotypes, suggesting that Tlk1 is dispensable in C. neoformans. The essentiality of TOR1 is independently confirmed by constructing the TOR1 promoter replacement strain by using a copper transporter 4 (CTR4) promoter and the TOR1/tor1 heterozygous mutant in diploid C. neoformans strain background followed by sporulation analysis. To further analyze the function of Tor1, we construct TOR1 overexpression mutant using a constitutively active histone H3 in C. neoformans. We find that the Tor1 overexpression mutant is resistant to rapamycin but the tlk1Δ mutant does not exhibit any altered resistance to rapamycin, further confirming that Tor1, but not Tlk1, is critical for TOR signaling. Furthermore, we found that Tor1 is involved in response to diverse stresses, including genotoxic stress, oxidative stress, thermo-stress, antifungal drug treatment, and production of melanin. To identify any TOR-related transcription factors, we screened C. neoformans transcription factor library that we constructed in our previous study and identified several potential downstream factors of Tor1, including Atf1, Crg1 and Bzp3. In conclusion, the current study provides insight into the role of the TOR signaling pathway in human fungal pathogens as well as C. neoformans.

Keywords: fungal pathogen, serine/threonine kinase, target of rapamycin, transcription factor

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Authors: Hui Wei, Zheng Dong

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Object recognition has long been a challenging task in computer vision. Yet the human brain, with the ability to rapidly and accurately recognize visual stimuli, manages this task effortlessly. In the past decades, advances in neuroscience have revealed some neural mechanisms underlying visual processing. In this paper, we present a novel model inspired by the visual pathway in primate brains. This multi-layer neural network model imitates the hierarchical convergent processing mechanism in the visual pathway. We show that local image features generated by this model exhibit robust discrimination and even better generalization ability compared with some existing image descriptors. We also demonstrate the application of this model in an object recognition task on image data sets. The result provides strong support for the potential of this model.

Keywords: biological model, feature extraction, multi-layer neural network, object recognition

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Authors: Hager Elsheikh, Matthias Sendler, Juliana Glaubnitz

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In pancreatitis, an inflammatory reaction occurs in the pancreatic secretory cells due to premature activation of proteases, leading to pancreatic self-digestion and necrotic cell death of acinar cells. Acute pancreatitis in patients is characterized by a severe immune reaction that could lead to serious complications, such as organ failure or septic shock, if left untreated. Chronic pancreatitis is a recurrence of episodes of acute pancreatitis resulting in a fibro-inflammatory immune response, in which the type 2 immune response is primarily driven by AAMs in the pancreas. One of the most important signaling pathways for M2 macrophage activation is the IL-4/STAT6 pathway. Pancreatic fibrosis is induced by the hyperactivation of pancreatic stellate cells by dysregulation in the inflammatory response, leading to further damage, autodigestion and possibly necrosis of pancreatic acinar cells. The aim of this research is to investigate the effect of STAT6 knockout in disease severity and development of fibrosis wound healing in the presence of different macrophage populations, regulated by the type 2 immune response, after inducing chronic and/or acute pancreatitis in mice models via cerulean injection. We further investigate the influence of the JAK/STAT6 signaling pathway on the balance of fibrosis and regeneration in STAT6 deficient and wild-type mice. The characterization of resident and recruited macrophages will provide insight into the influence of the JAK/STAT6 signaling pathway on infiltrating cells and, ultimately, tissue fibrosis and disease severity.

Keywords: acute and chronic pancreatitis, tissue regeneration, macrophage polarization, Gastroenterology

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Authors: Ç. Gökçek-Saraç, Ş. Özen, N. Derin

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The N-methyl-D-aspartate (NMDA)-dependent pathway is the major intracellular signaling pathway implemented in both short- and long-term memory formation in the hippocampus which is the most studied brain structure because of its well documented role in learning and memory. However, little is known about the effects of RF-EMR exposure on NMDA receptor signaling pathway including activation of protein kinases, notably Ca²⁺/calmodulin-dependent protein kinase II alpha (CaMKIIα). The aim of the present study was to investigate the effects of acute and chronic 900 MHz RF-EMR exposure on both passive avoidance behaviour and hippocampal levels of CaMKIIα and its phosphorylated form (pCaMKIIα). Rats were divided into the following groups: Sham rats, and rats exposed to 900 MHz RF-EMR for 2 h/day for 1 week (acute group) or 10 weeks (chronic group), respectively. Passive avoidance task was used as a behavioural method. The hippocampal levels of selected kinases were measured using Western Blotting technique. The results of passive avoidance task showed that both acute and chronic exposure to 900 MHz RF-EMR can impair passive avoidance behaviour with minor effects on chronic group of rats. The analysis of western blot data of selected protein kinases demonstrated that hippocampal levels of CaMKIIα and pCaMKIIα were significantly higher in chronic group of rats as compared to acute groups. Taken together, these findings demonstrated that different duration times (1 week vs 10 weeks) of 900 MHz RF-EMR exposure have different effects on both passive avoidance behaviour of rats and hippocampal levels of selected protein kinases.

Keywords: hippocampus, protein kinase, rat, RF-EMR

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Authors: M. Yaqoob, C. S. O’Neill, S. Faraj, C. L. O’Neill

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This paper presents the preliminary findings from a study exploring nurse’s contributions to end of life decisions and to the care of dying patients in ICU units in the Kingdom of Bahrain. The process of dying is complex as medical clinicians are frequently unable to say with certainty when death will occur. It is generally accepted that end of life care begins when it is possible to know that death is imminent. Nurses do not make medical treatment decisions when caring for a dying patient. There are, however, many other types of decisions made when a patient is approaching the end of life and nurses are either formally or informally part of these decision making processes. This study explored nurses care practices at the end of life, in two ICU units in large hospitals in the Kingdom of Bahrain. The research design was a grounded theory approach. Ten nurses participated, six of whom were Bahraini nationals and four were Indian. A core category death avoidance talk was supported by three major subcategories, degrees of involvement in decision making; signalling and creating an awareness of death; care shifting from dying patients to family. Despite nurses asserting that they carried out the orders of doctors and had no role in decision making processes at end of life this study showed that there were degrees of nurse involvement. Doctors frequently discussed the patient’s clinical condition with nurses and also sought information regarding the family. Information about the family was of particular relevance if the doctor was considering a DNR order, which the nurses equated with dying. Families were not always informed when a DNR decision was made. When families were not informed the nurses engaged in sophisticated rituals signalling and creating awareness to family members that the death of their loved one was near. This process also involved a subtle shifting of care from the dying patient to the family. This seminar paper will focus particularly on how nurses signal and create an awareness of death in an ICU setting. The findings suggest that despite the avoidance of death talk in the ICU nurses indirectly convey and create an awareness that death is near to family members.

Keywords: decision making, dying patients, end of life, intensive care unit

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Authors: Shu-Pin Huang, Pai-Chi Teng, Hao-Han Chang, Chia-Hsin Liu, Yung-Lun Lin, Shu-Chi Wang, Hsin-Chih Yeh, Chih-Pin Chuu, Jiun-Hung Geng, Li-Hsin Chang, Wei-Chung Cheng, Chia-Yang Li

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The emergence of immune checkpoint inhibitors (ICIs) targeting proteins like PD-1 and PD-L1 has changed the treatment paradigm of bladder cancer. However, not all patients benefit from ICIs, with some experiencing early death. There's a significant need for biomarkers associated with the PD-1 pathway in bladder cancer. Current biomarkers focus on tumor PD-L1 expression, but a more comprehensive understanding of PD-1-related biology is needed. Our study has developed a seven-gene risk score panel, employing a comprehensive bioinformatics strategy, which could serve as a potential prognostic and predictive biomarker for bladder cancer. This panel incorporates the FYN, GRAP2, TRIB3, MAP3K8, AKT3, CD274, and CD80 genes. Additionally, we examined the relationship between this panel and immune cell function, utilizing validated tools such as ESTIMATE, TIDE, and CIBERSORT. Our seven-genes panel has been found to be significantly associated with bladder cancer survival in two independent cohorts. The panel was also significantly correlated with tumor infiltration lymphocytes, immune scores, and tumor purity. These factors have been previously reported to have clinical implications on ICIs. The findings suggest the potential of a PD-1 pathway-based transcriptomic panel as a prognostic and predictive biomarker in bladder cancer, which could help optimize treatment strategies and improve patient outcomes.

Keywords: bladder cancer, programmed cell death protein 1, prognostic biomarker, immune checkpoint inhibitors, predictive biomarker

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Authors: Sachin K. Samuchiwal, Barbara Balestrieri, Amanda Paskavitz, Hannah Raff, Joshua A. Boyce

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IL-33, a recently discovered member of the IL-1 cytokine family, binds to the TLR/IL1R super family receptor ST2 and induces type 2 immune responses. IL-33 is constitutively expressed in structural cells at barrier sites such as skin, lung, and intestine, and also inducibly expressed by hematopoietic cells including macrophages. Stimulation of macrophages by Lipopolysaccharide (LPS) can induce de novo IL-33 expression, and also causes the production of prostaglandin-E2 (PGE2) via cyclooxygenase (COX)-2 and microsomal PGE2 synthase-1 (mPGES-1). Because PGE2 can regulate macrophage functions through both autocrine and paracrine mechanisms, the potential interplay of endogenous PGE2 on IL-33 production was explored. Bone-marrow derived murine macrophages (bmMF) that lack either mPGES-1 or EP2 receptor expression were stimulated with LPS in the absence or presence of exogenous PGE2 along with pharmacological agonists and antagonists. The study results demonstrate that endogenous PGE2 markedly enhances LPS-induced IL-33 production by bmMFs via EP2 receptors. Moreover, exogenous PGE2 can amplify LPS-induced IL-33 expression dominantly by EP2 and partly by EP4 receptors by a pathway involving cAMP and exchange protein activated by cAMP (EPAC), but not protein kinase A (PKA). Though both IL-33 production and PGE2 generation in response to LPS require activation of both p38 MAPK and NF-κB, PGE2 did not influence this activation. In conclusion, it is demonstrated that endogenous PGE2 signaling through EP2 and EP4 receptors is a prerequisite for LPS-induced IL-33 production in bmMFs and the underlying cAMP mediated pathway involves EPAC. Since IL-33 is a critical pro-inflammatory cytokine in various pathological disorders, this PGE2-EP2/EP4-cAMP mediated pathway can be exploited to intervene in IL-33 driven pathologies.

Keywords: bone marrow macrophages, EPAC, IL-33, PGE2

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Authors: Rahaba Marima, Clement Penny

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The Health-related quality of life (HRQoL) for HIV positive patients has improved since the introduction of the highly active antiretroviral treatment (HAART). However, in the present HAART era, HIV co-morbidities such as lung cancer, a non-AIDS (NAIDS) defining cancer have been documented to be on the rise. Under normal physiological conditions, cells grow, repair and proliferate through the cell-cycle as cellular homeostasis is important in the maintenance and proper regulation of tissues and organs. Contrarily, the deregulation of the cell-cycle is a hallmark of cancer, including lung cancer. The association between lung cancer and the use of HAART components such as Efavirenz (EFV) is poorly understood. This study aimed at elucidating the effects of EFV on the cell-cycle genes’ expression in lung cancer. For this purpose, the human cell-cycle gene array composed of 84 genes was evaluated on both normal lung fibroblasts (MRC-5) cells and adenocarcinoma (A549) lung cells, in response to 13µM EFV or 0.01% vehicle. The ±2 up or down fold change was used as a basis of target selection, with p < 0.05. Additionally, RT-qPCR was done to validate the gene array results. Next, In-silico bio-informatics tools, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Reactome, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Ingenuity Pathway Analysis (IPA) were used for gene/gene interaction studies as well as to map the molecular and biological pathways influenced by the identified targets. Interestingly, the DNA damage response (DDR) pathway genes such as p53, Ataxia telangiectasia mutated and Rad3 related (ATR), Growth arrest and DNA damage inducible alpha (GADD45A), HUS1 checkpoint homolog (HUS1) and Role of radiation (RAD) genes were shown to be upregulated following EFV treatment, as revealed by STRING analysis. Additionally, functional enrichment analysis by the KEGG pathway revealed that most of the differentially expressed gene targets function at the cell-cycle checkpoint such as p21, Aurora kinase B (AURKB) and Mitotic Arrest Deficient-Like 2 (MAD2L2). Core analysis by IPA revealed that p53 downstream targets such as survivin, Bcl2, and cyclin/cyclin dependent kinases (CDKs) complexes are down-regulated, following exposure to EFV. Furthermore, Reactome analysis showed a significant increase in cellular response to stress genes, DNA repair genes, and apoptosis genes, as observed in both normal and cancerous cells. These findings implicate the genotoxic effects of EFV on lung cells, provoking the DDR pathway. Notably, the constitutive expression of this pathway (DDR) often leads to uncontrolled cell proliferation and eventually tumourigenesis, which could be the attribute of HAART components’ (such as EFV) effect on human cancers. Targeting the cell-cycle and its regulation holds a promising therapeutic intervention to the potential HAART associated carcinogenesis, particularly lung cancer.

Keywords: cell-cycle, DNA damage response, Efavirenz, lung cancer

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Authors: Nurulhikma Md Isa, Intan Elya Suka, Nur Farhana Roslan, Chew Bee Lynn

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The evolutionarily conserved N-end rule pathway marks proteins for degradation by the Ubiquitin Proteosome System (UPS) based on the nature of their N-terminal residue. Proteins with a destabilizing N-terminal residue undergo a series of condition-dependent N-terminal modifications, resulting in their ubiquitination and degradation. Intensive research has been carried out in Arabidopsis previously. The group VII Ethylene Response Factor (ERFs) transcription factors are the first N-end rule pathway substrates found in Arabidopsis and their role in regulating oxygen sensing. ERFs also function as central hubs for the perception of gaseous signals in plants and control different plant developmental including germination, stomatal aperture, hypocotyl elongation and stress responses. However, nothing is known about the role of this pathway during fruit development and ripening aspect. The plant model system Arabidopsis cannot represent fleshy fruit model system therefore tomato is the best model plant to study. PROTEOLYSIS6 (PRT6) is an E3 ubiquitin ligase of the N-end rule pathway. Two homologs of PRT6 sequences have been identified in tomato genome database using the PRT6 protein sequence from model plant Arabidopsis thaliana. Homology search against Ensemble Plant database (tomato) showed Solyc09g010830.2 is the best hit with highest score of 1143, e-value of 0.0 and 61.3% identity compare to the second hit Solyc10g084760.1. Further homology search was done using NCBI Blast database to validate the data. The result showed best gene hit was XP_010325853.1 of uncharacterized protein LOC101255129 (Solanum lycopersicum) with highest score of 1601, e-value 0.0 and 48% identity. Both Solyc09g010830.2 and uncharacterized protein LOC101255129 were genes located at chromosome 9. Further validation was carried out using BLASTP program between these two sequences (Solyc09g010830.2 and uncharacterized protein LOC101255129) to investigate whether they were the same proteins represent PRT6 in tomato. Results showed that both proteins have 100 % identity, indicates that they were the same gene represents PRT6 in tomato. In addition, we used two different RNAi constructs that were driven under 35S and Polygalacturonase (PG) promoters to study the function of PRT6 during tomato developmental stages and ripening processes.

Keywords: ERFs, PRT6, tomato, ubiquitin

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Authors: Jolene M. Helena, Annie M. Joubert, Peace Mabeta, Magdalena Coetzee, Roy Lakier, Anne E. Mercier

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Targeting the distant tumour and its microenvironment whilst preserving bone density is important in improving the outcomes of patients with bone metastases. 2-Ethyl-3-O-sulphamoyl-estra1,3,5(10)16-tetraene (ESE-16) is an in-silico-designed 2- methoxyestradiol analogue which aimed at enhancing the parent compound’s cytotoxicity and providing a more favourable pharmacokinetic profile. In this study, the potential radiosensitization effects of ESE-16 were investigated in an in vitro bone metastasis model consisting of murine pre-osteoblastic (MC3T3-E1) and pre-osteoclastic (RAW 264.7) bone cells, metastatic prostate (DU 145) and breast (MDA-MB-231) cancer cells, as well as human umbilical vein endothelial cells (HUVECs). Cytotoxicity studies were conducted on all cell lines via spectrophotometric quantification of 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide. The experimental set-up consisted of flow cytometric analysis of cell cycle progression and apoptosis detection (Annexin V-fluorescein isothiocyanate) to determine the lowest ESE-16 and radiation doses to induce apoptosis and significantly reduce cell viability. Subsequent experiments entailed a 24-hour low-dose ESE-16-exposure followed by a single dose of radiation. Termination proceeded 2, 24 or 48 hours thereafter. The effect of the combination treatment was investigated on osteoclasts via tartrate-resistant acid phosphatase (TRAP) activity- and actin ring formation assays. Tumour cell experiments included investigation of mitotic indices via haematoxylin and eosin staining; pro-apoptotic signalling via spectrophotometric quantification of caspase 3; deoxyribonucleic acid (DNA) damage via micronuclei analysis and histone H2A.X phosphorylation (γ-H2A.X); and Western blot analyses of bone morphogenetic protein-7 and matrix metalloproteinase-9. HUVEC experiments included flow cytometric quantification of cell cycle progression and free radical production; fluorescent examination of cytoskeletal morphology; invasion and migration studies on an xCELLigence platform; and Western blot analyses of hypoxia-inducible factor 1-alpha and vascular endothelial growth factor receptor 1 and 2. Tumour cells yielded half-maximal growth inhibitory concentration (GI50) values in the nanomolar range. ESE-16 concentrations of 235 nM (DU 145) and 176 nM (MDA-MB-231) and a radiation dose of 4 Gy were found to be significant in cell cycle and apoptosis experiments. Bone and endothelial cells were exposed to the same doses as DU 145 cells. Cytotoxicity studies on bone cells reported that RAW 264.7 cells were more sensitive to the combination treatment than MC3T3-E1 cells. Mature osteoclasts were more sensitive than pre-osteoclasts with respect to TRAP activity. However, actin ring morphology was retained. The mitotic arrest was evident in tumour and endothelial cells in the mitotic index and cell cycle experiments. Increased caspase 3 activity and superoxide production indicated pro-apoptotic signalling in tumour and endothelial cells. Increased micronuclei numbers and γ-H2A.X foci indicated increased DNA damage in tumour cells. Compromised actin and tubulin morphologies and decreased invasion and migration were observed in endothelial cells. Western blot analyses revealed reduced metastatic and angiogenic signalling. ESE-16-induced radiosensitization inhibits metastatic signalling and tumour cell survival whilst preferentially preserving bone cells. This low-dose combination treatment strategy may promote the quality of life of patients with metastatic bone disease. Future studies will include 3-dimensional in-vitro and murine in-vivo models.

Keywords: angiogenesis, apoptosis, bone metastasis, cancer, cell migration, cytoskeleton, DNA damage, ESE-16, radiosensitization.

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Authors: Li Chen, Feng Zhang, Shizhong Zheng

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SaikosaponinD (SSD) is a major component of saikosaponins isolated from Bupleurumfalactum. Our current study was to examine the toxic effect of SSD on liver cells and explore the possible mechanism. The results demonstrated that SSD induced mouse liver injury and led to apoptosis in LO2 cells. HE staining and TUNEL analyses showed that SSD stimulated liver injury and hepatocyte apoptosis in vivo. Subsequent experiments showed that SSD down-regulated Bcl-2 but up-regulated Bax. In vitro, SSD-treated LO2 cells exhibited apparent down-regulated expression of p-p38. Moreover, PDGF-βR agonist PDGF-BB alone significantly upregulated p38 phosphorylation, while combined with SSD, p38 phosphorylation expression was reduced. Furthermore, shRNA-mediated PDGF-βR knockdown augmented the inactivation of p-p38 and Bcl2 but abrogated the activation of Bax, these results were more obvious when shRNA combined with SSD. These data indicated that SSD stimulated liver injury and apoptosis in hepatocytes and PDGF-βR /p38 pathway may be the potential mechanistic.

Keywords: saikosaponin D, hepatotoxicity, liver injury, apoptosis, platelet-derived growth factor-β receptor, p38

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Authors: Ali Bahri Lubis

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The study of dioxygenase enzymatic mechanism on tryptophan oxidation has been a wide interest since the reaction is rate-limiting step of kynurenine pathway. In this research, observation of tryptophan oxidation through h-IDO enzyme along with synthesis of enzyme products was conducted in order to comprehend how the enzyme works on distinct substrates. UV-vis spectrophotometry, LC-MS, H-NMR and HSQC measurement were carried out to characterise enzyme product. It is found that while tryptophan was oxidised to form Nformylkynurenine (NFK) as a major product and hydroxypyrroloindole amine carboxylic acid (HPIC) in cis and trans confirmed in HSQC, N-methyl tryptophan substrate was converted to NFK and trans HPIC only. Other intriguing results showed that 5-hydroxy- tryptophan and Stryptophan was degraded to become NFK and epoxide cyclic respectively. The formation of NFK was considered through dioxygenation pathway, however HPIC was formed via monooxygenation. The epoxide cyclic—considered as intermediate compound in the mechanism— from S-tryptophan was not able to cleave the epoxide ring since bond energy of epoxide was probably much stronger. This validates the enzymatic mechanism where the intermediate compound in the enzymatic mechanism is epoxide cyclic.

Keywords: tryptophan oxidation, heme-dioxygenases, N-formylkynurenine, hydroxypyrrroloindoleamine, monooxidation

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Authors: Simona Moravcova, Jiri Novotny, Zdenka Bendova

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The pineal gland of the vertebrate brain is a circumventricular organ which serves as a major neuroendocrine gland with the primary function of rhythmic secretion of neurohormone melatonin under the control of the hypothalamic suprachiasmatic nucleus (SCN). Soon after the onset of the darkness, the activity of the key rate-limiting enzyme for melatonin synthesis, arylalkylamine N-acetyltransferase (AANAT), raises due to the increased release of norepinephrine from sympathetic neurons terminating on the parenchymal cells where it binds to β-adrenergic receptors. Melatonin codes the length of the night, and it is well recognized for its anti-inflammatory effects. However, to our knowledge, less is known about the effect of the immune system on the melatonin biosynthesis and the precise role of the STAT3 in the signaling pathway leading to the expression of AANAT. Lipopolysaccharide (LPS) is the essential component in the outer surface membrane of gram-negative bacteria and acts as a strong stimulator of natural and innate immunity. STAT3 acts as an important factor in immune response. Here we investigated the effect of LPS on the components of the melatonergic synthetic pathway in the pineal gland. The experiments were performed both in vivo and in vitro. The changes in AANAT activity were determined by radioenzymatic assay. PCR analyses were carried out to detect aa-nat, icer, spi-3 and stat3 gene expression. From our results, it is apparent that the high basal level of phosphorylated forms of STAT3 can be elevated after systemic as well as in vitro administration of LPS. Our experiments have shown that LPS reduces melatonin synthesis, nevertheless, the activity of AANAT was increased. Moreover, the basal level of phosphorylated STAT3 counteracts β-adrenergic receptor-mediated aa-nat gene expression and sustains its own and spi-3 gene expression. In conclusion, LPS can affect immunomodulators such as melatonin in the pineal gland.

Keywords: AANAT, lipopolysaccharide, pineal gland, rat, STAT3

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Authors: Rishana Bilimoria, Selina Tang, Sajni Shah, Marianne Henien, Christopher Sproat

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Temporomandibular disorders (TMD) may affect up to a third of the general population, and there is evidence demonstrating the majority of Myofascial TMD cases improve after education and conservative measures. In 2015 our department implemented a modified care pathway for myofascial TMD patients in an attempt to improve the patient journey. This involved the use of an interactive group therapy approach to deliver education, reinforce conservative measures and promote self-management. Patient reported experience measures from the new group clinic revealed 71% patient satisfaction. This service is efficient in improving aspects of health status while reducing health-care costs and redistributing clinical time. Since its’ establishment, 52 hours of clinical time, resources and funding have been redirected effectively. This Quality Improvement Project was initiated because it was felt that this new service was being underutilised by our surgical teams. The ‘Plan-Do-Study-Act cycle’ (PDSA) framework was employed to analyse utilisation of the service: The ‘plan’ stage involved outlining our aims: to raise awareness amongst clinicians of the unified care pathway and to increase referral to this clinic. The ‘do’ stage involved collecting data from a sample of 96 patients over 4 month period to ascertain the proportion of Myofascial TMD patients who were correctly referred to the designated clinic. ‘Suitable’ patients who weren’t referred were identified. The ‘Study’ phase involved analysis of results, which revealed that 77% of suitable patients weren’t referred to the designated clinic. They were reviewed on other clinics, which are often overbooked, or managed by junior staff members. This correlated with our original prediction. Barriers to referral included: lack of awareness of the clinic, individual consultant treatment preferences and patient, reluctance to be referred to a ‘group’ clinic. The ‘Act’ stage involved presenting our findings to the team at a clinical governance meeting. This included demonstration of the clinical effectiveness of the care-pathway and explaining the referral route and criteria. In light of the evaluation results, it was decided to keep the group clinic and maximize utilisation. The second cycle of data collection following these changes revealed that of 66 Myofascial TMD patients over a 4 month period, only 9% of suitable patients were not seen via the designated pathway; therefore this QIP was successful in meeting the set objectives. Overall, employing the PDSA cycle in this QIP resulted in appropriate utilisation of the modified care pathway for patients with myofascial TMD in Guy’s Oral Surgery Department. In turn, this leads to high patient satisfaction with the service and effectively redirected 52 hours of clinical time. It permitted adoption of a collaborative working style with oral surgery colleagues to investigate problems, identify solutions, and collectively raise standards of clinical care to ensure we adopt a unified care pathway in secondary care management of Myofascial TMD patients.

Keywords: myofascial, quality Improvement, PDSA, TMD

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Authors: Hager Elsheikh

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Context: Pancreatitis is a condition characterized by inflammation in the pancreas, which can lead to serious complications if untreated. Both acute and chronic pancreatitis are associated with immune reactions and fibrosis, which further damage the pancreas. The type 2 immune response, primarily driven by alternative activated macrophages (AAMs), plays a significant role in the development of fibrosis. The IL-4/STAT6 pathway is a crucial signaling pathway for the activation of M2 macrophages. Pancreatic fibrosis is induced by dysregulated inflammatory responses and can result in the autodigestion and necrosis of pancreatic acinar cells. Research Aim: The aim of this study is to investigate the impact of STAT6, a crucial molecule in the IL-4/STAT6 pathway, on the severity and development of fibrosis during acute and chronic pancreatitis. The research also aims to understand the influence of the JAK/STAT6 signaling pathway on the balance between fibrosis and regeneration in the presence of different macrophage populations. Methodology: The research utilizes murine models of acute and chronic pancreatitis induced by cerulean injection. Animal models will be employed to study the effect of STAT6 knockout on disease severity and fibrosis. Isolation of acinar cells and cell culture techniques will be used to assess the impact of different macrophage populations on wound healing and regeneration. Various techniques such as PCR, histology, immunofluorescence, and transcriptomics will be employed to analyze the tissues and cells. Findings: The research aims to provide insights into the mechanisms underlying tissue fibrosis and wound healing during acute and chronic pancreatitis. By investigating the influence of the JAK/STAT6 signaling pathway and different macrophage populations, the study aims to understand their impact on tissue fibrosis, disease severity, and pancreatic regeneration. Theoretical Importance: This research contributes to our understanding of the role of specific signaling pathways, macrophage polarization, and the type 2 immune response in pancreatitis. It provides insights into the molecular mechanisms underlying tissue fibrosis and the potential for targeted therapies. Data Collection and Analysis Procedures: Data will be collected through the use of murine models, isolation and culture of acinar cells, and various experimental techniques such as PCR, histology, immunofluorescence, and transcriptomics. Data will be analyzed using appropriate statistical methods and techniques, and the findings will be interpreted in the context of the research objectives. Conclusion: By investigating the mechanisms of tissue fibrosis and wound healing during acute and chronic pancreatitis, this research aims to enhance our understanding of the disease progression and potential therapeutic targets. The findings have theoretical importance in expanding our knowledge of pancreatic fibrosis and the role of macrophage polarization in the context of the type 2 immune response.

Keywords: immunity in chronic diseases, pancreatitis, macrophages, immune response

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Authors: Mary Farrell, Maria Soubra, Sandra Vega, Dorothy Kakraba, Joanne Fontanilla, Moira Kendra, Danielle Tonzola, Stephanie Chiu

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Pneumonia is the most common infectious cause of hospitalizations in the United States, with more than one million admissions annually and costs of $10 billion every year, making it the 8th leading cause of death. Aspiration pneumonia is an aggressive type of pneumonia that results from inhalation of oropharyngeal secretions and/or gastric contents and is preventable. The authors hypothesized that an evidence-based aspiration pneumonia clinical care pathway could reduce 30-day hospital readmissions and mortality rates, while improving the overall care of patients. We conducted a retrospective chart review on 979 patients discharged with aspiration pneumonia from January 2021 to December 2022 at Overlook Medical Center. The authors identified patients who were coded with aspiration pneumonia and/or stable sepsis. Secondarily, we identified 30-day readmission rates for aspiration pneumonia from a SNF. The Aspiration Pneumonia Clinical Care Pathway starts in the emergency department (ED) with the initiation of antimicrobials within 4 hours of admission and early recognition of aspiration. Once this is identified, a swallow test is initiated by the bedside nurse, and if the patient demonstrates dysphagia, they are maintained on strict nothing by mouth (NPO) followed by a speech and language pathologist (SLP) referral for an appropriate modified diet recommendation. Aspiration prevention techniques included the avoidance of straws, 45-degree positioning, no talking during meals, taking small bites, placement of the aspiration wrist band, and consuming meals out of the bed in a chair. Nursing education was conducted with a newly created online learning module about aspiration pneumonia. The authors identified 979 patients, with an average age of 73.5 years old, who were diagnosed with aspiration pneumonia on the index hospitalization. These patients were reviewed for a 30-day readmission for aspiration pneumonia or stable sepsis, and mortality rates from January 2021 to December 2022 at Overlook Medical Center (OMC). The 30-day readmission rates were significantly lower in the cohort that received the clinical care pathway (35.0% vs. 27.5%, p = 0.011). When evaluating the mortality rates in the pre and post intervention cohort the authors discovered the mortality rates were lower in the post intervention cohort (23.7% vs 22.4%, p = 0.61) Mortality among non-white (self-reported as non-white) patients were lower in the post intervention cohort (34.4% vs. 21.0% , p = 0.05). Patients who reported as a current smoker/vaper in the pre and post cohorts had increased mortality rates (5.9% vs 22%). There was a decrease in mortality for the male population but an increase in mortality for women in the pre and post cohorts (19% vs. 25%). The authors attributed this increase in mortality in the post intervention cohort to more active smokers, more former smokers, and more being admitted from a SNF. This research identified that implementation of an Aspiration Pneumonia Clinical Care Pathway showed a statistically significant decrease in readmission rates and mortality rates in non-whites. The 30-day readmission rates were lower in the cohort that received the clinical care pathway (35.0% vs. 27.5%, p = 0.011).

Keywords: aspiration pneumonia, mortality, quality improvement, 30-day pneumonia readmissions

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Authors: Tatipamula Samiksha Goud, .A.Naveena, M.sresta

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Traffic congestion is a major issue in many cities throughout the world, particularly in urban areas, and it is past time to switch from a fixed timer mode to an automated system. The current traffic signalling system is a fixed-time system that is inefficient if one lane is more functional than the others. A structure for an intelligent traffic control system is being designed to address this issue. When traffic density is higher on one side of a junction, the signal's green time is extended in comparison to the regular time. This study suggests a technique in which the signal's time duration is assigned based on the amount of traffic present at the time. Infrared sensors can be used to do this.

Keywords: infrared sensors, micro-controllers, LEDs, oscillators

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Authors: Hamed Karimian, Noraziah Nordin, Mohamad Ibrahim Noordin, Syam Mohan, Mahboubeh Razavi, Najihah Mohd Hashim, Happipah Mohd Ali

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Satureja bachtiarica Bunge is a perennial medicinal plant belonging to the Lamiaceae family and endemic species in Iran. Satureja bachtiarica Bunge with the local name of Marzeh koohi is edible vegetable use as flavoring agent, anti-bacterial and to relieve cough and indigestion. In this study, the anti-cancer effect of Satureja bachtiarica Bunge on the MDA-MB-231 cell line as an Breast cancer cell model has been analyzed for the first time. Satureja bachtiarica Bunge was extracted using different solvents in the order of increasing polarity. Cytotoxicity activity of hexane extract of Satureja bachtiarica Bunge (SBHE) was observed using MTT assay. Acridine orange/Propidium iodide staining was used to detect early apoptosis; Annexin-V-FITC assay was carried out to observe the detection of cell-surface Phosphatidylserine (PS), with Annexin-Vserving as a marker for apoptotic cells. Caspase 3/7, 8 and-9 assays showed significantly activation of caspase-9 where lead intrinsic mitochondrial pathway. Bcl-2/Bax expressions and cell cycle arrest were also investigated. SBHE had exhibited significantly higher cytotoxicity against MDA-MB-231 Cell line compare to other cell lines. A significant increase in chromatin condensation in the cell nucleus was observed by fluorescence analysis. Treatment of MDA-MB-231 cells with SBHE encouraged apoptosis, by down-regulating Bcl-2 and up-regulating Bax, which lead the activation of caspase 9. Moreover, SBHE treatment significantly arrested MDA-MB-231 cells in the G1 phase. Together, the results presented in this study demonstrated that SBHE inhibited the proliferation of MDA-MB-231 cells, leading cell cycle arrest and programmed cell death, which was confirmed to be through the mitochondrial pathway.

Keywords: Satureja bachtiarica Bunge, MDA-MB-231, apoptosis, annexin-V, cell cycle

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Authors: Renalda El Samra, Elie Bou-Zeid, Hamza Kunhu Bangalath, Georgiy Stenchikov, Mutasem El Fadel

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The regional-scale impact of climate change over complex terrain was examined through high-resolution dynamic downscaling conducted using the Weather Research and Forecasting (WRF) model, with initial and boundary conditions from a High-Resolution Atmospheric Model (HiRAM). The analysis was conducted over the eastern Mediterranean, with a focus on the country of Lebanon, which is characterized by a challenging complex topography that magnifies the effect of orographic precipitation. Four year-long WRF simulations, selected based on HiRAM time series, were performed to generate future climate projections of extreme temperature and precipitation over the study area under the conditions of the Representative Concentration Pathway (RCP) 4.5. One past WRF simulation year, 2008, was selected as a baseline to capture dry extremes of the system. The results indicate that the study area might be exposed to a temperature increase between 1.0 and 3ºC in summer mean values by 2050, in comparison to 2008. For extreme years, the decrease in average annual precipitation may exceed 50% at certain locations in comparison to 2008.

Keywords: HiRAM, regional climate modeling, WRF, Representative Concentration Pathway (RCP)

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Authors: Deepa Gandhi, Pravin K. Naoghare, Amit Bafana, Krishnamurthi Kannan, Saravanadevi Sivanesana

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Oxidative stress is known to depreciate normal functioning of osteoblast cells. Present study reports oxidative/inflammatory signatures in fluoride exposed human osteosarcoma (HOS) cells and its possible association with the genes involved in bone developmental pathway. Microarray analysis was performed to understand the possible molecular mechanisms of stress-mediated bone lose in HOS cells. Cells were chronically exposed with sub-lethal concentration of fluoride. Global gene expression is profiling revealed 34 up regulated and 2598 down-regulated genes, which were associated with several biological processes including bone development, osteoblast differentiation, stress response, inflammatory response, apoptosis, regulation of cell proliferation. Microarray data were further validated through qRT-PCR and western blot analyses using key representative genes. Based on these findings, it can be proposed that chronic exposure of fluoride may impair bone development via oxidative and inflammatory stress. The present finding also provides important biological clues, which will be helpful for the development of therapeutic targets against diseases related bone.

Keywords: bone, HOS cells, microarray, stress

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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: S. A. El-Marasy, S. A. El Awdan, R. M. Abd-Elsalam

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This study aimed to investigate the possible neuroprotective effect of chrysin on thioacetamide (TAA)-induced hepatic encephalopathy in rats. Also, the effect of chrysin on motor impairment, cognitive deficits, oxidative stress, neuroinflammation, apoptosis and histopathological damage was assessed. Male Wistar rats were randomly allocated into five groups. The first group received the vehicle (distilled water) for 21 days and is considered as normal group. While the second one received intraperitoneal dose of TAA (200 mg/kg) at three alternative days during the third week of the experiment to induce HE and is considered as control group. The other three groups were orally administered chrysin for 21 days (25, 50, 100 mg/kg) and starting from day 17; rats received intraperitoneal dose of TAA (200 mg/kg) at three alternative days. Then behavioral, biochemical, histopathological and immunohistochemical analyses were assessed. Then behavioral, biochemical, histopathological and immunohistochemical analyses were assessed. Chrysin reversed TAA-induced motor coordination in rotarod test, cognitive deficits in object recognition test (ORT) and attenuated serum ammonia, hepatic liver enzymes, reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), reduced nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) brain contents. Chrysin administration also reduced Toll-4 receptor (TLR-4) gene expression, caspase-3 protein expression, hepatic necrosis and astrocyte swelling. This study depicts that chrysin exerted neuroprotective effect in TAA-induced HE rats, evidenced by improvement of cognitive deficits, motor incoordination and histopathological changes such as astrocyte swelling and vacuolization; hallmarks in HE, via reducing hyperammonemia, ameliorating hepatic function, in addition to its anti-oxidant, inactivation of TLR-4/NF-κB inflammatory pathway, and anti-apoptotic effects.

Keywords: chrysin, hepatic encephalopathy, oxidative stress, rats, thioacetamide, TLR4/NF-κB pathway

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Authors: S. M. Yasir Arafat

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Driving models are needed by many researchers to improve traffic safety and to advance autonomous vehicle design. To be most useful, a driving model must state specifically what information is needed and how it is processed. So we developed an “Obstacle Avoidance and Detection Autonomous Car” based on sensor application. The ever increasing technological demands of today call for very complex systems, which in turn require highly sophisticated controllers to ensure that high performance can be achieved and maintained under adverse conditions. Based on a developed model of brakes operation, the controller of braking system operation has been designed. It has a task to enable solution to the problem of the better controlling of braking system operation in a more accurate way then it was the case now a day.

Keywords: automobile, obstacle, safety, sensing

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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: 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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