Yaşam ve Doğa Bilimleri Fakültesi

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Akut Böbrek Hasarında Nötrofil Jelatinaz İlişkili Lipokalin ile Mortalite İlişkisi
(GALENOS YAYINCILIK, ERKAN MOR, MOLLA GURANI CAD 21-1, FINDIKZADE, ISTANBUL 34093, TURKEY, 2018) Aksebzeci, Bekir Hakan; Kayaaltı, Seda; Kayaaltı, Ömer; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü;
Objective: Almost half of intensive care patients are affected by acute kidney injury (AKI). The purpose of this study is to determine parameters that can be used for predicting of early (within 28 days) and late (within 90 days) mortality in patients who are followed-up with AKI in intensive care units. Materials and Methods: In this study, a dataset that contains 50 patients with AKI in intensive care units was used. This dataset contains blood urea nitrogen, creatinine, plasma and urinary neutrophil gelatinase-associated hpocalin (NGAL), lactate dehydrogenase, alkaline phosphatase and gammaglutamyl transpeptidase values of patients who were admitted to intensive care for various reasons and who developed AKI on the days 1, 3 and 7. In addition to these values, laboratory results such as serum electrolytes on day 1, blood gas; vital signs such as mean arterial pressure, central venous pressure; and demographic data were also recorded. Data mining techniques were applied to determine correlation between all of these data and mortality. Results: The threshold level of urinary NGAL on day 7 was determined to be 69 ng/mL, and strong correlation was found between this threshold level and early mortality. Similarly, the threshold level of plasma NGAL on day 7 was determined to be 150 ng/mL, and this was highly correlated with early mortality. Besides, strong correlation was also found between the difference in the urinary NGAL levels on day 1 and 7, and early mortality. Conclusion: In this study, plasma and urinary NGAL levels were found to be closely related to early mortality in patients who were followed-up with AKI in intensive care units. On the other hand, any parameter associated with late mortality was not found.
Akut Myeloid Lösemi Tedavisi için Hedgehog Ve Otofaji Yolaklarının Düzenlenmesi
(TUBİTAK, 2019) EL KHATIB, Mona; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; EL KHATIB, Mona
Akut myeloid lösemi (AML) çeşitli moleküler aberasyonlar ve sinyal yolaklarındaki bozuklukları içeren klonal hastalıklar ile karakterize edilen bir grup heterojen malignanttır. Hedgehog (HH) sinyal yolağı birçok kanserde deregüle edilen evrimsel olarak korunan bir sinyal yolağıdır. HH sinyal yolağı lizozomal degradasyon prosesi otofajinin temel regülatörü olan PI3K/AKT/mTOR aksesini de içeren diğer sinyal yolakları ile karşılıklı iletişim halindedir. Bu sinyal yolakları AML’de deregüle edilmiştir. Birçok çalışmada otofajinin AML için bir kaçış mekanizması olabileceği ortaya konulmuştur. Bizim çalışmamızda, HH ve otofaji yolaklarının farklı AML türleri üzerine etkileri incelenmiştir. Çalışmamızda KML hücresi olan K562 ve CMK, MV4-11, MOLM-13 ve NB4 AML hücreleri GLI1 inhibitörü GANT61 ve farklı otofaji modülatörleri ile muamele edilmiştir.MTT sonuçları NB4, MOLM-13 ve MV4-11hücre proliferasyonun GLI inhibisyonu sonrasında düştüğünü ancak CMK’nin diğer AML hücre hatlarına kıyasla GLI inhibisyonuna daha az sensitif olduğunu ortaya koymuştur. Daha sonra, otofaji modülasyonunun farklı AML hücre hatlarının proliferasyonu üzerine etkileri incelenmiştir. Otofajinin gerek otofagozom-lizozom füzyonu aşamasında gerekse otofagolizozomal degradasyon aşamasında inhibisyonunun ilaç konsantrasyonu ve muamele süresine bağlı olarak AML sağkalımını azalttığı gözlemlenmiştir. Otofaji modülatörleri ve GANT61’in kombinasyonunun MOLM-13 hücre hattı üzerinde sinerjistik bir etkisinin olduğu fakat CMK hücre hattı üzerinde sinerjistik etkisinin olmadığı gözlemlenmiştir. GANT61 muamelesinin AML hücre hatlarında otofajiyi artırdığı LC3II ekspresyonu ile western blot yöntemi ile ortaya konulmuştur. Buna ek olarak, kombinasyonun MOLM-13 hücresinde LC3II’yi artırdığı gözlenirken, bu oran CMK hücre hattında daha düşüktür. AKT proteinin ekspresyonu ilaca ve hücre hattına gore farklılık göstermektedir. Sonuç olarak, HH ve otofaji sinyal yolaklarının hedeflenmesi MOLM-13 hücre hattı için umut vaatedici bir terapi iken, CMK hücre hattında benzer sonuçlara ulaşılamamıştır.
Analyzing the genetic diversity and biotechnological potential of Leuconostoc pseudomesenteroides by comparative genomics
(Frontiers Media S.A., 2023) Gumustop, Ismail; Ortakci, Fatih; 0000-0003-1319-0854; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Gumustop, Ismail; Ortakci, Fatih
Leuconostoc pseudomesenteroides is a lactic acid bacteria species widely exist in fermented dairy foods, cane juice, sourdough, kimchi, apple dumpster, caecum, and human adenoid. In the dairy industry, Ln. pseudomesenteroides strains are usually found in mesophilic starter cultures with lactococci. This species plays a crucial role in the production of aroma compounds such as acetoin, acetaldehyde, and diacetyl, thus beneficially affecting dairy technology. We performed genomic characterization of 38 Ln. pseudomesenteroides from diverse ecological niches to evaluate this species’ genetic diversity and biotechnological potential. A mere ~12% of genes conserved across 38 Ln. pseudomesenteroides genomes indicate that accessory genes are the driving force for genotypic distinction in this species. Seven main clades were formed with variable content surrounding mobile genetic elements, namely plasmids, transposable elements, IS elements, prophages, and CRISPR-Cas. All but three genomes carried CRISPR-Cas system. Furthermore, a type IIA CRISPR-Cas system was found in 80% of the CRISPR-Cas positive strains. AMBR10, CBA3630, and MGBC116435 were predicted to encode bacteriocins. Genes responsible for citrate metabolism were found in all but five strains belonging to cane juice, sourdough, and unknown origin. On the contrary, arabinose metabolism genes were only available in nine strains isolated from plant-related systems. We found that Ln. pseudomesenteroides genomes show evolutionary adaptation to their ecological environment due to niche-specific carbon metabolism and forming closely related phylogenetic clades based on their isolation source. This species was found to be a reservoir of type IIA CRISPR-Cas system. The outcomes of this study provide a framework for uncovering the biotechnological potential of Ln. pseudomesenteroides and its future development as starter or adjunct culture for dairy industry.
An answer to colon cancer treatment by mesenchymal stem cell originated from adipose tissue
(MASHHAD UNIV MED SCIENCES, VICE-CHANCELLOR FOR RES CTR OFF IJBMS, DANESHGAH ST, PO BOX 9138813944 - 445, MASHHAD, 00000, IRAN, 2018) Iplik, Elif; Ertugrul, Baris; Kozanoglu, İlknur; Baran, Yusuf; Cakmakoglu, Bedia; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü;
Objective(s): Colon cancer is risen up with its complex mechanism that directly impacts on its treatment as well as its common prevalence. Mesenchymal stem cells (MSCs) have been considered as a therapeutic candidate for conventional disease including cancer. In this research, we have focused on apoptotic effects of adipose tissue-derived MSCs in colon cancer. Materials and Methods: MSCs were obtained from adipose tissue and characterized by Flowcytometer using suitable antibodies. MSCs, HT-29, HCT-116, RKO and healthy cell line MRC5 were cultured by different seeding procedure. After cell viability assay, changes in caspase 3 enzyme activity and the level of phosphatidylserine were measured. Results: For cell viability assay, a 48 hr incubation period was chosen to seed all cells together. There was a 1.36-fold decrease in caspase 3 enzyme activity by co-treatment of RKO and MSCs in addition to 2.02-fold decrease in HT-29 and MSCs co-treatment, and 1.103-fold increase in HCT-116 and MSCs. The results demonstrated that HCT-116 led to the highest rate of apoptotic cell death (7.5%) compared with other cells. Conclusion: We suggest that MSCs might remain a new treatment option for cancer by its differentiation and repair capacity.
Apatinib Sensitizes Human Breast Cancer Cells against Navitoclax and Venetoclax Despite Up-regulated Bcl-2 and Mcl-1 Gene Expressions
(KARE PUBLCONCORD ISTANBUL, DUMLUPINAR MAH, CIHAN SK NO 15, B BLOK 162 KADIKOY, ISTANBUL, TURKEY, 2021) Kavakcioglu Yardimci, Berna; Ozgun Acar, Ozden; Semiz, Asli; Sen, Alaattin; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Sen, Alaattin
OBJECTIVE Defects in apoptotic cell death which restrict the success of conventional cytotoxic therapies have pivotal roles in a number of pathological conditions including cancer. However, a novel drug class targeting pro-survival Bcl-2 protein family members has been developed with the understanding of the structures and interactions of Bcl-2 proteins. Within this new class, Bcl-2/Bcl-xL inhibitor Navitoclax and Bcl-2 specific inhibitor Venetoclax have been shown to demonstrate strong anticancer activities on several types of cancers. But their low affinity to other anti-apoptotic proteins limits their clinical usage. Here, we investigated the cytotoxic and apoptotic effects of Navitoclax/Venetoclax and their combinations with specific tyrosine kinase inhibitor Apatinib on estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cell lines. METHODS MTT assay was used for the evaluation of the inhibition of cancer cell proliferation. ELISA test and Quantitative real-time PCR assay was performed to determine the role of caspase-3, Bak, Bax, Bcl-2, Bcl-xL and Mcl-1 proteins in the inhibition of cell proliferation triggered by the tested agents. RESULTS We found that aggressive MDA-MB-231 cell line was more sensitive to all tested agents. Apatinib significantly enhanced Navitoclax/Venetoclax mediated inhibition of cell viability in both cancer cell lines despite up-regulation in the expression levels of Bcl-2 and Mcl-1 genes. We further demonstrated significant Bak/Bax and caspase-3 expression in less aggressive MCF-7 cells. CONCLUSION Our findings have impacts on Navitoclax/Venetoclax plus Apatinib based therapy for breast adenocarcinoma. On the other hand, further studies should be conducted to elucidate the mechanisms underlying synergistic effects of Navitoclax/Venetoclax plus Apatinib combinations.
Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells
(SAGE PUBLICATIONS LTD, 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND, 2016) Kiraz, Yagmur; Neergheen-Bhujun, Vidushi S.; Rummun, Nawraj; Baran, Yusuf; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü;
Multiple myeloma is of great concern since existing therapies are unable to cure this clinical condition. Alternative therapeutic approaches are mandatory, and the use of plant extracts is considered interesting. Punica granatum and its derived products were suggested as potential anticancer agents due to the presence of bioactive compounds. Thus, polypenolic-rich extracts of the non-edible parts of P. granatum were investigated for their antiproliferative and apoptotic effects on U266 multiple myeloma cells. We demonstrated that there were dose-dependent decreases in the proliferation of U266 cells in response to P. granatum extracts. Also, exposure to the extracts triggered apoptosis with significant increases in loss of mitochondrial membrane potential in U266 cells exposed to the leaves and stem extracts, while the flower extract resulted in slight increases in loss of MMP. These results were confirmed by Annexin-V analysis. These results documented the cytotoxic and apoptotic effects of P. granatum extracts on human U266 multiple myeloma cells via disruption of mitochondrial membrane potential and increasing cell cycle arrest. The data suggest that the extracts can be envisaged in cancer chemoprevention and call for further exploration into the potential application of these plant parts.
ARL13B regulates juxtaposed cilia-cilia elongation in BBSome dependent manner in Caenorhabditis elegans
(CELL PRESS, 2025) Turan, Merve Gul; Kantarci, Hanife; Cevik, Sebiha; Kaplan, Oktay I.; 0000-0002-0935-1929; 0000-0002-8733-0920; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Turan, Merve Gul; Kantarci, Hanife; Cevik, Sebiha; Kaplan, Oktay I.
The interaction of cilia with various cellular compartments, such as axons, has emerged as a new form of cellular communication. Cilia often extend in proximity to cilia from neighboring cells. However, the mechanisms driving this process termed juxtaposed cilia-cilia elongation (JCE) remain unclear. We use fluorescence-based visualization to study the mechanisms of coordinated cilia elongation in sensory neurons of Caenorhabditis elegans. Conducting a selective gene-based screening strategy reveals that ARL-13/ARL13B and MKS-5/RPGRIP1L are essential for JCE. We demonstrate that ARL-13 modulates JCE independently of cilia length. Loss of NPHP-2/inversin along with HDAC-6 enhances the cilia misdirection phenotype of arl-13 mutants, while disruption of the BBSome complex, but not microtubule components, partially suppresses the JCE defects in arl-13 mutants. We further show changes in the phospholipid compositions in arl-13 mutants. We suggest that ARL-13 contributes to JCE, in part, through the modulation of the ciliary membrane.
Aurora Kinases: Their Role in Cancer and Cellular Processes
(Bingöl Üniversitesi Fen Bilimleri Enstitüsü, 2024) Sarı, Sibel; Özsoy, Elif Rumeysa; 0000-0002-2505-5804; 0009-0008-6040-9875; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Sarı, Sibel; Özsoy, Elif Rumeysa
Aurora kinases, belonging to a highly conserved family of serine/threonine kinases with critical roles in the regulation of the cell cycle, comprise three members: Aurora kinase A, B, and C, which serve as key mitotic regulators essential for maintaining chromosome stability. Aurora kinases play crucial roles in multiple events in mitotic such as the coordination of chromosomal and cytoskeletal events, regulation of the spindle assembly checkpoint pathway and cytokinesis to ensure the smooth progression of the cell cycle. Besides their mitotic functions, Aurora kinases are also involved in the regulation of meiosis. Gene amplification/mutation and overexpression of Aurora kinases have been detected in various solid and haematological cancers. In human tumours, Aurora kinases exhibit oncogenic roles associated with their mitotic roles, which drive the cancer cell proliferation and survival. Deregulation of Aurora kinase activity causes failure in centrosome function, spindle assembly, chromosomal alignment, and cytokinesis, eventually resulting in the mitotic abnormalities and genetic instability. These findings emphasize the crucial functions of Aurora kinases in cancer, prompting their recognition as valuable targets for cancer therapy. This review provides an overview of the structures and functions of Aurora kinases and sheds light on their oncogenic roles in cancer.
Berberine-containing natural-medicine with boiled peanut-OIT induces sustained peanut-tolerance associated with distinct microbiota signature
(FRONTIERS MEDIA SA, 2023) Srivastava, Kamal; Cao, Mingzhuo; Fidan, Ozkan; Shi, Yanmei; Yang, Nan; Nowak-Wegrzyn, Anna; Miao, Mingsan; Zhan, Jixun; Sampson, Hugh A.; Li, Xiu-Min; 0000-0001-5312-4742; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Fidan, Ozkan
BackgroundGut microbiota influence food allergy. We showed that the natural compound berberine reduces IgE and others reported that BBR alters gut microbiota implying a potential role for microbiota changes in BBR function. ObjectiveWe sought to evaluate an oral Berberine-containing natural medicine with a boiled peanut oral immunotherapy (BNP) regimen as a treatment for food allergy using a murine model and to explore the correlation of treatment-induced changes in gut microbiota with therapeutic outcomes. MethodsPeanut-allergic (PA) mice, orally sensitized with roasted peanut and cholera toxin, received oral BNP or control treatments. PA mice received periodic post-therapy roasted peanut exposures. Anaphylaxis was assessed by visualization of symptoms and measurement of body temperature. Histamine and serum peanut-specific IgE levels were measured by ELISA. Splenic IgE(+)B cells were assessed by flow cytometry. Fecal pellets were used for sequencing of bacterial 16S rDNA by Illumina MiSeq. Sequencing data were analyzed using built-in analysis platforms. ResultsBNP treatment regimen induced long-term tolerance to peanut accompanied by profound and sustained reduction of IgE, symptom scores, plasma histamine, body temperature, and number of IgE(+) B cells (p <0.001 vs Sham for all). Significant differences were observed for Firmicutes/Bacteroidetes ratio across treatment groups. Bacterial genera positively correlated with post-challenge histamine and PN-IgE included Lachnospiraceae, Ruminococcaceae, and Hydrogenanaerobacterium (all Firmicutes) while Verrucromicrobiacea. Caproiciproducens, Enterobacteriaceae, and Bacteroidales were negatively correlated. ConclusionsBNP is a promising regimen for food allergy treatment and its benefits in a murine model are associated with a distinct microbiota signature.
Biochemical, pharmacological, and toxicological attributes of caper (Capparis ovata) flowering buds and berries pickles
(WILEY, 2022) Ozgun-Acar, Ozden; Celik-Turgut, Gurbet; Guner, Huseyin; Sezer, Serdar; Sen, Alaattin; 0000-0002-8444-376X; 0000-0002-0220-5224; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Güner, Hüseyin; Şen, Alaattin
Capparis ovata is a natural plant that grows widely in Turkey and its flowering buds and berry pickle are used in traditional medicine. Thus, the current study was expanded to evaluate the biochemical, pharmacological, and toxicological aspects of the Capparis ovata water extract (COWE). To determine the biochemical properties of COWE, mineral and fatty acid content, elemental analysis, flavonoid/phenolic content, radicalscavenging capacity, and pesticide analysis were performed. Furthermore, to find out whether it had anti-inflammatory properties, reverse transcription-polymerase chain reaction (RT-PCR) and nuclear factor kappa B (NF-κB) luciferase activity tests were conducted. Whole-genome transcriptomic profiling was carried out at a dose level of 500 mg/kg COWE to understand its pharmacological effect. Transaminases in serum were tested, and quantitative polymerase chain reaction (qPCR) was done using a custom design array that included the stress and molecular toxicology pathway to establish its toxicological qualities. As a result of the evaluations, it was observed that COWE has a high mineral and unsaturated fatty acid content, flavonoid/phenolic content, and radical-scavenging ability. It significantly inhibited NF-κB transcriptional activity as well as inflammatory cytokine expression in T-lymphoblast cells. Wholegenome transcriptomic profiling depicted that COWE modulates immune responses by upregulating natural killer cell activation, cellular response to type I interferon, B-cell proliferation and differentiation, and Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathways. Molecular Toxicology Pathfinder RT2 Profiler PCR array analysis revealed that COWE at or lower dose of 500 mg/kg/day did not cause a comparatively adverse effect. According to the findings, COWE is a rich source of nutrients and can be used as an adjunct therapy for various inflammatory diseases
Biodiversity, drug discovery, and the future of global health: Introducing the biodiversity to biomedicine consortium, a call to action
(UNIV EDINBURGH, GLOBAL HEALTH SOC, CENTRE POPULATION HEALTH SCIENCES, TEVIOT PL, EDINBURGH, EH8 9AG, SCOTLAND, 2017) Neergheen-Bhujun, Vidushi; Awan, Almas Taj; Baran, Yusuf; Bunnefeld, Nils; Chan, Kit; Edison Dela Cruz, Thomas; Egamberdieva, Dilfuza; Elsasser, Simon; Johnson, Mari-Vaughn V.; Komai, Shoji; Konevega, Andrey L.; Malone, John H.; Mason, Paul; Nguon, Rothsophal; Piper, Ross; Shrestha, Uttam Babu; Pesic, Milica; Kagansky, Alexander; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü;
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Biosynthesis of Novel Naphthoquinone Derivatives in the Commonly-used Chassis Cells Saccharomyces cerevisiae and Escherichia coli
(Pleiades journals, 2021) Wu W.; Wang S.; Zhang H.; Guo W.; Lu H.; Xu H.; Zhan R.; Fidan O.; Sun L.; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Fidan, O.
Naphthoquinones harboring 1,4-naphthoquinone pharmacophore are considered as privileged structures in medicinal chemistry. In pharmaceutical industry and fundamental research, polyketide naphthoquinones were widely produced by heterologous expression of polyketide synthases in microbial chassis cells, such as Saccharomyces cerevisiae and Escherichia coli. Nevertheless, these cell factories still remain, to a great degree, black boxes that often exceed engineers’ expectations. In this work, the biotransformation of juglone or 1,4-naphthoquinone was conducted to generate novel derivatives and it was revealed that these two naphthoquinones can indeed be modified by the chassis cells. Seventeen derivatives, including 6 novel compounds, were isolated and their structural characterizations indicated the attachment of certain metabolites of chassis cells to naphthoquinones. Some of these biosynthesized derivatives were reported as potent antimicrobial agents with reduced cytotoxic activities. Additionally, molecular docking as simple and quick in silico approach was performed to screen the biosynthesized compounds for their potential antiviral activity. It was found that compound 11 and 17 showed the most promising binding affinities against Nsp9 of SARS-CoV-2, demonstrating their potential antiviral activities. Overall, this work provides a new approach to generate novel molecules in the commonly used chassis cells, which would expand the chemical diversity for the drug development pipeline. It also reveals a novel insight into the potential of the catalytic power of the most widely used chassis cells. © 2021, Pleiades Publishing, Inc.
Characterization of genomic, physiological, and probiotic features Lactiplantibacillus plantarum DY46 strain isolated from traditional lactic acid fermented shalgam beverage
(ELSEVIER, 2022) Yetiman, Ahmet E.; Keskin, Abdullah; Darendeli, Busra Nur; Kotil, Seyfullah Enes; Ortakci, Fatih; Dogan, Mahmut; 0000-0001-5340-5106; 0000-0003-1319-0854; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Keskin, Abdullah; Ortakci, Fatih
Lactiplantibacillus plantarum is a significant probiotic where it could be found in ubiquitous niches. In this study, a new Lb. plantarum strain DY46 was isolated from a traditional lactic-acid-fermented beverage called shalgam. The whole genome of the DY46 was sequenced and obtained sequences were assembled into a 3.32 Mb draft genome using PATRIC (3.6.8.). The DY46 genome consists of a single circular chromosome of 3,332,827 bp that is predicted to carry 3219 genes, including 61 tRNA genes, 2 rRNA operons. The genome has a GC content of 44.3% includes 98 predicted pseudogenes, 25 complete or partial transposases and 3 intact prophages. The genes encoding enzymes related in the intact EMP (Embden–Meyerhof–Parnas) and PK (phosphoketolase) pathways were predicted using BlastKOALA which is an indicator of having facultative heterofermentative pathways. DY46 genome also predicted to carry genes of Pln E, Pln F and Pln K showing the antimicrobial potential of this bacterium which can be linked to in vitro antagonism tests that DY46 can inhibit S.enterica sv. Typhimurium ATCC14028, K. pneumonie ATCC13883, and P. vulgaris ATCC8427. Moreover, it is determined that all resistome found in its genome were intrinsically originated and the strain was found to be tolerant to acid and bile concentrations by mimicking human gastrointestinal conditions. In conclusion, L. plantarum DY46 is a promising bacterium that appears to have certain probiotic properties, confirmed by “in vitro” and “in silico” analyses, and is a potential dietary supplement candidate that may provide functional benefits to the host.
CiliaMiner: an integrated database for ciliopathy genes and ciliopathies
(OXFORD UNIV PRESS, 2023) Turan, Merve Gül; Orhan, Mehmet Emin; Cevik, Sebiha; Kaptan, Oktay I.; 0000-0001-5783-7168; 0000-0002-1757-1374; 0000-0002-0935-1929; 0000-0002-8733-0920; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Turan, Merve Gül; Orhan, Mehmet Emin; Cevik, Sebiha; Kaptan, Oktay I.
Cilia are found in eukaryotic species ranging from single-celled organisms, such as Chlamydomonas reinhardtii, to humans, but not in plants. The ability to respond to repellents and/or attractants, regulate cell proliferation and differentiation and provide cellular mobility are just a few examples of how crucial cilia are to cells and organisms. Over 30 distinct rare disorders generally known as ciliopathy are caused by abnormalities or functional impairments in cilia and cilia-related compartments. Because of the complexity of ciliopathies and the rising number of ciliopathies and ciliopathy genes, a ciliopathy-oriented and up-to-date database is required. Here, we present CiliaMiner, a manually curated ciliopathy database that includes ciliopathy lists collected from articles and databases. Analysis reveals that there are 55 distinct disorders likely related to ciliopathy, with over 4000 clinical manifestations. Based on comparative symptom analysis and subcellular localization data, diseases are classifed as primary, secondary or atypical ciliopathies. CiliaMiner provides easy access to all of these diseases and disease genes, as well as clinical features and gene-specifc clinical features, as well as subcellular localization of each protein. Additionally, the orthologs of disease genes are also provided for mice, zebrafsh, Xenopus, Drosophila, Caenorhabditis elegans and Chlamydomonas reinhardtii. CiliaMiner (https://kaplanlab.shinyapps.io/ciliaminer) aims to serve the cilia community with its comprehensive content and highly enriched interactive heatmaps, and will be continually updated.
CilioGenics: an integrated method and database for predicting novel ciliary genes
(Oxford University Press, 2024) Pir, Mustafa Samet; Begar, Efe; Yenisert, Ferhan; Demirci, Hasan C.; Korkmaz, Mustafa E.; Karaman, Asli; Tsiropoulou, Sofia; Firat-Karalar, Elif Nur; Blacque, Oliver E.; Oner, Sukru S.; Doluca, Osman; Cevik, Sebiha; Kaplan, Oktay Ismail; 0000-0002-4645-7626; 0000-0002-0935-1929; 0000-0002-8733-0920; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Pir, Mustafa Samet; Yenisert, Ferhan; Demirci, Hasan C.; Korkmaz, Mustafa E.; Cevik, Sebiha; Kaplan, Oktay Ismail
Uncovering the full list of human ciliary genes holds enormous promise for the diagnosis of cilia-related human diseases, collectively known as ciliopathies. Currently, genetic diagnoses of many ciliopathies remain incomplete (1–3). While various independent approaches theoretically have the potential to reveal the entire list of ciliary genes, approximately 30% of the genes on the ciliary gene list still stand as ciliary candidates (4,5). These methods, however, have mainly relied on a single strategy to uncover ciliary candidate genes, making the categorization challenging due to variations in quality and distinct capabilities demonstrated by different methodologies. Here, we develop a method called CilioGenics that combines several methodologies (single-cell RNA sequencing, protein-protein interactions (PPIs), comparative genomics, transcription factor (TF) network analysis, and text mining) to predict the ciliary capacity of each human gene. Our combined approach provides a CilioGenics score for every human gene that represents the probability that it will become a ciliary gene. Compared to methods that rely on a single method, CilioGenics performs better in its capacity to predict ciliary genes. Our top 500 gene list includes 258 new ciliary candidates, with 31 validated experimentally by us and others. Users may explore the whole list of human genes and CilioGenics scores on the CilioGenics database (https://ciliogenics.com /).
Circular RNA-MicroRNA-MRNA interaction predictions in SARS-CoV-2 infection
(WALTER DE GRUYTER GMBHGENTHINER STRASSE 13, D-10785 BERLIN, GERMANY, 2021) Demirci, Yilmaz Mehmet; Demirci, Muserref Duygu Sacar; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Demirci, Yilmaz Mehmet; Demirci, Muserref Duygu Sacar
Different types of noncoding RNAs like microRNAs (miRNAs) and circular RNAs (circRNAs) have been shown to take part in various cellular processes including post-transcriptional gene regulation during infection. MiRNAs are expressed by more than 200 organisms ranging from viruses to higher eukaryotes. Since miRNAs seem to be involved in host-pathogen interactions, many studies attempted to identify whether human miRNAs could target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNAs as an antiviral defence mechanism. In this work, a machine learning based miRNA analysis work flow was developed to predict differential expression patterns of human miRNAs during SARS-CoV-2 infection. In order to obtain the graphical representation of miRNA hairpins, 36 features were defined based on the secondary structures. Moreover, potential targeting interactions between human circRNAs and miRNAs as well as human miRNAs and viral mRNAs were investigated.
Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells
(De Gruyter, 2022) Adan, Aysun; Şahin, Hande Nur; 0000-0002-3747-8580; 0000-0002-2382-3160; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Biyoloji ve Genetik Bölümü; Adan, Aysun; Şahin, Hande Nur
Objectives Therapeutic potential of clinically approved FLT3 inhibitor midostaurin has been neglected in wild-type FLT3 positive acute myeloid leukemia (AML). Sphingosine kinase-1 (SK-1) having anti-proliferative functions is studied in various cancers, but not in FLT3 wild-type AML. We aimed to develop new therapeutic strategies to combat FLT3 wild-type AML by combining midostaurin with SK-1 inhibitor (SKI II) in THP1 cells. Methods The anti-proliferative effects of midostaurin, SKI II and in combination on THP1 cells were determined by MTT assay. The combination indexes were calculated using calcusyn software. SK-1 expression and PARP cleavage were checked by western blot. Cell cycle distributions (PI staining) and apoptosis (annexin-V/PI dual staining) were assessed by flow cytometry for each agent alone and in combinations. Results Midostaurin decreased SK-1 protein level. Midostaurin, SKI II and certain combinations decreased cell viability in a dose dependent manner. The combined anti-leukemic effects of the aforementioned drug combination afforded additive effect. Co-administration induced both necrosis and apoptosis via phosphatidylserine externalization, PARP cleavage and cell cycle arrest at G0/G1 and S phases. Conclusions Targeting sphingosine kinase-1 together with FLT3 inhibition could be a novel mechanism to increase limited clinic response to midostaurin in wild-type FLT3 overexpressing AML after further pre-clinical studies.
Comparative Genomics of Lentilactobacillus parabuchneri isolated from dairy, KEM complex, Makgeolli, and Saliva Microbiomes
(BMC, 2022) Gumustop, Ismail; Ortakci, Fatih; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Ortakçı, Fatih; Gümüştop, İsmail
Background: Lentilactobacillus parabuchneri is of particular concern in fermented food bioprocessing due to causing unwanted gas formation, cracks, and off-flavor in fermented dairy foods. This species is also a known culprit of histamine poisonings because of decarboxylating histidine to histamine in ripening cheese. Twenty-eight genomes in NCBI GenBank were evaluated via comparative analysis to determine genomic diversity within this species and identify potential avenues for reducing health associated risks and economic losses in the food industry caused by these organisms. Result: Core genome-based phylogenetic analysis revealed four distinct major clades. Eight dairy isolates, two strains from an unknown source, and a saliva isolate formed the first clade. Three out of five strains clustered on clade 2 belonged to dairy, and the remaining two strains were isolated from the makgeolli and Korean effective microorganisms (KEM) complex. The third and fourth clade members were isolated from Tete de Moine and dairy-associated niches, respectively. Whole genome analysis on twenty-eight genomes showed similar to 40% of all CDS were conserved across entire strains proposing a considerable diversity among L. parabuchneri strains analyzed. After assigning CDS to their corresponding function, similar to 79% of all strains were predicted to carry putative intact prophages, and similar to 43% of the strains harbored at least one plasmid; however, all the strains were predicted to encode genomic island, insertion sequence, and CRISPR-Cas system. A type I-E CRISPR-Cas subgroup was identified in all the strains, with the exception of DSM15352, which carried a type II-A CRISPR-Cas system. Twenty strains were predicted to encode histidine decarboxylase gene cluster that belongs to not only dairy but also saliva, KEM complex, and unknown source. No bacteriocin-encoding gene(s) or antibiotic resistome was found in any of the L. parabuchneri strains screened. Conclusion: The findings of the present work provide in-depth knowledge of the genomics of L. parabuchneri by comparing twenty-eight genomes available to date. For example, the hdc gene cluster was generally reported in cheese isolates; however, our findings in the current work indicated that it could also be encoded in those strains isolated from saliva, KEM complex, and unknown source. We think prophages are critical mobile elements of L. parabuchneri genomes that could pave the way for developing novel tools to reduce the occurrence of this unwanted species in the food industry.
Comparative genomics of Leuconostoc lactis strains isolated from human gastrointestinal system and fermented foods microbiomes
(BMCCAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND, 2022) Gümüştop, İsmail; Ortakçı, Fatih; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Gümüştop, İsmail; Ortakçı, Fatih
Background: Leuconostoc lactis forms a crucial member of the genus Leuconostoc and has been widely used in the fermentation industry to convert raw material into acidified and flavored products in dairy and plant-based food systems. Since the ecological niches that strains of Ln. lactis being isolated from were truly diverse such as the human gut, dairy, and plant environments, comparative genome analysis studies are needed to better understand the strain differences from a metabolic adaptation point of view across diverse sources of origin. We compared eight Ln. lactis strains of 1.2.28, aa_0143, BIOML-A1, CBA3625, LN19, LN24, WIKIM21, and WiKim40 using bioinformatics to elucidate genomic level characteristics of each strain for better utilization of this species in a broad range of applications in food industry. Results: Phylogenomic analysis of twenty-nine Ln. lactis strains resulted in nine clades. Whole-genome sequence analysis was performed on eight Ln. lactis strains representing human gastrointestinal tract and fermented foods microbiomes. The findings of the present study are based on comparative genome analysis against the reference Ln. lactis CBA3625 genome. Overall, a similar to 41% of all CDS were conserved between all strains. When the coding sequences were assigned to a function, mobile genetic elements, mainly insertion sequences were carried by all eight strains. All strains except LN24 and WiKim40 harbor at least one intact putative prophage region, and two of the strains contained CRISPR-Cas system. All strains encoded Lactococcin 972 bacteriocin biosynthesis gene clusters except for CBA3625. Conclusions: The findings in the present study put forth new perspectives on genomics of Ln. lactis via complete genome sequence based comparative analysis and further determination of genomic characteristics. The outcomes of this work could potentially pave the way for developing elements for future strain engineering applications.
Comparative genomics of Loigolactobacillus coryniformis with an emphasis on L. coryniformis strain FOL-19 isolated from cheese
(ELSEVIER, 2023) Gumustop, Ismail; Ortakci, Fatih; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Gumustop, Ismail
Loigolactobacillus coryniformis is a member of lactic acid bacteria isolated from various ecological niches. We isolated a novel L. coryniformis strain FOL-19 from artisanal Tulum cheese and performed the whole-genome sequencing for FOL-19. Then, genomic characterization of FOL-19 against ten available whole genome sequences of the same species isolated from kimchi, silage, fermented meat, air of cowshed, dairy, and pheasant chyme was performed to uncover the genetic diversity and biotechnological potential of overall species. The average genome size of 2.93 +/- 0.1 Mb, GC content of 42.96% +/- 0.002, number of CDS of 2905 +/- 165, number of tRNA of 56 +/- 10, and number of CRISPR elements of 6.55 +/- 1.83 was found. Both Type I and II Cas clusters were observed in L. coryniformis. No bacteriocin biosynthesis gene clusters were found. All strains harbored at least one plasmid except KCTC 3167. All strains were predicted to carry multiple IS elements. The most common origin of the IS elements was belong to Lactiplantibacillus plantarum. Comparative genomic analysis of L. coryniformis revealed hypervariability at the strain level and the presence of CRISPR/Cas suggests that L. coryniformis holds a promising potential for being a reservoir for new CRISPR-based tools. All L. coryniformis strains except PH-1 were predicted to harbor pdu and cbi-cob-hem gene clusters encoding industrially relevant traits of reuterin and cobalamin biosynthesis, respectively. These findings put a step forward for the genomic characterization of L. coryniformis strains for biotechnological applications via genome-guided strain selection to identify industrially relevant traits.

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