New Bounds for the Harmonic Energy and Harmonic Estrada index of Graphs

Let $G$ be a finite simple undirected graph with $n$ vertices and $m$ edges. The Harmonic energy of a graph $G$, denoted by $\mathcal{H}E(G)$, is defined as the sum of the absolute values of all Harmonic eigenvalues of $G$. The Harmonic Estrada index of a graph $G$, denoted by $\mathcal{H}EE(G)$, is defined as $\mathcal{H}EE=\mathcal{H}EE(G)=\sum_{i=1}^{n}e^{\gamma_i},$ where $\gamma_1\geqslant \gamma_2\geqslant \dots\geqslant \gamma_n$ are the $\mathcal{H}$-$eigenvalues$ of $G$. In this paper we present some new bounds for $\mathcal{H}E(G)$ and $\mathcal{H}EE(G)$ in terms of number of vertices, number of edges and the sum-connectivity index

True prediction of lowest observed adverse effect levels

Summary A database of structurally heterogeneous chemical structures with their experimental values of Lowest Observed Adverse Effect Levels (LOAELs) was modeled using graph theoretical descriptors. Variable selection for multiple linear regression (MLR) and linear discriminant analysis (LDA) was accomplished by the Internal Test Set (ITS) method in order to achieve true predicted LOAEL values. The results obtained can be considered good if we take in count the structural diversity of the training set

Effects of oleanolic acid on small intestine morphology and enzymes of glutamine metabolism in diabetic rats.

M. Sc. University of KwaZulu-Natal, Durban 2014.The small intestine (SI) is the main site for food absorption and glutamine utilization hence critical in metabolic disorders that involve energy balance such as diabetes and obesity. This study aims to assess the effects of a known hypoglycaemic compound, oleanolic acid (OA), on some enzymes of glutamine metabolism as well as morphological changes in the SI of diabetic rats. Diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of 60 and 40 mg/kg body weight streptozotocin for type 1 diabetes (T1D) and T2D respectively. One week later, different groups of the diabetic rats were treated with OA, insulin or OA + insulin in the T1D study and OA or metformin for T2D. Untreated diabetic groups served as controls and non-diabetic rats were grouped and treated similarly. After 2 weeks of treatment, all the animals were euthanized and the SI was differently processed for histological and enzymatic studies. The results in both studies indicate significant (p<0.05) increase in the size of the SI and villi in the diabetic compared to the non-diabetic groups and these were not ameliorated by all treatments. The results suggest that treatment with OA increases villi size independent of diabetes. On the other hand, the activity of phosphate dependent glutaminase (PDG) was slightly decreased only in T1D and this was not reversed by treatments. Expression of PDG detected by dot blots was not different in all groups. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GDH) were significantly (p<0.05) elevated in diabetic control groups compared to normal controls and all treatments decreased ALT and AST activities while only insulin decreased GDH activity. Furthermore, hexokinase activity was elevated by diabetes and OA induces further increase. It is concluded that in the early stages of diabetes, OA treatment does not adversely affect PDG activity or expression in the SI but affects other enzymes important in energy metabolism in this tissue

Grafovi čija je najmanja karakteristična vrednost minimalna u nekim klasama grafova

Spectral graph theory is an important interdisciplinary field of science and mathematics in which methods of linear algebra are used to solve problems in graph theory. It has numerous applications for modelling problems in chemistry, computers science, medicine, economy, and physics, to name just a few. By representing a graph as an adjacency matrix, matrix theory can be applied to graph theory. Features of the graph can be investigated using the eigenvalues and the eigenvectors of the adjacency matrix, and these give us information about the graph’s structure. The eigenvalues of a graph G can be ordered decreasingly, where the first is denoted by (G) and is called the index of the graph and the least eigenvalue is denoted by (G). A graph’s spread s(G) is defined as the difference between the greatest and the least eigenvalue of the graph’s adjacency matrix, i.e. s(G) = (G) − (G). The principal topic of this doctoral thesis is the least eigenvalue of a graph. The structure of a graph G that has the minimum least eigenvalue within a certain class of graphs is determined. This graph is referred to as an extremal graph

Investigation of Anti-Inflammatory and Antioxidants Properties of Phenolic Compounds from Inonotus obliquus Using Different Extraction Methods

Inonotus obliquus, commonly known as Chaga, is a fungal pathogen of birch trees, known to synthesize a range of phenolic compounds with remarkable health benefits. These presumed medicinal properties have generated increased interest in Chaga consumption. Prior research has demonstrated the diverse chemical composition of Chaga sourced from a variety of geographical locations. However, to our knowledge, there is currently no available literature regarding the extraction of bioactive compounds from Chaga grown in the United States. Additionally, the effect of the extraction method on the antioxidant and anti-inflammation properties specifically, has yet to be validated. Therefore, the present study was developed to examine the effects of extraction conditions on phenolic compounds in Maine sourced Chaga and correlate these findings to anti-inflammatory benefits. A high-performance liquid chromatography–diode array detection (HPLC–DAD) method was developed to determine the phenolic acids content in Chaga. The method demonstrated good linearity (0.994-0.999) and precision within (RSD ≤ 3) and between (RSD ≤ 4.2) -day precisions. The procedure also produced good recovery within (≥ 90.1) and between (≥88.5) -day precisions, as well. The majority of phenolic acids were extracted from the base hydrolysis fraction (2794.91 μg/g). The response surface methodology (RSM) was also applied to establish optimum extraction conditions to obtain phenolic-rich extracts. Results indicate that an extraction temperature of 170°C and ethanol concentration of 66% were optimal for recovering phenolic compounds, with a total phenolic content (TPC) value of 39.32 mg GAL/g DW and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity of 76.59%. The extractions that produced the highest yields of TPC and DPPH were then assessed for the ability to remediate inflammation using lipopolysaccharide (LPS) activated RAW 264.7 macrophages. The results showed various Chaga extracts have significant antiinflammatory activity on LPS-stimulated RAW 264.7 cells. The inhibitory effect was evident through a decrease in the production of nitric oxide (NO) and down-regulation of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-β (IL-1β) in RAW 264.7 macrophages. Therefore, findings confirm that Maine harvested Chaga demonstrates anti-inflammatory properties. However, the phenolic yields (total phenolic acids and TPC) and antioxidant activity are highly dependent upon the extraction methodology

Pharmacological neuroprotection of rat spinal locomotor networks against experimental spinal cord injury in vitro

Background: Mammalian locomotor behaviour called fictive locomotion can be elicited in an isolated spinal cord in the absence of higher brain center or sensory input. This relatively simple behaviour is produced by the motoneuronal rhythmic activity which is under the control of spinal neuronal networks called central pattern generators (CPGs). Disturbance of this rhythmic motor output can occur following spinal cord injury (SCI). This elementary isolated spinal cord model gives us an opportunity to study the basic physiology of locomotion during control conditions, the pathological processes following lesion (which can be induced chemically), and eventually the application of therapeutic approaches curbing injury. Objectives: Multiple aspects of spinal functions can be demonstrated by stimulating or/and blocking specific inputs and measuring the outputs using electrophysiological, immunohistochemical and calcium imaging tools. Using isolated neonatal rat spinal cords and organotypic spinal slices as SCI models, the basic mechanisms (such as dysmetabolic state or excitotoxicity) which can develop during the early phase of the lesion were addressed and studied. The injury was evoked chemically by applying either pathological medium (to mimic dysmetabolic/hypoxic conditions) or kainate (to produce excitotoxicity that completely abolishes fictive locomotion and network synaptic transmission) for 1 h. Fictive locomotion was examined stimulating the lumbar dorsal root and recording from the ipsilateral and ipsi-segmental ventral roots. Other network parameters were also studied such as synaptic transmission and rhythmicity. Various therapeutic drugs such as methylprednisolone sodium succinate (MPSS), propofol, nicotine and celastrol were used during or after the injury (to produce neuroprotection) and network properties were characterized during the treatment and after 24 h as well. Subsequently, the structural properties were monitored using different biomarkers (isolated spinal cord sectioned slices) and calcium imaging (here organotypic spinal slices were used). Results and conclusions: We found that dose-dependent application of MPSS produced modest recovery of white matter damage evoked by pathological medium resulting in the emergence of sluggish chemically induced fictive locomotor patterns. However, it could not prevent damage (to gray matter) evoked by the excitotoxic agent kainate. Therefore, to provide better neuroprotection to gray matter, we tested the widely used intravenous anaesthetic propofol. This drug has shown comparatively good protection to spinal neurons and motoneurons in the gray matter. As it is an anesthetic it acted by depressing the functional network characteristics by lowering the N-methyl-D-aspartate (NMDA) and potentiating the \u3b3 aminobutyric acid (GABAA) mediated receptor responses. The next issue we addressed was to study the neuroprotective roles of nicotinic acetylcholine receptors (nAChRs) by using the receptor agonist nicotine. Recent studies have shown that nicotine could provide good neuroprotection to the rat brainstem. To further investigate its effect on the spinal cord, we applied nicotine at the same concentration used in previous studies in the brainstem: such a concentration was toxic to spinal ventral motoneurons. Therefore the correct dose of nicotine was optimized and was found to be ten times lower. Thus, satisfactory protective effects to spinal neurons and motoneurons and the fictive locomotor patterns were observed. These neuroprotective effects were replicated with calcium imaging by using organotypic spinal slice cultures. The mechanism of protection predominantly involved \u3b14\u3b22 and less \u3b17 nAChRs. In addition, the subsequent goal of our study was to explore whether the motoneuron survival after excitotoxicity relies on cell expression of heat shock protein 70 (HSP70) or some other mechanisms. To test this hypothesis we used a bioactive drug, celastrol which induces the expression of HSP70. Prior application of the drug followed by kainate preserved network polysynaptic transmission and fictive locomotion, however, it could not reverse the depression of monosynaptic reflex responses. In vivo studies are necessary in the future to further investigate the long-term neuroprotective role of these drugs

Development of novel hybrid phosphorated quinoline derivatives as topoisomerase 1B inhibitors with antiproliferative activity

466 p.El presente trabajo de Tesis Doctoral recopila la síntesis y evaluación biológica de nuevos derivados híbridos de quinolinas fosforadas como inhibidores de topoisomerasa 1B humana (hTOP1B) con actividad antiproliferativa. Se estudiaron varias metodologías sintéticas basadas en la reacción de Povarov, que permitieron la obtención de dichos derivados mediante procesos one-pot y estrategias multicomponente. Se estudió el comportamiento de los compuestos como inhibidores de hTOP1B, identificando los compuestos con mayor actividad inhibitoria de la diana y estudiando su mecanismo de inhibición, resultando en inhibidores catalíticos (supresores) de hTOP1B. A mayores, se desarrolló un nuevo método cuantitativo de drug screening para la detección de nuevas moléculas con capacidad de inhibir hTOP1B, así como elucidar su afectación al ciclo catalítico de hTOP1B. Por otro lado, se investigó la actividad antiproliferativa de los compuestos mediante ensayos de viabilidad celular in vitro en líneas celulares humanas cancerosas/embrionaria/no-cancerosa (A-549, SK-OV-3/HEK-293/MRC-5) y se estudió como afecta selectivamente la diana hTOP1B a la citotoxicidad inducida por los compuestos en las líneas celulares RMPI-8402/CPT-K5 y HEK-293 con knockdown de hTOP1B

Regulatory roles of photoreceptors and non-coding RNA in Fusarium fujikuroi

The genus Fusarium comprises hundreds of species of pathogenic and saprophytic fungi, usually characterized by a complex secondary metabolism. This includes the production of carotenoids, terpenoid pigments that give a characteristic orange color to their colonies. All the biosynthetic genes have been identified, and two of them are grouped in a coregulated cluster. Light plays a major role in promoting their synthesis by activating their transcription, but their effects on fungal biology are much wider. Light is presumably perceived by F. fujikuroi by a battery of photoreceptors, including members of the White-Collar complex, cryptochromes and photolyases, rhodopsins, and phytochromes. The main photoresponses in fungi are normally dependent on the White-collar complex, and carotenoid biosynthesis in Fusarium mainly depends on it, with WcoA as the light-absorbing component. Another photoreceptor, the DASH cryptochrome CryD, also affects the response of carotenogenesis to light, although the available information suggests its participation in a post-transcriptional regulation. Carotenogenesis is downregulated by a protein of the RING Finger family, called CarS, whose mutation results in a carotenoid overproduction phenotype. The carS gene is preceded by a 4 kb sequence with no known genes, in which the presence of two putative genes for microRNA like precursors had previously been suggested. In this Thesis, a massive sequencing specific for small RNAs has been carried out in F. fujikuroi, which confirmed their occurrence in this fungus. The result was consistent with the existence of a functional RNA interference system, supported by the identification of all the predicted enzymatic components encoded in the genome. This system seems to play a role in the biology of the fungus, as suggests the association between some sRNAs and the sequences of some transposons, indicating their role in silencing of these mobile elements. Deletion of one of the components, the gene for a Dicer protein predictably involved in their generation, showed no phenotype under laboratory conditions, suggesting other roles of the produced sRNAs in processes related with other stages of its life cycle, such as pathogenesis or sexual reproduction. The global sRNA analysis failed to identify possible sRNA elements upstream of carS, contradicting the former hypothesis on the participation of microRNAS in carS regulation. However, a new 1.2 kb transcript, that was denominated carP, was identified in carS upstream region. Its sequence lacks relevant open reading frames and the few that exist do not coincide in the equivalent sequence of the close relative Fusarium oxysporum, indicating that the transcript is a long non-coding RNA (lncRNA). The results showed that carP is independently transcribed from carS, and its deletion produces an albino phenotype due to a drop in transcription of the structural car genes, probably as a result of the higher transcription of carS gene. This phenotype was only complemented by reintegration of the carP gene in the native locus, while its ectopic integration did not allow to recover carotenoid production in the recipient carP mutant, indicating a cis-acting regulatory mechanism for carP on carS expression. Global transcriptomic data showed that carP deletion affects the expression of many genes, most of them predictably through its effect on CarS. However, some of the differentially expressed genes are hardly affected by the carS mutation, pointing to specific regulatory effects of carP on other target genes. Global transcriptomic data after different illumination times revealed a diversity of kinetics patterns in mRNA accumulation in the wild strain. Photoinduced genes exhibited fast, intermediate and late responses, while only intermediate and late responses were found for light-repressed genes. A vast majority of these photoresponses were lost in the wcoA mutant, indicating that WcoA is the main photoreceptor responsible for light regulation in F. fujikuroi. Outstandingly, the wcoA mutation brought about massive changes in the transcriptome, affecting about 20% of the genes. Most of these effects were produced regardless of illumination, indicating that WcoA plays a more general light-independent regulatory role in F. fujikuroi. Outstandingly, many of the genes influenced by WcoA were related to secondary metabolism biosynthetic clusters, raising a biotechnological interest for this protein. Parallel analysis of the effect of light on a cryD deletion mutant revealed less severe transcriptomic effects. However, it resulted in changes in the degrees of photoinduction or photorepression of many genes, suggesting an accessory function of CryD in Fusarium photobiology. The summarized results constitute a significant contribution to the knowledge of the regulation of carotenogenesis in F. fujikuroi and its photobiology and provide further evidence on its molecular complexity

Bioactive Molecules from Extreme Environments II

This Special Issue, as a continuation of the previous Special Issue, “Bioactive Molecules from Extreme Environments” (https://www.mdpi.com/journal/marinedrugs/special_issues/Extreme_Environments accessed on 4 November 2021), includes 10 research articles and 2 reviews, providing a wide overview of the chemical biodiversity offered by different marine organisms inhabiting extreme environments to be used for biotechnological and pharmaceutical applications. The six articles in this Special Issue are focused on the polar regions, which represent an untapped source of marine natural products and are still largely unexplored compared to more accessible sites. Many of these articles refer to Antarctica, which is the coldest and most inaccessible continent on the Earth, where extreme temperatures, light and ice have selected biological communities with a unique suite of bioactive metabolites. The marine organisms of Arctic and Antarctic environments are a reservoir of natural compounds, exhibiting huge structural diversity and significant bioactivities that could be used in human applications

Antitumoral Properties of Natural Products

Cancer is one of the major causes of death worldwide. It is a multifactorial heterogeneous disease characterized by the transformation of normal cells into malignant cells, which acquire an uncontrolled growth, immortality, invasiveness, and ability to form distant metastasis. Natural bioactive molecules may interfere with these processes and inhibit the carcinogenesis process. In this book, new molecules and extracts, mainly derived from plants, have been described as being able to alter tumor cell behavior and target several abnormal molecular pathways in cancer cells. Among different cancer cells, the more studied include those derived from glioblastoma, osteosarcoma, lung, breast and gastric cancer. These natural products could be an attractive source for the development of new preventative and therapeutic agents against cancer. They may be more selective and have weaker adverse effects compared to conventional chemotherapy drugs that are actually used for cancer treatment. Clinical trials are necessary to demonstrate whether the in vitro and in vivo animal data are reproduced in humans before the application of natural products in cancer prevention and treatment