Risk Prediction of Severe Bronchopulmonary Dysplasia (BPD) Using the Respiratory Severity Score (RSS) in Extremely Preterm Infants: A Retrospective Study From Saudi Arabia.

Background Bronchopulmonary dysplasia (BPD) is a significant complication in extremely preterm infants. Therefore, early diagnosis of BPD is important for planning treatment strategies. In this study, we aimed to assess the predictive efficacy of the Respiratory Severity Score (RSS) in determining severe BPD or death outcomes in very preterm infants. Methodology This retrospective study included preterm infants born with a gestational age of ≤30 weeks. The inclusion criteria comprised individuals who were mechanically ventilated (<1 week) during the first four weeks of life. Any patients who died during the first seven days of life were excluded. RSS values were recorded on days 3, 14, 21, and 28 of life. Multivariate logistic regression was used to identify a correlation between RSS and patient outcomes. Results A total of 154 infants were included in the analysis, of whom 82 (53.24%) developed severe BPD and 38 (24.67%) died. RSS was higher in patients who either died or developed severe BPD compared to those who survived. The multivariate logistic regression analysis revealed that RSSs at postnatal day 14 (odds ratio (OR) = 3.970; 95% confidence interval (CI) = 1.114-14.147; p < 0.05), day 21 (OR = 6.201; 95% CI = 1.937-19.851; p < 0.05), and day 28 (OR = 8.925; 95% CI = 3.331-28.383; p < 0.05) was significantly associated with a higher risk of death or severe BPD. Conclusions The findings of the present study revealed that RSS can help predict the risk of severe BPD in very preterm infants.

Ratiometric Fluorescence Aptasensor of Allergen Protein Based on Multivalent Aptamer-Encoded DNA Flowers as Fluorescence Resonance Energy Transfer Platform.

Life-threatening allergic reactions to food allergens, particularly peanut protein Ara h1, are a growing public health concern affecting millions of people worldwide. Thus, accurate and rapid detection is necessary for allergen labeling and dietary guidance and ultimately preventing allergic incidents. Herein, we present a novel ratiometric fluorescence aptasensor based on multivalent aptamer-encoded DNA flowers (Mul-DNFs) for the high-stability and sensitive detection of allergen Ara h1. The flower-shaped Mul-DNFs were spontaneously packaged using ultralong polymeric DNA amplicons driven by a rolling circle amplification reaction, which contains a large number of Ara h1 specific recognition units and has excellent binding properties. Furthermore, dual-color fluorescence-labeled Mul-DNFs probes were developed by hybridizing them with Cy3- and Cy5-labeled complementary DNA (cDNA) to serve as a ratiometric fluorescence aptasensor platform based on fluorescence resonance energy transfer. Benefiting from the combined merits of the extraordinary synergistic multivalent binding ability of Mul-DNFs, the excellent specificity of the aptamer, and the sensitivity of the ratiometric sensor to avoid exogenous interference. The developed ratiometric aptasensor showed excellent linearity (0.05-2000 ng mL-1) with a limit of detection of 0.02 ng mL-1. Additionally, the developed ratiometric fluorescence aptasensor was utilized for quantifying the presence of Ara h1 in milk, infant milk powder, cookies, bread, and chocolate with recoveries of 95.7-106.3%. The proposed ratiometric aptasensor is expected to be a prospective universal aptasensor platform for the rapid, sensitive, and accurate determination of food and environmental hazards.

Locustamigratoria (L.) (Orthoptera) in a warming world: unravelling the ecological consequences of climate change using GIS.

The migratory locust, Locustamigratoria (L.), a significant grasshopper species known for its ability to form large swarms and cause extensive damage to crops and vegetation, is subject to the influence of climate change. This research paper employs geographic information system (GIS) and MaxEnt ecological modelling techniques to assess the impact of climate change on the distribution patterns of L.migratoria. Occurrence data and environmental variables are collected and analysed to create predictive models for the current and future distribution of the species. The study highlights the crucial role of climate factors, particularly temperature and precipitation, in determining the locust's distribution. The MaxEnt models exhibit high-performance indicators, accurately predicting the potential habitat suitability of L.migratoria. Additionally, specific bioclimatic variables, such as mean temperature and annual precipitation, are identified as significant factors influencing the species' presence. The generated future maps indicate how this species will invade new regions especially in Europe. Such results predict the risk of this destructive species for many agriculture communities as a direct result of a warming world. The research provides valuable insights into the complex relationship between locust distribution and environmental factors, enabling the development of effective strategies for locust management and early warning systems to mitigate the impact on agriculture and ecosystems.

Evaluation of efficacy and safety profile of tadalafil 5 mg daily dose in the tablet form versus oral dispersible film in men with mild-to-moderate erectile dysfunction: a comparative placebo-controlled study.

PURPOSE: We aimed to compare the efficacy, safety, and compliance of tadalafil 5 mg daily dose in the tablet form versus oral dispersible film (ODF) in men with mild-to-moderate erectile dysfunction (ED). METHODS: One hundred thirty-five randomized patients were equally divided into three groups according to age where each group included forty-five patients. Within each group, 15 patients received oral tadalafil 5 mg, 15 patients received ODF tadalafil 5 mg and 15 patients received a placebo once daily for 1 month. All participants were assessed by the validated Arabic version of the international index of erectile function (ArIIEF-5) at baseline and after 1 month. Also, the efficacy of different forms of tadalafil 5 mg was assessed by responding affirmatively to a questionnaire. RESULTS: Patients aged > 25 to < 40 years and 40-55 years and > 55 years showed a statistically significant improvement of ArIIEF-5 scores after tadalafil 5 mg tablet and ODF tadalafil 5 mg compared to placebo ODF (23 ± 1.4; 22.7 ± 0.9; 20 ± 0.9; 20.4 ± 1.3; 20.2 ± 1.2; 16.6 ± 1.2; 18.5 ± 1.7; 19.6 ± 1.4; 16.3 ± 1.4; p < 0.001, respectively). Three patients (> 25 to < 40 years) who received tadalafil 5 mg tablet showed muscle and back pain. Gastrointestinal (GIT) upset (eight patients) followed by headache (seven patients) were the main side effects reported in patients (40-55 years) who received tadalafil 5 mg tablet. While GIT upset was the main side effect reported in patients (> 55 years) who received tadalafil 5 mg tablet. CONCLUSION: ODF tadalafil 5 mg is an effective, tolerable, and safe formulation that can be used in patients with mild-to-moderate ED.

Single-atom nanozymes with peroxidase-like activity: A review.

Single-atom nanozymes (SANs) are nanomaterials-based nanozymes with atomically dispersed enzyme-like active sites. SANs offer improved as well as tunable catalytic activity. The creation of extremely effective SANs and their potential uses have piqued researchers' curiosity due to their advantages of cheap cost, variable catalytic activity, high stability, and large-scale production. Furthermore, SANs with uniformly distributed active centers and definite coordination structures offer a distinctive opportunity to investigate the structure-activity correlation and control the geometric and electrical features of metal centers. SANs have been extensively explored in photo-, thermal-, and electro-catalysis. However, SANs suffer from the following disadvantages, such as efficiency, non-mimicking of the 3-D complexity of natural enzymes, limited and narrow range of artificial SANs, and biosafety aspects. Among a quite limited range of artificial SANs, the peroxidase action of SANs has attracted significant research attention in the last five years with the aim of producing reactive oxygen species for use in cancer therapy, and water treatment among many other applications. In this review, we explore the recent progress of different SANs as peroxidase mimics, the role of the metal center in enzymatic activity, possible prospects, and underlying limitations in real-time applications.

Mass Spectrometry Applications to Study Human Microbiome.

Microbiotas are an adaptable component of ecosystems, including human ecology. Microorganisms influence the chemistry of their specialized niche, such as the human gut, as well as the chemistry of distant surroundings, such as other areas of the body. Metabolomics based on mass spectrometry (MS) is one of the primary methods for detecting and identifying small compounds generated by the human microbiota, as well as understanding the functional significance of these microbial metabolites. This book chapter gives basic knowledge on the kinds of untargeted mass spectrometry as well as the data types that may be generated in the context of microbiome study. While data analysis remains a barrier, the emphasis is on data analysis methodologies and integrative analysis, particularly the integration of microbiome sequencing data. Mass spectrometry (MS)-based techniques have resurrected culture methods for studying the human gut microbiota, filling in the gaps left by high-throughput sequencing methods in terms of culturing minor populations.

Applications of Proteomics in Probiotics Having Anticancer and Chemopreventive Properties.

Proteomics has grown in importance in molecular sciences because it gives vital information on protein identification, expression levels, and alteration. Cancer is one of the world's major causes of death and is the major focus of much research. Cancer risk is determined by hereditary variables as well as the body's immunological condition. Probiotics have increasing medical importance due to their therapeutic influence on the human body in the prevention and treatment of numerous chronic illnesses, including cancer, with no adverse effects. Several anticancer, anti-inflammatory, and chemopreventive probiotics are studied using different proteomic approaches like two-dimensional gel electrophoresis, liquid chromatography-mass spectrometry, and matrix-assisted laser desorption/ionization mass spectrometry. To gain relevant information about probiotic characteristics, data from the proteomic analysis are evaluated and processed using bioinformatics pipelines. Proteomic studies showed the significance of different proteomic approaches in characterization, comparing strains, and determination of oxidative stress of different probiotics. Moreover, proteomic approaches identified different proteins that are involved in glucose metabolism and the formation of cell walls or cell membranes, and the differences in the expression of critical enzymes in the HIF-1 signaling pathway, starch, and sucrose metabolism, and other critical metabolic pathways.

Synthesis, toxicological and in silico evaluation of novel spiro pyrimidines against Culex pipiens L. referring to chitinase enzyme.

The exponential development of resistance to conventional chemical insecticides adds another important motive for the creation of novel insecticidal active agents. One of the keys to meeting this challenge is the exploration of novel classes of insecticidal molecules with different modes of action. Herein, a novel series of spiro pyrimidine derivatives was prepared using some green synthetic methodologies such as microwave irradiation, and sonication under ultrasound waves. Spiro pyrimidine aminonitrile 1 is a key starting material for the synthesis of targets 2-9 by reaction with different carbon electrophiles and nitrogen nucleophiles. The structures of all the newly synthesized compounds were approved using spectral data. The toxicological efficiency and biological impacts of the synthesized spiro pyrimidine derivatives were assessed against Culex pipiens L. larvae. The toxicity of synthesized compounds showed remarkable variations against the C. pipiens larvae. Where, 3, 4 and 2 were the most efficient compounds with LC50 values of 12.43, 16.29 and 21.73 µg/mL, respectively. While 1 was the least potent compound with an LC50 value of 95.18 µg/mL. As well, other compounds were arranged according to LC50 values as follows 5 > 7 > 6 > 9 > 8. In addition, 3 and 4 exhibited significant prolongation of the developmental duration and greatly inhibited adult emergence. Moreover, many morphological deformities were observed in all developmental stages. Furthermore, cytotoxicity of the most effective compounds was assessed against the normal human cells (WI-38) as non-target organisms, where compounds 2, 4 and 3 showed weak to non-toxic effects. The study of binding affinity and correlation between chemical structure and reactivity was carried out using molecular docking study and DFT calculations to investigate their mode of action. This study shed light on promising compounds with larvicidal activity and biological impacts on the C. pipiens life cycle.

ByeTAC: Bypassing an E3 Ligase for Targeted Protein Degradation.

Targeted protein degradation utilizing a bifunctional molecule to initiate ubiquitination and subsequent degradation by the 26S proteasome has been shown to be a powerful therapeutic intervention. Many bifunctional molecules, including covalent and non-covalent ligands to proteins of interest, have been developed. The traditional target protein degradation methodology targets the protein of interest in both healthy and diseased cell populations, and a therapeutic window is obtained based on the overexpression of the targeted protein. We report here a series of bifunctional degraders that do not rely on interacting with an E3 ligase, but rather a 26S proteasome subunit, which we have named ByeTACs: Bypassing E3 Targeting Chimeras. Rpn-13 is a non-essential ubiquitin receptor for the 26S proteasome. Cells under significant stress or require significant ubiquitin-dependent degradation of proteins for survival, incorporate Rpn-13 in the 26S to increase protein degradation rates. The targeted protein degraders reported here are bifunctional molecules that include a ligand to Rpn-13 and BRD4, the protein of interest we wish to degrade. We synthesized a suite of degraders with varying PEG chain lengths and showed that bifunctional molecules that incorporate a Rpn-13 binder (TCL1) and a BRD4 binder (JQ1) with a PEG linker of 3 or 4 units are the most effective to induce BRD4 degradation. We also demonstrate that our new targeted protein degraders are dependent upon proteasome activity and Rpn-13 expression levels. This establishes a new mechanism of action for our ByeTACs that can be employed for the targeted degradation of a wide variety of protein substrates.

Synthesis and evaluation of larvicidal efficacy against C. pipiens of some new heterocyclic compounds emanated from 2-cyano-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide.

Several infectious diseases are transmitted and spread by mosquitoes, and millions of people die annually from them. The mosquito, Culex pipiens is a responsible for the emergence of various Virus in Egypt. So, we devote our work to evaluate the larvicidal efficacy against C. pipiens of some new heterocyclic compounds containing chlorine motifs. The implementation was emanated from using 2-cyano-N'-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide (3) as scaffold to synthesize some new heterocyclic compounds. The structures of the synthesized compounds were interpreted scrupulously by spectroscopic and elemental analyses. Thereafter, the larvicidal activity against C. pipiens of thirteen synthesized compounds was estimated. Noteworthy, cyanoacetohydrazide derivative 3 and 3-iminobenzochromene derivative 12 showed a fabulous potent efficacy with LC50 equal to 3.2 and 3.5 ppm against C. pipiens, respectively, and are worth being further evaluated in the field of pest control.

Exploring the Antiproliferative Potency of Pyrido[2,3-d]Pyrimidine Derivatives: Studies on Design, Synthesis, Anticancer Evaluation, SAR, Docking, and DFT Calculations.

Herein, an efficient method for the synthesis of a new series of pyrido[2,3-d]pyrimidine derivatives has been adopted through the reaction of hydrazinyl pyrido[2,3-d] pyrimidine derivative (1) with different electrophilic species, such as ethyl cyanoacetate and different 1,3 diketone derivatives, gave the corresponding derivatives (2-5). Meanwhile, pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines (6-11) were synthesized via reaction of hydrazine derivative 1 with phenylisothiocyanate, potassium thiocyanate, and carbon disulfide. Compound 1 was also submitted to react with different carbonyl compounds to afford pyrido-pyrimidine derivatives (12-15). All the newly synthesized compounds were tested in vitro for their antiproliferative activities against HCT-116 and MCF-7 cell lines. Compounds 2, 3, 7, and 8 displayed very strong inhibitory activity against the two cell lines compared with the standard drug doxorubicin. Furthermore, a docking study of the most active compounds was performed with the thymidylate synthase enzyme (PDB: Code 6qxg). Moreover, DFT calculation was carried out for the most biologically active compounds and a reference drug (Doxorubicin) using the B3LYP/6-31G+(d,p) level of theory. The calculated EHOMO and ELUMO energies were used to calculate the global reactivity parameters. Finally, Molecular electrostatic potential (MEP) and structure activity relationship (SAR) were studied to correlate the relation between chemical structure and reactivity.

Rational design and eco-friendly one-pot multicomponent synthesis of novel ethylidenehydrazineylthiazol-4(5H)-ones as potential apoptotic inducers targeting wild and mutant EGFR-TK in triple negative breast cancer.

A novel series of ethylidenehydrazineylthiazol-4(5H)-ones were synthesized using various eco-friendly one-pot multicomponent synthetic techniques. The anticancer activity of compounds (4a-m) was tested against 11 cancer cell lines. While the IC50 of all compounds was evaluated against the most sensitive cell lines (MDA-MB-468 and FaDu). Our SAR study pinpointed that compound 4a, having a phenyl substituent, exhibited a significant growth inhibition % against all cancer cell lines. The frontier anticancer candidates against the MDA-MB-468 were also examined against the wild EGFR (EGFR-WT) and mutant EGFR (EGFR-T790M) receptors. Most of the synthesized compounds exhibited a higher inhibitory potential against EGFR-T790M than the wild type of EGFR. Remarkably, compound 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M with IC50 values (0.051 and 0.021 µM), respectively. The pro-apoptotic protein markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9) and the anti-apoptotic key marker (BCL-2) were also measured to propose a mechanism of action for the compound 4k as an apoptotic inducer for MDA-MB-468. Investigation of the cell cycle arrest potential of compound 4k was also conducted on MDA-MB-468 cancer cells. We also evaluated the inhibitory activities of compounds (4a-m) against both EGFR-WT and EGFR-T790M using two different molecular docking processes.

A Clinical Audit of Thyroid Hormonal Replacement After Total Thyroidectomy.

Background Thyroid hormone replacement (THR) in athyreotic patients post-thyroidectomy due to thyroid cancer might seem like a straightforward clinical issue to address. To investigate the impact of THR on enhancing thyroid-stimulating hormone (TSH) levels, we conducted a clinical audit, tailoring the dosage based on patient weight and aligning with the standards outlined by the National Institute for Health and Care Excellence and the American Thyroid Association guidelines. Methodology This retrospective and prospective audit analyzed outpatient clinic records for hormone replacement therapy (HRT) post-total thyroidectomy. Retrospective data from March to May 2022 were collected, followed by prospective data after interventions adjusting HRT based on patient weight to digitize clinic notes. The second phase involved changes for 20 scheduled thyroidectomy patients among the total 37 included in the study. Results The thyroid profiles of both groups in the initial and subsequent cycles, treated with adjusted doses of THR, exhibited normal levels of thyroid hormones and calcium. No substantial differences were observed between the groups. On multivariate logistic regression analysis, we found that older age, male sex, body mass index, and preoperative TSH level were the only significant predictors of the need for hormonal therapy. Conclusions Optimal dose of THR after total thyroidectomy had a positive effect on TSH levels in hypothyroidism patients. Hence, THR should be prescribed according to patient weight based on standards and guidelines.

NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections.

Lower respiratory tract infections caused by Streptococcus pneumoniae (Spn) are a leading cause of death globally. Here we investigate the bronchial epithelial cellular response to Spn infection on a transcriptomic, proteomic and metabolic level. We found the NAD+ salvage pathway to be dysregulated upon infection in a cell line model, primary human lung tissue and in vivo in rodents, leading to a reduced production of NAD+. Knockdown of NAD+ salvage enzymes (NAMPT, NMNAT1) increased bacterial replication. NAD+ treatment of Spn inhibited its growth while growth of other respiratory pathogens improved. Boosting NAD+ production increased NAD+ levels in immortalized and primary cells and decreased bacterial replication upon infection. NAD+ treatment of Spn dysregulated the bacterial metabolism and reduced intrabacterial ATP. Enhancing the bacterial ATP metabolism abolished the antibacterial effect of NAD+. Thus, we identified the NAD+ salvage pathway as an antibacterial pathway in Spn infections, predicting an antibacterial mechanism of NAD+.

Modeling the potential global distribution of the Egyptian cotton leafworm, Spodoptera littoralis under climate change.

The Egyptian cotton leafworm, Spodoptera littoralis is a highly invasive insect pest that causes extensive damage to many of the primary food crops. Considering the recent challenges facing global food production including climate change, knowledge about the invasive potential of this pest is essential. In this study, the maximum entropy model (MaxEnt) was used to predict the current global spatial distribution of the pest and the future distribution using two representative concentration pathways (RCPs) 2.6 and 8.5 in 2050 and 2070. High AUC and TSS values indicated model accuracy and high performance. Response curves showed that the optimal temperature for the S. littoralis is between 10 and 28 °C. The pest is currently found in Africa and is widely distributed across the Middle East and throughout Southern Europe. MaxEnt results revealed that the insect will shift towards Northern Europe and the Americas. Further, China was seen to have a suitable climate. We also extrapolated the impact of these results on major producing countries and how this affects trade flow, which help decision makers to take the invasiveness of such destructive pest into their account.

Marine Natural Compound (Neviotin A) Displays Anticancer Efficacy by Triggering Transcriptomic Alterations and Cell Death in MCF-7 Cells.

We investigated the anticancer mechanism of a chloroform extract of marine sponge (Haliclona fascigera) (sample C) in human breast adenocarcinoma (MCF-7) cells. Viability analysis using MTT and neutral red uptake (NRU) assays showed that sample C exposure decreased the proliferation of cells. Flow cytometric data exhibited reactive oxygen species (ROS), nitric oxide (NO), dysfunction of mitochondrial potential, and apoptosis in sample C-treated MCF-7 cells. A qPCR array of sample C-treated MCF-7 cells showed crosstalk between different pathways of apoptosis, especially BIRC5, BCL2L2, and TNFRSF1A genes. Immunofluorescence analysis affirmed the localization of p53, bax, bcl2, MAPKPK2, PARP-1, and caspase-3 proteins in exposed cells. Bioassay-guided fractionation of sample C revealed Neviotin A as the most active compound triggering maximum cell death in MCF-7, indicating its pharmacological potency for the development of a drug for the treatment of human breast cancer.

Back to Old Books Toward Affordable Research: Homemade Phenol-Based Reagent for Triphasic RNA Purification.

Covid-19 crisis did hit many socio-economic aspects in the whole world. In the scientific research, the problem is getting even worse, since most of materials and consumable are allocated to the health sector. Many research laboratories around the world have big delay in receiving their purchases to accomplish their research projects. In the developing countries, the situation is much more difficult, since most of the funding resources are directed to the Covid-19 crisis and there is a notable increase in reagents' prices. Therefore, the aim of the present study is to make a homemade reagents for RNA purification from eukaryotic cells/tissues. The homemade phenol-based RNA extraction reagents were prepared using saturated phenol pH 4.3 (adjusted by 0.5 M citrate buffer) and guanidine thiocyanate. To validate the phenol-based reagent, RNA was purified from different biological samples (cell line, tissues, and fungi) using homemade phenol-based versus a commercial one. Concentration of RNA samples extracted from the same number of cells were compared to assess the homemade preparation of phenol-based reagent. In conclusion, homemade phenol-based reagent is cost effective and comparable to the commercial one. Using homemade phenol-based, RNA extraction was successfully purified from different biological sources.

Evaluation of novel pyrazol-4-yl pyridine derivatives possessing arylsulfonamide tethers as c-Jun N-terminal kinase (JNK) inhibitors in leukemia cells.

A series of 36 pyrazol-4-yl pyridine derivatives (8a-i, 9a-i, 10a-i, and 11a-i) was designed, synthesized, and evaluated for its antiproliferative activity over NCI-60 cancer cell line panel and inhibitory effect against JNK isoforms (JNK1, JNK2, and JNK3). All the synthesized compounds were tested against the NCI-60 cancer cell line panel. Compounds 11b, 11c, 11g, and 11i were selected to determine their GI50s and exerted a superior potency over the reference standard SP600125 against the tested cell lines. 11c showed a GI50 of 1.28 µM against K562 leukemic cells. Vero cells were used to assess 11c cytotoxicity compared to the tested cancer cells. The target compounds were tested against hJNK isoforms in which compound 11e exhibited the highest potency against JNK isoforms with IC50 values of 1.81, 12.7, and 10.5 nM against JNK1, JNK2, and JNK3, respectively. Kinase profiling of 11e showed higher JNK selectivity in 50 kinase panels. Compounds 11c and 11e showed cell population arrest at the G2/M phase, induced early apoptosis, and slightly inhibited beclin-1 production at higher concentrations in K562 leukemia cells relative to SP600125. NanoBRET assay of 11e showed intracellular JNK1 inhibition with an IC50 of 2.81 µM. Also, it inhibited CYP2D6 and 3A4 with different extent and its hERG activity showed little cardiac toxicity with an IC50 of 4.82 µM. hJNK3 was used as a template to generate the hJNK1 crystal structure to explore the binding mode of 11e (PDB ID: 8ENJ) with a resolution of 2.8 °A and showed a typical type I kinase inhibition against hJNK1. Binding energy scores showed that selectivity of 11e towards JNK1 could be attributed to additional hydrophobic interactions relative to JNK3.

Discovery of a non-covalent ligand for Rpn-13, a therapeutic target for hematological cancers.

The ubiquitin-proteasome system serves as the major proteolytic degradation pathway in eukaryotic cells. Many inhibitors that covalently bind to the proteasome's active sites have been developed for hematological cancers, but resistance can arise in patients. To overcome limitations of active-site proteasome inhibitors, we and others have focused on developing ligands that target subunits on the 19S regulatory particle (19S RP). One such 19S RP subunit, Rpn-13, is a ubiquitin receptor required for hematological cancers to rapidly degrade proteins to avoid apoptosis. Reported Rpn-13 inhibitors covalently bind to the Rpn-13's Pru domain and have been effective anti-hematological cancer agents. Here, we describe the discovery of TCL-1, a non-covalent binder to the Pru domain. Optimization of TCL-1's carboxylate group to an ester increases its cytotoxicity in hematological cancer cell lines. Altogether, our data provides a new scaffold for future medicinal chemistry optimization to target Rpn-13 therapeutically.

Associations between Nutrigenomic Effects and Incidences of Microbial Resistance against Novel Antibiotics.

Nutrigenomics is the study of the impact of diets or nutrients on gene expression and phenotypes using high-throughput technologies such as transcriptomics, proteomics, metabolomics, etc. The bioactive components of diets and nutrients, as an environmental factor, transmit information through altered gene expression and hence the overall function and traits of the organism. Dietary components and nutrients not only serve as a source of energy but also, through their interactions with genes, regulate gut microbiome composition, the production of metabolites, various biological processes, and finally, health and disease. Antimicrobial resistance in pathogenic and probiotic microorganisms has emerged as a major public health concern due to the presence of antimicrobial resistance genes in various food products. Recent evidence suggests a correlation between the regulation of genes and two-component and other signaling systems that drive antibiotic resistance in response to diets and nutrients. Therefore, diets and nutrients may be alternatively used to overcome antibiotic resistance against novel antibiotics. However, little progress has been made in this direction. In this review, we discuss the possible implementations of nutrigenomics in antibiotic resistance against novel antibiotics.