DNA Damage in Healthy Individuals and Respiratory Patients after Treating Whole Blood In vitro with the Bulk and Nano Forms of NSAIDs

YesNon-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX enzyme activity which affects the inflammatory response. Inflammation is associated with increasing cancer incidence. Pre-clinical and clinical studies have shown that NSAID treatment could cause an anti-tumor effect in cancers. In the present study, blood was taken from healthy individuals (n = 17) and patients with respiratory diseases or lung cancer (n = 36). White blood cells (WBC) were treated with either a micro-suspension, i.e., bulk (B) or nano-suspension (N) of aspirin (ASP) or ibuprofen (IBU) up to 500 μg/ml in the comet assay and up to 125 μg/ml in the micronucleus assay. In this study results were compared against untreated lymphocytes and their corresponding treated groups. The results showed, that NSAIDs in their nano form significantly reduced the DNA damage in WBCs from lung cancer patients in bulk and nano compared to untreated lymphocytes. Also, there was a decrease in the level of DNA damage in the comet assay after treating WBCs from healthy individuals, asthma and COPD groups with aspirin N (ASP N) but not with IBU N. In addition, the number of micronuclei decreased after treatment with NSAIDs in their nano form (ASP N and IBU N) in the healthy as well as in the lung cancer group. However, this was not the case for micronucleus frequency in asthma and COPD patients. These data show that lymphocytes from different groups respond differently to treatment with ASP and IBU as measured by comet assay and micronucleus assay, and that the size of the suspended particles of the drugs affects responses.The present study was part funded by United Kingdom India Education Research Initiative (UKERI) SA 07-067

Confronting the low-scale seesaw and leptogenesis with neutrinoless double beta decay

We revisit the impact of heavy neutrinos with masses in the MeV-GeV range on neutrinoless double beta decay ($0\nu\beta\beta$) in view of updated results for the lifetime of this process. Working in a minimal realistic extension of the Standard Model by two right-handed neutrino flavours, we show that the non-observation of $0\nu\beta\beta$ will impose strong bounds on the heavy neutrino properties that are complementary to the limits obtained from Big Bang Nucleosynthesis and collider searches. For an inverted mass hierarchy of the light neutrinos we find that improved limits on $0\nu\beta\beta$ from next-generation experiments will restrict the allowed parameter space for fixed mass splitting to narrow bands in the mass-mixing plane. Further combining this with the requirement to explain the baryon asymmetry of the universe via leptogenesis reduces these bands to windows in parameter space that are constrained in all directions and can be targeted by direct searches at accelerators. For a normal mass hierarchy, only parts of the parameter space can be probed by such experiments.Comment: 27 pages, 10 figure

Unusual anti-leukemia activity of nanoformulated naproxen and other non-steroidal anti-inflammatory drugs

The non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used pharmaceuticals worldwide. Interestingly, many of them have significant anticancer properties too. However, the poor water solubility of certain NSAIDs limits their application for cancer treatment. Nanosizing of such drugs can help to improve the solubility and this may result in enhanced anticancer activities too. Moreover, over dosages and the accompanying side effects of NSAIDs can be minimized by improving their solubility and bioavailability. Successful nanoformulation of three NSAIDs: ibuprofen (IBP), ketoprufen (KP) and naproxen (NAP) using a novel evaporation assisted solvent-antisolvent interaction (EASAI) method is reported here. Three water soluble and biocompatible polymers: polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and hydroxypropyl methylcellulose (HPMC) were used to stabilize the drug nanoparticles. Particles having spherical morphology with average size below 30 nm were thoroughly characterized using dynamic light scattering and field emission scanning electron microscopy (FESEM) imaging. The nanoformulation resulted in ten to fifteen fold improvements in the solubility and significant enhancement in the in-vitro drug release profiles of the NSAIDs. Anticancer screening of the nanoformulated NSAIDs against five different cancer cell lines such as MCF-7 (Human breast cancer cell line), (Human pancreatic cancer cell line) MIA-PA-CA-2, (Human colon cancer cell line) HT-29, (Human leukemia cell line) Jurkat and (human ovarian carcinoma cell line) A2780 was performed. All the nanoformulated samples showed improved anticancer activity against the Leukemia cancer cell line, out of which NAP-PVP showed the highest anti-cancer activity. The anti-Leukemia activity of NAP-PVP was more than twice that of doxorubicin which is a standard anticancer drug

Chronic β3-AR Stimulation Activates Distinct Thermogenic Mechanisms in Brown and White Adipose Tissue and Improves Systemic Metabolism in Aged Mice

Adipose thermogenesis has been actively investigated as a therapeutic target for improving metabolic dysfunction in obesity. However, its applicability to middle-aged and older populations, which bear the highest obesity prevalence in the United States (approximately 40%), remains uncertain due to age-related decline in thermogenic responses. In this study, we investigated the effects of chronic thermogenic stimulation using the β3-adrenergic (AR) agonist CL316,243 (CL) on systemic metabolism and adipose function in aged (18-month-old) C57BL/6JN mice. Sustained β3-AR treatment resulted in reduced fat mass, increased energy expenditure, increased fatty acid oxidation and mitochondrial activity in adipose depots, improved glucose homeostasis, and a favorable adipokine profile. At the cellular level, CL treatment increased uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT). However, in white adipose tissue (WAT) depots, CL treatment increased glycerol and lipid de novo lipogenesis (DNL) and turnover suggesting the activation of the futile substrate cycle of lipolysis and reesterification in a UCP1-independent manner. Increased lipid turnover was also associated with the simultaneous upregulation of proteins involved in glycerol metabolism, fatty acid oxidation, and reesterification in WAT. Further, a dose-dependent impact of CL treatment on inflammation was observed, particularly in subcutaneous WAT, suggesting a potential mismatch between fatty acid supply and oxidation. These findings indicate that chronic β3-AR stimulation activates distinct cellular mechanisms that increase energy expenditure in BAT and WAT to improve systemic metabolism in aged mice. Considering that people lose BAT with aging, activation of futile lipid cycling in WAT presents a novel strategy for improving age-related metabolic dysfunction

Implications of Hypothalamic Neural Stem Cells on Aging and Obesity-Associated Cardiovascular Diseases

The hypothalamus, one of the major regulatory centers in the brain, controls various homeostatic processes, and hypothalamic neural stem cells (htNSCs) have been observed to interfere with hypothalamic mechanisms regulating aging. NSCs play a pivotal role in the repair and regeneration of brain cells during neurodegenerative diseases and rejuvenate the brain tissue microenvironment. The hypothalamus was recently observed to be involved in neuroinflammation mediated by cellular senescence. Cellular senescence, or systemic aging, is characterized by a progressive irreversible state of cell cycle arrest that causes physiological dysregulation in the body and it is evident in many neuroinflammatory conditions, including obesity. Upregulation of neuroinflammation and oxidative stress due to senescence has the potential to alter the functioning of NSCs. Various studies have substantiated the chances of obesity inducing accelerated aging. Therefore, it is essential to explore the potential effects of htNSC dysregulation in obesity and underlying pathways to develop strategies to address obesity-induced comorbidities associated with brain aging. This review will summarize hypothalamic neurogenesis associated with obesity and prospective NSC-based regenerative therapy for the treatment of obesity-induced cardiovascular conditions

Model catalogues and histograms of KSVZ axion models with multiple heavy quarks

<p>This record contains the files pertaining to the results mentioned in the linked work Plakkot & Hoof, <em>“Anomaly Ratio Distributions of KSVZ Axion Models with Multiple Heavy Quarks.”</em> The contents are:</p> <ul> <li>4 histogram files</li> <li>2 compressed <code>tar.gz</code> files containing detailed catalogues,</li> <li>2 Python scripts to extract information from the files (requires Python 3 and the <code>numpy</code>, <code>matplotlib</code> and <code>h5py</code> packages)</li> </ul> <p><strong>Histogram files</strong></p> <p>The columns of the histogram files (listed below) correspond to the numerator of <em>E</em>, denominator of <em>E</em>, numerator of <em>N</em>, denominator of <em>N</em>, and the number of models (frequency) with that <em>E/N</em> ratio. The file <code>histogram_complete_NQ_1_to_9.txt</code> contains additional columns showing the number of models per entry for each <em>N<sub>Q</sub></em>.</p> <ol> <li><code>histogram_all_LP_allowed_models.txt</code> for all LP-allowed models</li> <li><code>histogram_additive_LP_allowed_models.txt</code> for LP-allowed additive models</li> <li><code>histogram_same_reps_LP_allowed_models.txt</code> for LP-allowed additive models where all new quarks live on the same representation</li> <li><code>histogram_complete_NQ_1_to_9.txt</code> for all possible models with <em>N<sub>Q</sub></em> ≤ 9, regardless of the LP criterion</li> </ol> <p><strong>Catalogues</strong></p> <p>The catalogues are contained in the two compressed <code>HDF5</code> files listed below. The catalogues contain groups for different <em>N<sub>Q</sub></em>, each with subgroups for numerators and denominators of E and N, model representation (as a list). The file <code>catalogue_additive_models_NQ_1_to_9.tar.gz</code> contains additionally the energy scale at which the first LP appears. The integers in the model lists represent the quark representations (integer <em>m</em> for the representation <em>r<sub>m</sub></em> in the text), and the negative signs indicate opposite PQ charge.</p> <ol> <li><code>catalogue_additive_models_NQ_1_to_9.tar.gz</code> contains the catalogue for additive models with <em>N<sub>Q</sub></em> ≤ 9 (9 groups, 6 subgroups)</li> <li><code>catalogue_all_LP_allowed_models.tar.gz</code> Contains catalogues for all LP-allowed models (28 groups, 5 subgroups)</li> </ol> <p><strong>Scripts</strong></p> <p>The two scripts are:</p> <ol> <li><code>print_histogram_info.py</code> is a sample script to extract information from the histogram files. The default choice for <em>N<sub>Q</sub></em> can be adjusted by e.g. invoking <code>python print_histogram_info.py 5</code> for <em>N<sub>Q</sub></em> = 5</li> <li><code>read_catalogue.py</code> is a sample script to extract data from the catalogue files (which need to be unpacked first). The default settings can be overwritten by e.g. invoking <code>python read_catalogue.py 5 file.h5</code> for <em>N<sub>Q</sub></em> = 5 and the catalogues contained in <code>file.h5</code></li> </ol><p><span>The updated version replaces the "histogram_complete_NQ_1_to_9.txt" file, whose column for NQ = 9 contained incorrect frequencies and several models with unphysical N. We thank Luca Di Luzio for suggesting to check our catalogues against the quantisation conditions from Ref. [arXiv:2309.03937], which led to the discovery of these problems. Neither the other files nor the results of the associated publication were affected by this issue.</span></p&gt

Anomaly ratio distributions of hadronic axion models with multiple heavy quarks

We consider hadronic axion models that extend the Standard Model by one complex scalar field and one or more new heavy quarks, i.e. $N_\mathcal{Q} \geq 1$. We review previously suggested selection criteria as well as categorize and catalog all possible models for $N_\mathcal{Q} \leq 9$. In particular, allowing for $N_\mathcal{Q} > 1$ can introduce models that spoil the axion solution of the strong CP problem. Demanding that Landau poles do not appear below some energy scale limits the number of preferred models to a finite number. For our choice of criteria, we find that $N_\mathcal{Q} \leq 28$ and only 820 different anomaly ratios $E/N$ exist (443 when considering additive representations, 12 when all new quarks transform under the same representation). We analyze the ensuing $E/N$ distributions, which can be used to construct informative priors on the axion-photon coupling. The hadronic axion model band may be defined as the central region of one of these distributions, and we show how the band for equally probable, preferred models compares to present and future experimental constraints.Comment: 9+1 pages, 4 figures. V2 corresponds to the published version. Supplementary material available on Zenodo at https://dx.doi.org/10.5281/zenodo.509170