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Biochemical and Biophysical Research... Sep 2024In patients with high-level radiation exposure, gastrointestinal injury is the main cause of death. Despite the severity of damage to the gastrointestinal tract, no...
In patients with high-level radiation exposure, gastrointestinal injury is the main cause of death. Despite the severity of damage to the gastrointestinal tract, no specific therapeutic option is available. Tauroursodeoxycholic acid (TUDCA) is a conjugated form of ursodeoxycholic acid that suppresses endoplasmic reticulum (ER) stress and regulates various cell-signaling pathways. We investigated the effect of TUDCA premedication in alleviating intestinal damage and enhancing the survival of C57BL/6 mice administered a lethal dose (15Gy) of focal abdominal irradiation. TUDCA was administered to mice 1 h before radiation exposure, and reduced apoptosis of the jejunal crypts 12 h after irradiation. At later timepoint (3.5 days), irradiated mice manifested intestinal morphological changes that were detected via histological examination. TUDCA decreased the inflammatory cytokine levels and attenuated the decrease in serum citrulline levels after radiation exposure. Although radiation induced ER stress, TUDCA pretreatment decreased ER stress in the irradiated intestinal cells. The effect of TUDCA indicates the possibility of radiation therapy for cancer in tumor cells. TUDCA did not affect cell proliferation and apoptosis in the intestinal epithelium. TUDCA decreased the invasive ability of the CT26 metastatic colon cancer cell line. Reduced invasion after TUDCA treatment was associated with decreased matrix metalloproteinase (MMP)-7 and MMP-13 expression, which play important roles in invasion and metastasis. This study shows a potential role of TUDCA in protecting against radiation-induced intestinal damage and inhibiting tumor cell migration without any radiation and radiation therapy effect.
Topics: Animals; Taurochenodeoxycholic Acid; Mice, Inbred C57BL; Endoplasmic Reticulum Stress; Apoptosis; Radiation-Protective Agents; Mice; Male; Intestines; Disease Models, Animal; Intestinal Mucosa; Radiation Injuries, Experimental; Matrix Metalloproteinase 13; Cell Proliferation
PubMed: 38865815
DOI: 10.1016/j.bbrc.2024.150226 -
Journal of Medicinal Chemistry Jun 2024Colloidal aggregation is one of the largest contributors to false positives in early drug discovery. Here, we consider aggregation's role in cell-based infectivity...
Colloidal aggregation is one of the largest contributors to false positives in early drug discovery. Here, we consider aggregation's role in cell-based infectivity assays in Covid-19 drug repurposing. We investigated the potential aggregation of 41 drug candidates reported as SARs-CoV-2 entry inhibitors. Of these, 17 formed colloidal particles by dynamic light scattering and exhibited detergent-dependent enzyme inhibition. To evaluate the impact of aggregation on antiviral efficacy in cells, we presaturated the colloidal drug suspensions with BSA or spun them down by centrifugation and measured the effects on spike pseudovirus infectivity. Antiviral potencies diminished by at least 10-fold following both BSA and centrifugation treatments, supporting a colloid-based mechanism. Aggregates induced puncta of the labeled spike protein in fluorescence microscopy, consistent with sequestration of the protein on the colloidal particles. These observations suggest that colloidal aggregation is common among cell-based antiviral drug repurposing and offers rapid counter-screens to detect and eliminate these artifacts.
Topics: Antiviral Agents; Humans; SARS-CoV-2; Colloids; Spike Glycoprotein, Coronavirus; COVID-19 Drug Treatment; Drug Repositioning; COVID-19
PubMed: 38864383
DOI: 10.1021/acs.jmedchem.4c00597 -
Molecular Neurodegeneration Jun 2024RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is...
RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.
Topics: Animals; Humans; Mice; Amyotrophic Lateral Sclerosis; Brain; Disease Models, Animal; Disease Progression; Frontotemporal Dementia; Mice, Transgenic; Protein Aggregation, Pathological; RNA-Binding Protein FUS
PubMed: 38862967
DOI: 10.1186/s13024-024-00737-5 -
Methods in Molecular Biology (Clifton,... 2024Structural studies require the production of target proteins in large quantities and with a high degree of purity. For membrane proteins, the bottleneck in determining...
Structural studies require the production of target proteins in large quantities and with a high degree of purity. For membrane proteins, the bottleneck in determining their structure is the extraction of the target protein from the cell membranes. A detergent that improperly mimics the hydrophobic environment of the protein of interest can also significantly alter its structure. Recently, using lipodiscs with styrene-maleic acid (SMA), copolymers became a promising strategy for the purification of membrane proteins. Here, we describe in detail the one-step affinity purification of potassium ion channels solubilized in SMA and sample preparation for future structural studies.
Topics: Maleates; Potassium Channels; Polystyrenes; Chromatography, Affinity; Styrene; Polymers; Detergents; Humans
PubMed: 38856895
DOI: 10.1007/978-1-0716-3818-7_4 -
Cureus May 2024Introduction The onset of the COVID-19 pandemic necessitated a shift in global lifestyles as individuals sought to safeguard themselves and their loved ones from the...
Introduction The onset of the COVID-19 pandemic necessitated a shift in global lifestyles as individuals sought to safeguard themselves and their loved ones from the virus. This adaptation involved embracing a distinct way of life marked by social distancing, reduced outdoor engagements, and home confinement. Consequently, this period of quarantine led to diminished social interactions, challenges in accessing essential resources such as food, heightened unemployment rates, and increased burden on healthcare systems. Understandably, these circumstances gave rise to heightened emotions including fear, depression, and anxiety. In response to these dynamics, our research aimed to explore the psychological and behavioral shifts among medical students residing in Islamabad and Rawalpindi (the twin cities of Pakistan) during the year 2020 amidst the COVID-19 pandemic. Methods A structured, self-administered questionnaire was constructed, based on previously conducted surveys, assessing the psychological impact and behavioral changes due to the COVID-19 pandemic. The questionnaire was made available online through Google Forms and was provided to students of the various medical colleges of the twin cities of Pakistan. The results were further stratified based on gender. Results Categorical data were collected from 400 medical students studying in Rawalpindi and Islamabad. The negative psychological impact was shown by increased stress, 260 (65%), feeling of less energy, 211 (52.8%), and increased anxiety with upper respiratory symptoms, 202 (50.5%). Behavioral changes were also a reflection of the psychological changes depicted by an increased use of disinfectants, 256 (64%), increased desire to clean surfaces, 262 (65.6%), increased use of soaps and detergents, 300 (75%), reduced number of times one left their house 281, (70.3%), and decreased consumption of food products from outside, 226 (56.5%). When compared between the two genders, females had significantly increased stress levels (p=0.034), decreased food consumption from outside (p=0.026), and increased avoidance of people not wearing masks (p=0.001). Conclusion Through our study, we identified the various psychological and behavioral changes among our population due to the COVID-19 pandemic. Our study not only highlights these changes but also discusses the various ways to address them. This study would help relevant organizations to understand the broader aspect of how this pandemic has affected individual lives and will also give them ideas regarding how to cater to these changes in a positive way.
PubMed: 38854319
DOI: 10.7759/cureus.59860 -
Journal of Clinical Laboratory Analysis May 2024Severe acute pancreatitis (SAP) is associated with tremendous systemic inflammation, T-helper 17 (Th17) cells, and regulatory T (Treg) cells play an essential role in...
BACKGROUND
Severe acute pancreatitis (SAP) is associated with tremendous systemic inflammation, T-helper 17 (Th17) cells, and regulatory T (Treg) cells play an essential role in the inflammatory responses. Meanwhile, soluble fibrinogen-like protein 2 (Sfgl2) is a critical immunosuppressive effector cytokine of Treg cells and modulates immune responses. However, the impact of SAP induction on Sfgl2 expression and the role of Sfgl2 in immunomodulation under SAP conditions are largely unknown.
METHODS
A taurocholate-induced mouse SAP model was established. The ratios of CD4CD25Foxp3 Treg cells or CD4IL-17 Th17 cells in blood and pancreatic tissues as well as surface expression of CD80, CD86, and major histocompatibility complex class II (MHC-II) were determined by flow cytometry. Gene mRNA expression was determined by qPCR. Serum amylase and soluble factors were quantitated by commercial kits. Bone marrow-derived dendritic cells (DCs) were generated, and NF-κB/p65 translocation was measured by immunofluorescence staining.
RESULTS
SAP induction in mice decreased the Th17/Treg ratio in the pancreatic tissue and increased the Th17/Treg ratio in the peripheral blood. In addition, SAP was associated with a reduced level of Sfgl2 in the pancreatic tissue and blood: higher levels of serum IL-17, IL-2, IFN-α, and TNF-α, and lower levels of serum IL-4 and IL-10. Furthermore, the SAP-induced reduction in Sfgl2 expression was accompanied by dysregulated maturation of bone marrow-derived DCs.
CONCLUSIONS
SAP causes reduced Sfgl2 expression and Th17/Treg imbalance, thus providing critical insights for the development of Sfgl2- and Th17/Treg balance-targeted immunotherapies for patients with SAP.
Topics: Animals; Th17 Cells; T-Lymphocytes, Regulatory; Taurocholic Acid; Pancreatitis; Disease Models, Animal; Mice; Fibrinogen; Male; Mice, Inbred C57BL; Down-Regulation; Dendritic Cells; Acute Disease; Pancreas
PubMed: 38853390
DOI: 10.1002/jcla.25076 -
International Journal of Biological... Jun 2024The multifunctionality of advanced laundry detergents primarily relies on the inclusion of functional solid particles, such as pearlescent powder, enzymes, and perfume...
The multifunctionality of advanced laundry detergents primarily relies on the inclusion of functional solid particles, such as pearlescent powder, enzymes, and perfume microcapsules. However, the high-content surfactants in these detergents can render most existing suspending rheology modifiers ineffective, making it challenging to achieve uniform suspension of these functional particles. This compromises the overall functionality of laundry products. To address this, we have developed a binary rheology modifier comprising cellulose microgel and HPMC (hydroxypropyl methylcellulose), acting as the "island" and "chain," respectively. Together, they form an interconnected dynamic network that effectively "encapsulates" the functional particles. Furthermore, the cellulose microgel/HPMC rheology modifier demonstrates versatility, proving effective with various surfactants. Despite its potential, the suspension mechanism of cellulose microgel/HPMC remains elusive. Therefore, we conducted a comprehensive investigation, fabricating cellulose microgels with varying nanofabrication degrees and surface charges through TEMPO oxidation. Our findings highlight the critical role of the surficial structure of T-Microgel, specifically its nanofabrication degree, in influencing the dynamic network's fabrication, thereby impacting yield and thixotropic properties. The surface charge of T-microgel does not significantly influence the process. This research not only elucidates the intricate dynamics of cellulose microgel/HPMC interaction but also provides fundamental insights essential for the development of innovative rheology modifiers tailored for high-content surfactant applications.
PubMed: 38851620
DOI: 10.1016/j.ijbiomac.2024.132966 -
The Science of the Total Environment Sep 2024Surfactants as synergistic agents are necessary to improve the stability and utilization of pesticides, while their use is often accompanied by unexpected release into...
Surfactants as synergistic agents are necessary to improve the stability and utilization of pesticides, while their use is often accompanied by unexpected release into the environment. However, there are no efficient strategies available for screening low-toxicity surfactants, and traditional toxicity studies rely on extensive experimentation which are not predictive. Herein, a commonly used agricultural adjuvant Triton X (TX) series was selected to study the function of amphipathic structure to their toxicity in zebrafish. Molecular dynamics (MD) simulations, transcriptomics, metabolomics and machine learning (ML) were used to study the toxic effects and predict the toxicity of various TX. The results showed that TX with a relatively short hydrophilic chain was highly toxic to zebrafish with LC of 1.526 mg/L. However, TX with a longer hydrophilic chain was more likely to damage the heart, liver and gonads of zebrafish through the arachidonic acid metabolic network, suggesting that the effect of surfactants on membrane permeability is the key to determine toxic results. Moreover, biomarkers were screened through machine learning, and other hydrophilic chain lengths were predicted to affect zebrafish heart health potentially. Our study provides an advanced adjuvants screening method to improve the bioavailability of pesticides while reducing environmental impacts.
Topics: Machine Learning; Animals; Zebrafish; Molecular Dynamics Simulation; Pesticides; Surface-Active Agents; Water Pollutants, Chemical; Octoxynol
PubMed: 38851350
DOI: 10.1016/j.scitotenv.2024.173697 -
Luminescence : the Journal of... Jun 2024The mechanism of bioluminescence in the luminous land snails remains largely unknown. Here, we analyzed basic biochemical properties of the luminous land snail, Quantula...
The mechanism of bioluminescence in the luminous land snails remains largely unknown. Here, we analyzed basic biochemical properties of the luminous land snail, Quantula weinkauffiana. The luminescence activity was extracted from the light organ located near the mouth using a neutral buffer containing detergent. The reaction of the crude buffer extract was triggered by the addition of only hydrogen peroxide (HO). These results are inconsistent with the single precedent report on the bioluminescence in the Quantula striata by Shimomura and Haneda in 1986, in which the luminescence of the buffer extract (without detergent) from the light organ was induced by the coaddition of three indispensable components HO, ferrous ion, and 2-mercaptoethanol. Based on the present findings, we suggested that an insoluble photoprotein is involved in the bioluminescence of the luminous land snails and the luminescence reaction is simply triggered by HO.
Topics: Animals; Snails; Hydrogen Peroxide; Luminescence; Luminescent Measurements
PubMed: 38850210
DOI: 10.1002/bio.4796 -
Current Environmental Health Reports Jun 2024Wastewater is a term used to describe water that has undergone degradation in quality owing to anthropogenic activities or natural processes. Wastewater encompasses... (Review)
Review
PURPOSE OF THE REVIEW
Wastewater is a term used to describe water that has undergone degradation in quality owing to anthropogenic activities or natural processes. Wastewater encompasses liquid waste originating from academic institutions, households, agricultural sector, industries, mines and hospitals. Hospital wastewater contains potentially hazardous substances including residues of pharmaceuticals, radioisotopes, detergents and pathogens, with detrimental impacts to the environment and human health. Nevertheless, studies related to hospital waste management are limited in Africa, particularly in Southern Africa. This research offers an overview of aspects surrounding hospital wastewater in Southern Africa, focusing on Zimbabwe. Already published and grey literature was reviewed to compile the paper.
RECENT FINDINGS
Number of patients, nature of medical services offered and hospital size influences generation of hospital wastewater. Partially and non-treated hospital wastewater is managed together with municipal wastewater. Management of hospital wastewater is impeded by shortage of resources, lack of co-ordination among responsible authorities and ineffective legal framework enforcement, among other challenges. Inappropriate hospital wastewater management results in environmental contamination, causing human ailments. Attainment of sustainable hospital wastewater management requires clearly defined and enforced legislation, collaboration of accountable stakeholders, sufficient resources and enhanced awareness of involved stakeholders. Application of technologies that uphold recycling and reuse of wastewater is essential to reach Sustainable Development Goals, Zimbabwe Vision 2030 and National Development Strategy 1 targets, particularly those dealing with environmental protection while upholding human health.
PubMed: 38849638
DOI: 10.1007/s40572-024-00452-9