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BioRxiv : the Preprint Server For... Jun 2024Hepatic endothelial cell (EC) dysfunction and centrilobular hepatocyte necrosis occur with acetaminophen (APAP) overdose. The protease thrombin, which is acutely...
BACKGROUND & AIMS
Hepatic endothelial cell (EC) dysfunction and centrilobular hepatocyte necrosis occur with acetaminophen (APAP) overdose. The protease thrombin, which is acutely generated during APAP overdose, can signal through protease-activated receptors 1 and 4 (PAR1/PAR4). PAR1 is a high-affinity thrombin receptor that is known to signal on ECs, whereas PAR4 is a low-affinity thrombin receptor, and evidence for its expression and function on ECs is mixed. This study aims to exploit the high levels of thrombin generated during APAP overdose to determine (1) if hepatic endothelial PAR4 is a functional receptor, and (2) endothelial-specific functions for PAR1 and PAR4 in a high thrombin setting.
METHODS
We generated mice with conditional deletion(s) of in ECs and overdosed them with APAP. Hepatic vascular permeability, erythrocyte congestion/bleeding, and liver function were assessed following overdose. Additionally, we investigated the expression levels of endothelial PARs and how they influence transcription in APAP-overdosed liver ECs using endothelial Translating Ribosome Affinity Purification followed by next-generation sequencing (TRAPseq).
RESULTS
We found that mice deficient in high-expressing endothelial or low-expressing had equivalent reductions in APAP-induced hepatic vascular instability but no effect on hepatocyte necrosis. Additionally, mice with loss of endothelial and had reduced permeability at an earlier time point after APAP overdose when compared to mice singly deficient in either receptor in ECs. We also found that endothelial PAR1-but not PAR4-can regulate transcription in hepatic ECs.
CONCLUSIONS
Low-expressing PAR4 can react similarly to high-expressing PAR1 in APAP-overdosed hepatic ECs, demonstrating that PAR4 is a potent thrombin receptor. Additionally, these receptors are functionally redundant but act divergently in their expression and ability to influence transcription in hepatic ECs.
PubMed: 38895465
DOI: 10.1101/2024.06.07.598028 -
International Journal of Molecular... Jun 2024Acute liver failure is an infrequent yet fatal condition marked by rapid liver function decline, leading to abnormalities in blood clotting and cognitive impairment...
Acute liver failure is an infrequent yet fatal condition marked by rapid liver function decline, leading to abnormalities in blood clotting and cognitive impairment among individuals without prior liver ailments. The primary reasons for liver failure are infection with hepatitis virus or overdose of certain medicines, such as acetaminophen. (PT), a type of microalgae known as a diatom species, has been reported to contain an active ingredient with anti-inflammatory and anti-obesity effects. In this study, we evaluated the preventive and therapeutic activities of PT extract in acute liver failure. To achieve our purpose, we used two different acute liver failure models: acetaminophen- and D-GalN/LPS-induced acute liver failure. PT extract showed protective activity against acetaminophen-induced acute liver failure through attenuation of the inflammatory response. However, we failed to demonstrate the protective effects of PT against acute liver injury in the D-GalN/LPS model. Although the PT extract did not show protective activity against two different acute liver failure animal models, this study clearly demonstrates the importance of considering the differences among animal models when selecting an acute liver failure model for evaluation.
Topics: Animals; Acetaminophen; Mice; Chemical and Drug Induced Liver Injury; Microalgae; Disease Models, Animal; Liver Failure, Acute; Male; Protective Agents; Ethanol; Diatoms; Liver; Lipopolysaccharides
PubMed: 38892435
DOI: 10.3390/ijms25116247 -
International Journal of Molecular... May 2024Acetaminophen overdose is a leading cause of acute liver failure (ALF), and effective treatment depends on early prediction of disease progression. ALF diagnosis...
Acetaminophen overdose is a leading cause of acute liver failure (ALF), and effective treatment depends on early prediction of disease progression. ALF diagnosis currently requires blood collection 24-72 h after APAP ingestion, necessitating repeated tests and hospitalization. Here, we assessed earlier ALF diagnosis using positron emission tomography (PET) imaging of translocator proteins (TSPOs), which are involved in molecular transport, oxidative stress, apoptosis, and energy metabolism, with the radiotracer [F]GE180. We intraperitoneally administered propacetamol hydrochloride to male C57BL/6 mice to induce ALF. We performed in vivo PET/CT imaging 3 h later using the TSPO-specific radiotracer [F]GE180 and quantitatively analyzed the PET images by determining the averaged standardized uptake value (SUV) in the liver parenchyma. We assessed liver TSPO expression levels via real-time polymerase chain reaction, Western blotting, and immunohistochemistry. [F]GE180 PET imaging 3 h after propacetamol administration (1500 mg/kg) significantly increased liver SUV compared to controls ( = 0.001). Analyses showed a 10-fold and 4-fold increase in TSPO gene and protein expression, respectively, in the liver, 3 h after propacetamol induction compared to controls. [F]GE180 PET visualized and quantified propacetamol-induced ALF through TSPO overexpression. These findings highlight TSPO PET's potential as a non-invasive imaging biomarker for early-stage ALF.
Topics: Animals; Liver Failure, Acute; Acetaminophen; Male; Mice; Mice, Inbred C57BL; Receptors, GABA; Positron-Emission Tomography; Liver; Positron Emission Tomography Computed Tomography; Fluorine Radioisotopes; Radiopharmaceuticals; Disease Models, Animal; Carbazoles
PubMed: 38892130
DOI: 10.3390/ijms25115942 -
Cell Communication and Signaling : CCS Jun 2024Balloon flower root-derived exosome-like nanoparticles (BDEs) have recently been proposed as physiologically active molecules with no cytotoxicity. However, the...
A novel approach to alleviate acetaminophen-induced hepatotoxicity with hybrid balloon flower root-derived exosome-like nanoparticles (BDEs) with silymarin via inhibition of hepatocyte MAPK pathway and apoptosis.
INTRODUCTION
Balloon flower root-derived exosome-like nanoparticles (BDEs) have recently been proposed as physiologically active molecules with no cytotoxicity. However, the therapeutic effects of drug-induced hepatotoxicity of BDEs have not been elucidated. BDEs contain a large amount of platycodin D, which is widely known to be effective in regulating inflammation and ameliorating systemic toxicity. Thus, the main therapeutic activity of BDEs is attributed to inhibiting the inflammatory response and alleviating toxicity. In this study, we fabricated the hybrid BDEs fused with liposomes containing silymarin (SM) to enhance the synergistic effect on inhibition of acetaminophen-induced hepatotoxicity (APAP).
OBJECTIVE
Considering the potential therapeutic effects of BDEs, and the potential to achieve synergistic effects to improve therapeutic outcomes, we constructed hybrid BDEs with a soy lecithin-based liposome loaded with SM. Since liposomes can provide higher thermal stability and have greater structural integrity, these might be more resistant to clearance and enzymatic degradation of drug molecules.
METHODS
Hybrid BDEs with liposome-loaded SM (BDEs@lipo-SM) were fabricated by thin-film hydration and extrusion. BDEs@lipo-SM were characterized using dynamic light scattering and high-performance liquid chromatography. After confirmation of the physical properties of BDEs@lipo-SM, various therapeutic properties were evaluated.
RESULTS
BDEs@lipo-SM were internalized by hepatocytes and immune cells and significantly decreased mRNA expression of apoptosis and inflammation-relevant cytokines by inhibiting the hepatocyte MAPK pathway. BDEs@lipo-SM significantly induced an increase in glutathione levels and inhibited APAP-induced hepatotoxicity.
CONCLUSION
From this study, we know that BDEs are reliable and safe nanovesicles containing natural metabolites derived from balloon flower, and they can facilitate intercellular communication. BDEs are also easily modified to enhance drug loading capacity, targeting effects, and long-term accumulation in vivo. BDEs@lipo-SM have therapeutic benefits for acute liver injury and can alleviate cell death and toxicity. They can be efficiently delivered to the liver and effectively inhibit APAP-induced hepatotoxicity by inhibiting the MAPK signaling pathway and apoptosis, which accelerates liver recovery in the APAP-induced acute liver injury model. These findings highlight that BDEs represent an attractive delivery vehicle for drug delivery.
Topics: Acetaminophen; Apoptosis; Animals; Nanoparticles; Exosomes; Hepatocytes; Silymarin; MAP Kinase Signaling System; Mice; Chemical and Drug Induced Liver Injury; Humans; Liposomes; Male; Plant Roots; Mice, Inbred C57BL
PubMed: 38890646
DOI: 10.1186/s12964-024-01700-z -
Scandinavian Journal of Pain Jan 2024Chronic pain is highly prevalent in nursing home residents and often occurs with depression as well as cognitive impairment, which can severely influence and limit the...
OBJECTIVES
Chronic pain is highly prevalent in nursing home residents and often occurs with depression as well as cognitive impairment, which can severely influence and limit the expression of pain.
METHODS
The present cross-sectional study aimed to estimate the prevalence of pain, depressive mood, and cognitive impairment in association with pharmacological treatment against pain and depressive symptoms among Swedish nursing home residents.
RESULTS
We found an overall pain prevalence of 52.8%, a prevalence of 63.1% for being in a depressive mood, and a prevalence of cognitive impairment of 68.3%. Among individuals assessed to have depressive mood, 60.5% were also assessed to have pain. The prevalence of pharmacological treatment for pain was 77.5 and 54.1% for antidepressants. Prescription of pharmacological treatment against pain was associated with reports of currently having pain, and paracetamol was the most prescribed drug. A higher cognitive function was associated with more filled prescriptions of drugs for neuropathic pain, paracetamol, and nonsteroidal anti-inflammatory drugs (NSAIDs), which could indicate an undertreatment of pain in those cognitively impaired.
CONCLUSION
It is important to further explore the relationship between pain, depressive mood, and cognitive impairment in regard to pain management in nursing home residents.
Topics: Humans; Nursing Homes; Sweden; Male; Female; Cross-Sectional Studies; Prevalence; Depression; Aged, 80 and over; Aged; Cognitive Dysfunction; Pain Management; Antidepressive Agents; Chronic Pain; Acetaminophen; Analgesics
PubMed: 38887790
DOI: 10.1515/sjpain-2024-0007 -
PloS One 2024Photobiomodulation is a safe option for controlling pain, edema, and trismus when applied postoperatively in third molar surgery. However, administration prior to... (Randomized Controlled Trial)
Randomized Controlled Trial
Assessment of the pre-emptive effect of photobiomodulation in the postoperative period of impacted lower third molar extractions: A randomized, controlled, double-blind study protocol.
Photobiomodulation is a safe option for controlling pain, edema, and trismus when applied postoperatively in third molar surgery. However, administration prior to surgery has been under-explored. This study aims to explore the effectiveness of pre-emptive photobiomodulation in reducing postoperative edema in impacted lower third molar extractions. Two groups of healthy individuals undergoing tooth extraction will be randomly assigned: Control group receiving pre-emptive corticosteroid and simulated photobiomodulation, and Photobiomodulation Group receiving intraoral low-intensity laser and extraoral LED cluster application. The primary outcome will be postoperative edema after 48 h. The secondary outcomes will be pain, trismus dysphagia, and analgesic intake (paracetamol). These outcomes will be assessed at baseline as well as two and seven days after surgery. Adverse effects will be recorded. Data will be presented as means ± SD and a p-value < 0.05 will be indicative of statistical significance.
Topics: Humans; Molar, Third; Tooth Extraction; Low-Level Light Therapy; Tooth, Impacted; Double-Blind Method; Pain, Postoperative; Edema; Female; Male; Postoperative Period; Postoperative Complications; Adult
PubMed: 38885236
DOI: 10.1371/journal.pone.0300136 -
Cureus May 2024The purpose of this study was to assess the awareness of ototoxicity among medical doctors in Arar City, Saudi Arabia.
OBJECTIVES
The purpose of this study was to assess the awareness of ototoxicity among medical doctors in Arar City, Saudi Arabia.
METHODS
This is a cross-sectional study based on a pre-formed validated questionnaire (Appendix) that included three sections covering participants' demographic data (three questions), their attitudes (five questions), and knowledge (13 questions) regarding drug-induced ototoxicity.
RESULTS
After obtaining their informed consent, 213 physicians from government and private sector health facilities in Arar were enrolled in the study. Interns and general practitioners represented 57.8% of the participants; consultants represented 17.8%. Only 71.8% of participants were interested in drug-induced ototoxicity, while 26.3% considered ototoxicity a rare complication. Approximately 90% of the participants were knowledgeable about the adverse effects of drugs on the vestibulocochlear system, and 26.7% reported having experienced cases of drug-induced ototoxicity in their practice. Participants showed an overall knowledge score about ototoxicity of 9.3±3.27 (out of 14). The knowledge score was significantly higher (p-value=0.0007) for participants with more years of clinical experience. The most widely known ototoxic drug for participants was frusemide (72.3%), followed by aminoglycoside (68.5%), while acetaminophen (44.1%) ototoxicity was the least known among participants.
CONCLUSION
Awareness of drug-induced ototoxicity is satisfactory among physicians in the Northern Borders region. However, workshops about all types of drugs with ototoxic effects and the main lines for the management of drug-induced ototoxicity are recommended to increase awareness.
PubMed: 38882992
DOI: 10.7759/cureus.60429 -
Heliyon Jun 2024Drought stress poses a significant threat to (L.), impacting its growth, yield, and profitability. This study investigates the effects of foliar application of...
Drought stress poses a significant threat to (L.), impacting its growth, yield, and profitability. This study investigates the effects of foliar application of individual and interactive pharmaceutical (Paracetamol; 0 and 250 mg L) and amino acid (0 and 4 ml/L) on the growth, physiology, and yield of under drought stress. Seedlings were subjected to varying levels of drought stress (100% field capacity (FC; control) and 50% FC). Sole amino acid application significantly improved chlorophyll content, proline content, and relative water contents, as well as the activities of antioxidative enzymes (such as superoxide dismutase and catalase) while potentially decreased malondialdehyde and hydrogen peroxide contents under drought stress conditions. Pearson correlation analysis revealed strong positive correlations between these parameters and seed yield (R = 0.8-1), indicating their potential to enhance seed yield. On the contrary, sole application of paracetamol exhibited toxic effects on seedling growth and physiological aspects of . Furthermore, the combined application of paracetamol and amino acids disrupted physio-biochemical functions, leading to reduced yield. Overall, sole application of amino acids proves to be more effective in ameliorating the negative effects of drought on
PubMed: 38882271
DOI: 10.1016/j.heliyon.2024.e31544 -
Supportive Care in Cancer : Official... Jun 2024We assumed that in Palliative Care, even in common clinical situations, the choice of drugs differs substantially between physicians. Therefore, we assessed the practice... (Comparative Study)
Comparative Study
PURPOSE
We assumed that in Palliative Care, even in common clinical situations, the choice of drugs differs substantially between physicians. Therefore, we assessed the practice of pharmaceutical treatment choices of physicians for cancer pain and opioid-induced nausea and vomiting (OINV) and the rationale for their choices.
METHODS
An online survey was conducted with physicians covering the following domains: i) Cancer pain therapy: non-opioids in addition to opioids: choice of drug ii) prevention of OINV: choice of drug and mode of application. Current guidelines concerning cancer pain therapy and prevention of OINV were compared.
RESULTS
Two-hundred-forty European physicians responded to our survey. i) Use of non-opioids in addition to opioids for the treatment of cancer pain: Only 1.3% (n = 3) of respondents never used an additional non-opioid. Others mostly used: dipyrone/metamizole (49.2%, n = 118), paracetamol/acetaminophen (34.2%, n = 82), ibuprofen / other NSAIDs (11.3%, n = 27), specific Cox2-inhibitors (2.1%, n = 5), Aspirin (0.4%, n = 1), no answer (2.9%, n = 7). ii) Antiemetics to prevent OINV: The drugs of choice were metoclopramide (58.3%, n = 140), haloperidol (26.3%, n = 63), 5-HT3 antagonists (9.6%, n = 23), antihistamines (1.3%, n = 3) and other (2.9%, n = 7); no answer (1.7%, n = 4). Most respondents prescribed the substances on-demand (59.6%, n = 143) while others (36.3%, n = 87) provided them as around the clock medication. Over both domains, most physicians answered that their choices were not based on solid evidence from randomized controlled trials (RCTs). Guidelines were inconsistent regarding if and what non-opioid to use for cancer pain and recommend anti-dopaminergic drugs for prevention or treatment of OINV.
CONCLUSIONS
Physician's practice in palliative care for the treatment of cancer pain and OINV differed substantially. Respondents expressed the lack of high-quality evidence- based information from RCTs. We call for evidence from methodologically high-quality RCTs to be available to inform physicians about the benefits and harms of pharmacological treatments for common symptoms in palliative care.
Topics: Humans; Analgesics, Opioid; Cancer Pain; Nausea; Vomiting; Practice Guidelines as Topic; Practice Patterns, Physicians'; Antiemetics; Palliative Care; Male; Europe; Health Care Surveys; Surveys and Questionnaires; Female; Middle Aged; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 38879720
DOI: 10.1007/s00520-024-08628-7 -
Food and Chemical Toxicology : An... Jun 2024Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and paracetamol can be administered off-label to cattle. Since the use of these veterinary medicines in cattle may pose a...
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and paracetamol can be administered off-label to cattle. Since the use of these veterinary medicines in cattle may pose a public health risk after meat consumption, it is important to translate measured concentrations in urine and tissues into concentrations in meat for human consumption. A generic physiologically-based kinetic (PBK) model for cattle can enable this translation. In this work, a beef cattle PBK model was applied to calculate the relationships between concentrations in different bovine tissues and those were compared to measured concentrations in different matrices. Sixty-seven kidney samples, the corresponding urine and meat samples, and available 19 serum samples were analysed. Overall, 70% of the PBK model predictions are within a 2-fold factor and relationships for kidney/meat, urine/meat, and plasma/meat ratios were established. The conversions of measured kidney concentrations into meat concentrations were mostly within a factor two, while those based on plasma and urine were underpredicted. Based on these ratios, plasma and urine could be used as an appropriate surrogate matrix for a fast, simple in vivo sample screening test under field conditions, such as in local farms and slaughterhouses, to predict a maximum residue level exceedance in meat, reducing the number of test samples.
PubMed: 38879144
DOI: 10.1016/j.fct.2024.114812