Deletion of TP signaling in macrophages delays liver repair following APAP-induced liver injury by reducing accumulation of reparative macrophage and production of HGF.

BACKGROUND: Acetaminophen (APAP)-induced liver injury is the most common cause of acute liver failure. Macrophages are key players in liver restoration following APAP-induced liver injury. Thromboxane A2 (TXA2) and its receptor, thromboxane prostanoid (TP) receptor, have been shown to be involved in tissue repair. However, whether TP signaling plays a role in liver repair after APAP hepatotoxicity by affecting macrophage function remains unclear. METHODS: Male TP knockout (TP-/-) and C57BL/6 wild-type (WT) mice were treated with APAP (300 mg/kg). In addition, macrophage-specific TP-knockout (TP△mac) and control WT mice were treated with APAP. We explored changes in liver inflammation, liver repair, and macrophage accumulation in mice treated with APAP. RESULTS: Compared with WT mice, TP-/- mice showed aggravated liver injury as indicated by increased levels of alanine transaminase (ALT) and necrotic area as well as delayed liver repair as indicated by decreased expression of proliferating cell nuclear antigen (PCNA). Macrophage deletion exacerbated APAP-induced liver injury and impaired liver repair. Transplantation of TP-deficient bone marrow (BM) cells to WT or TP-/- mice aggravated APAP hepatotoxicity with suppressed accumulation of macrophages, while transplantation of WT-BM cells to WT or TP-/- mice attenuated APAP-induced liver injury with accumulation of macrophages in the injured regions. Macrophage-specific TP-/- mice exacerbated liver injury and delayed liver repair, which was associated with increased pro-inflammatory macrophages and decreased reparative macrophages and hepatocyte growth factor (HGF) expression. In vitro, TP signaling facilitated macrophage polarization to a reparative phenotype. Transfer of cultured BM-derived macrophages from control mice to macrophage-specific TP-/- mice attenuated APAP-induced liver injury and promoted liver repair. HGF treatment mitigated APAP-induced inflammation and promoted liver repair after APAP-induced liver injury. CONCLUSIONS: Deletion of TP signaling in macrophages delays liver repair following APAP-induced liver injury, which is associated with reduced accumulation of reparative macrophages and the hepatotrophic factor HGF. Specific activation of TP signaling in macrophages may be a potential therapeutic target for liver repair and regeneration after APAP hepatotoxicity.

Dual anti-inflammatory effects of curcumin and berberine on acetaminophen-induced liver injury in mice by inhibiting NF-κB activation via PI3K/AKT and PPARγ signaling pathways.

Acetaminophen (APAP) overdose is still a leading cause of drug-induced liver injury (DILI), accompanied with severe inflammatory response. However, the therapy for APAP-induced DILI is rather limited. The combined application of natural products to treat DILI induced by APAP may be a new direction of the research. This study was conducted to evaluate the dual anti-inflammatory activity of curcumin (CUR) combined with berberine (BBR) against APAP-mediated DILI. Network pharmacology found that PI3K-Akt and PPAR signaling pathways were primarily involved in anti-DILI of the combination of CUR and BBR. APAP injection enhanced the levels of ALT, AST, IL-1ß, IL-6, and TNF-α in mice, while such phenomenon was significantly reversed by the cotreatment of CUR and BBR, which was more effective than either single treatment. The increase of p-NF-κB and p-IKKα/ß protein expression and the decrease of p-PI3K, p-AKT, and PPARγ protein expression in APAP-treated mice were markedly inhibited by the coadministration of CUR and BBR. Molecular docking further demonstrated that both CUR and BBR could stably bind to PI3K, AKT, and PPARγ protein. In conclusion, the combination of CUR and BBR more effectively protected liver from APAP-triggered DILI than individual treatment. The mechanism is to alleviate hepatic inflammation by inhibiting NF-κB activation, which is possibly mediated by PI3K/Akt and PPARγ signaling pathways.

The Prophylactic Effect of Acetaminophen and Caffeine on Post Dural Puncture Headache after Spinal Anesthesia for Cesarean Section: A Randomized Double-Blind Clinical Trial.

Background: Post-dural puncture headache (PDPH) is the most common complication following spinal anesthesia among parturients undergoing cesarean section surgery. The purpose of this study was to evaluate the effectiveness of acetaminophen and caffeine in preventing PDPH. Methods: This double-blind, randomized clinical trial was conducted on 96 obstetric women, who were candidates for elective cesarean section. Following the randomization of participants into two groups, participants in the intervention group received tablets of acetaminophen (500 mg)+caffeine (65 mg), and participants in the control group received placebo tablets orally 2 hours before spinal anesthesia induction and then every 6 hours after surgery up to 24 hours. All parturients were evaluated for frequency and intensity of PDPH every 6 hours until 24 hours after surgery and then 48 and 72 hours after surgery. Overall satisfaction during the first 72 hours of postpartum was evaluated. The data were analyzed using SPSS software. P<0.05 was considered statistically significant. Results: Participants in the intervention group were 70% less likely to experience PDPH after spinal anesthesia (OR=0.31 P=0.01, 95% CI [0.12-0.77]). They also experienced significantly milder headaches 18 hours, 48 hours, and 72 hours later. Participants in the intervention group reported higher levels of satisfaction at the end of the study (P=0.01). No side effects related to the intervention were reported. Conclusion: Prophylactic administration of acetaminophen+caffeine decreases 70% the risk of PDPH and significantly attenuates pain intensity in obstetric patients who underwent spinal anesthesia for cesarean section.

Hepatotoxic assessment in a microphysiological system: Simulation of the drug absorption and toxic process after an overdosed acetaminophen on intestinal-liver-on-chip.

To compensate the limitation of animal models, new models were proposed for drug safety evaluation to refine and reduce existing models. To mimic drug absorption and metabolism and predict toxicokinetic and toxic effects in an in vitro intestinal-liver microphysiological system (MPS), we constructed an intestinal-liver-on-chip and detected the acute liver injury process after an overdose of acetaminophen (APAP). Caco-2 and HT29-MTX-E12 cell lines were utilized to establish intestinal equivalents, along with HepG2, HUVEC-T1, and THP-1 induced by PMA and human hepatic stellate cell to establish liver equivalents. The APAP concentration was determined using high-performance liquid chromatography, and the toxicokinetic parameters were fitted using the non-compartmental analysis method by Phoenix. Changes in liver injury biomarkers aspartate aminotransferase and alanine aminotransferase, and liver function marker albumin indicated that the short-term culture of the two organs-on-chip model was stable for 4 days. Reactive oxygen species signaling was enhanced after APAP administration, along with decreased mitochondrial membrane potential, activated caspase-3, and enhanced p53 signaling, indicating a toxic response induced by APAP overdose. In the gut-liver MPS model, we fitted the toxicokinetic parameters and simulated the hepatotoxicity procedure following an APAP overdose, which will facilitate the organ-on-chips application in drug toxicity assays.

Early brain neuroinflammatory and metabolic changes identified by dual tracer microPET imaging in mice with acute liver injury.

Background: Acute liver injury (ALI) that progresses into acute liver failure (ALF) is a life-threatening condition with an increasing incidence and associated costs. Acetaminophen (N-acetyl-p-aminophenol, APAP) overdosing is among the leading causes of ALI and ALF in the Northern Hemisphere. Brain dysfunction defined as hepatic encephalopathy is one of the main diagnostic criteria for ALF. While neuroinflammation and brain metabolic alterations significantly contribute to hepatic encephalopathy, their evaluation at early stages of ALI remained challenging. To provide insights, we utilized post-mortem analysis and non-invasive brain micro positron emission tomography (microPET) imaging of mice with APAP-induced ALI. Methods: Male C57BL/6 mice were treated with vehicle or APAP (600 mg/kg, i.p.). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver damage (using H&E staining), hepatic and serum IL-6 levels, and hippocampal IBA1 (using immunolabeling) were evaluated at 24h and 48h. Vehicle and APAP treated animals also underwent microPET imaging utilizing a dual tracer approach, including [11C]-peripheral benzodiazepine receptor ([11C]PBR28) to assess microglia/astrocyte activation and [18F]-fluoro-2-deoxy-2-D-glucose ([18F]FDG) to assess energy metabolism. Brain images were pre-processed and evaluated using conjunction and individual tracer uptake analysis. Results: APAP-induced ALI and hepatic and systemic inflammation were detected at 24h and 48h by significantly elevated serum ALT and AST levels, hepatocellular damage, and increased hepatic and serum IL-6 levels. In parallel, increased microglial numbers, indicative for neuroinflammation were observed in the hippocampus of APAP-treated mice. MicroPET imaging revealed overlapping increases in [11C]PBR28 and [18F]FDG uptake in the hippocampus, thalamus, and habenular nucleus indicating microglial/astroglial activation and increased energy metabolism in APAP-treated mice (vs. vehicle-treated mice) at 24h. Similar significant increases were also found in the hypothalamus, thalamus, and cerebellum at 48h. The individual tracer uptake analyses (APAP vs vehicle) at 24h and 48h confirmed increases in these brain areas and indicated additional tracer- and region-specific effects including hippocampal alterations. Conclusion: Peripheral manifestations of APAP-induced ALI in mice are associated with brain neuroinflammatory and metabolic alterations at relatively early stages of disease progression, which can be non-invasively evaluated using microPET imaging and conjunction analysis. These findings support further PET-based investigations of brain function in ALI/ALF that may inform timely therapeutic interventions.

Artemether ameliorates acetaminophen-induced liver injury through Nrf2 pathway.

Acetaminophen (APAP) overdose is a prevalent cause of clinical pharmacological liver injury worldwide. Artemether (ART), a first-line antimalarial drug, has demonstrated hepatoprotective activity. However, its effect on APAP-induced acute liver injury (AILI) remains unclear. In this study, we investigated whether ART can protect against AILI and examined its underlying mechanisms. In vivo, ART mitigated APAP-induced liver histological changes, including mitochondrial damage, hepatocyte necrosis, hepatocyte apoptosis, and inflammatory infiltration. Additionally, ART reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in APAP-induced mice. ART also activated the Nrf2-HO-1/GPX4 signaling pathway, exerting antioxidant effects in both in vitro and in vivo models of AILI. To confirm Nrf2 as a target of ART in vivo, we pretreated C57BL/6 mice with the Nrf2 inhibitor, ML385. The results indicated that inhibiting Nrf2 diminishes the protective effect of ART against AILI. Overall, our findings suggest that ART's protective effect against AILI is mediated through the Nrf2-related antioxidant pathway.

Pentagalloylglucose alleviates acetaminophen-induced acute liver injury by modulating inflammation via cGAS-STING pathway.

BACKGROUND: The cGAS-STING pathway is an important component of the innate immune system and plays significant role in acetaminophen-induced liver injury (AILI). Pentagalloylglucose (PGG) is a natural polyphenolic compound with various beneficial effects, including anti-cancer, antioxidant, anti-inflammatory, and liver-protective properties; however, whether it can be used for the treatment of AILI and the specific mechanism remain unclear. MATERIALS AND METHODS: A cell culture model was created to study the effect of PGG on cGAS-STING pathway activation using various techniques including western blotting (WB), real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence (IF), and immunoprecipitation (IP). The effect of PGG was investigated in vivo by establishing a dimethylxanthenone acetic acid (DMXAA)-mediated activation model. An AILI model was used to evaluate the hepatoprotective and therapeutic effects of PGG by detecting liver function indicators, liver histopathology, and cGAS-STING pathway-related indicators in mice with AILI. RESULTS: PGG blocked cGAS-STING pathway activation in bone marrow-derived macrophages (BMDMs), THP-1 cells, and peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, PGG inhibited the generation of type I interferons (IFN-I) and the secretion of inflammatory factors in DMXAA-induced in vivo experiments. In addition, PGG also reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), improved liver tissue damage and apoptosis, and inhibited the cGAS-STING pathway activation caused by acetaminophen. In terms of the mechanism, PGG disrupted the connection between STING and TBK1. CONCLUSIONS: PGG exerts a protective effect against AILI by blocking the cGAS-STING pathway, offering a promising treatment strategy.

Integrated electrochemical-adsorption for simultaneous removal of pharmaceuticals from water: Process optimization and synergistic insights.

Water contamination with pharmaceuticals has become an evident environmental challenge. Treatment processes such as electrochemical oxidation (EO) and adsorption have limitations in the simultaneous removal of pharmaceuticals from water. Therefore, this study examined the potential of coupled process (EO followed by adsorption) in binary pharmaceuticals (acetaminophen (ACM) + ciprofloxacin (CIP)) removal from water, with an emphasis on coupled process optimization. Consequently, optimized coupled process conditions including current density (22 mA/cm2), pH (5.5), EO time (40 min), adsorbent dose (0.1 g/L) and adsorption time (60 min) were obtained. Under optimal conditions, removal efficiencies of 94.6% (ACM)+92% (CIP), 94.07% (ACM)+91.15% (CIP), and > 99.8% (ACM + CIP) were recorded for 20 mg/L (ACM + CIP) removal in EO, adsorption and EO + adsorption, respectively. Further, the coupled process was employed in multiple pharmaceuticals (20 mg/L of ACM + CIP + ATN (atenolol) + AMX (amoxicillin)) removal from water and removal of > 97.56% (ACM + CIP + ATN + AMX) was achieved. Removal efficiencies of ACM (83.35%) + CIP (73.1%) + ATN (68.52%) + AMX (63.05%) and ACM (80.37%) + CIP (66.5%) + ATN (73.07%) + AMX (60.5%) were obtained in EO and adsorption, respectively. The noted lower removal efficiencies in EO and adsorption are associated with the diverse nature of the pharmaceuticals, limited adsorbent active sites, and the shared utilization of reactive oxygen species (ROS) among the pharmaceuticals in EO. The total organic carbon (TOC) removal of 40.24%, and 99% and chemical oxygen demand (COD) removal of 72.45%, and 99.6% were obtained under optimal conditions of EO, and coupled process, respectively. These findings indicate that the pharmaceuticals are only partially mineralized in EO and the subsequent adsorption effectively eliminated the remaining target pharmaceuticals, and degradation by-products from water. Additionally, integrating EO with adsorption reduced the electrical energy consumption of the EO process from 31.6 kWh/m³ to 6 kWh/m³ under optimal conditions. Overall, coupling EO with adsorption offers the utmost advantages when removing multiple pharmaceuticals from complex water matrices.

The Staged Photocatalytic Reactor in the Removal of Acetaminophen: Aspects of Adsorption and Photocatalysis.

The efficiency of a staged photocatalytic reactor prototype was evaluated on a semi-pilot scale with the removal of acetaminophen, for which anatase particles were synthesized by Sol-Gel and impregnated on rectangular plates of clay. X-ray diffraction and Energy Dispersive X-ray Fluorescence patterns show that the final composite is made up of Al2O3 (14 %), SiO2 (41 %), CaO (3 %) TiO2 (34 %), and Fe2O3 (7 %). The impregnation method favors the dispersion of Anatase on the surface of the adsorbent. TiO2-Anatase/Clay, classified as a macro-porous solid with H3-type hysteresis loops by N2 physisorption. Adsorption processes are improved when using TiO2-Anatase/Clay compared to using TiO2-Anatase. The external mass transfer has a greater influence on the removal rate. The dimensionless parameters of the Biot number indicate there are no limitations due to the diffusive effect on the interior of the particle. The evaluation of the kinetic data under the Langmuir-Hinshelwood equation shows a decrease in efficiency as the initial concentration increases. The acetaminophen molecule shows destabilization in the structure of the aromatic ring with a visible decrease in the signals of this functional group evaluated by High-Performance Liquid Chromatography and Raman Spectroscopy.

Neurodevelopmental outcomes following paracetamol use for treatment of patent ductus arteriosus: A review.

AIM: Concerns exist regarding potential adverse neurodevelopmental outcomes associated with paracetamol exposure during pregnancy and early infancy. This review evaluates the evidence for the impact of paracetamol use for patent ductus arteriosus (PDA) treatment on neurodevelopmental outcomes in preterm infants. METHODS: A literature search was performed via Medline, Ovid Embase and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. The search details are below: ('Infant, Newborn' [MeSH] OR 'neonate*' [Title/Abstract]) AND ('Paracetamol' [MeSH] OR 'Acetaminophen' [Title/Abstract]) AND ('Ductus Arteriosus, Patent/drug therapy' [MeSH] OR 'patent ductus arteriosus' [Title/Abstract]) AND ('Neurodevelopmental Disorders' [MeSH] OR 'neurodevelopment*' [Title/Abstract] OR 'Child Development' [MeSH] OR 'Developmental Disabilities' [MeSH]). All studies were critically appraised and synthesised. RESULTS: Seven studies reported neurodevelopmental outcomes after paracetamol use for PDA treatment in preterm infants <32 weeks gestation. The studies varied in dosage, route, and duration of paracetamol administration and in the methods used to assess neurodevelopmental outcomes. None of the studies revealed different outcomes between paracetamol-exposed preterm infants and controls. CONCLUSION: Current low-to-moderate quality evidence suggests no association between paracetamol used for PDA treatment and adverse neurodevelopmental outcomes in preterm infants. Future well-powered studies with standardised neurodevelopmental assessments are warranted to strengthen the current evidence base.

Chlorzoxazone-Induced Fixed Drug Eruption: A Clinical Case Report.

Fixed drug eruptions (FDEs) are dermatological manifestations characterized by recurrent lesions at the same site upon re-exposure to the causative drug. We present a novel case of a 32-year-old female who developed bilateral symmetrical erythematous papules on her thighs following the use of chlorzoxazone for chronic back pain. This case is particularly significant as it underscores the potential for this specific drug, which is commonly prescribed, to induce FDE-a reaction previously unreported in the literature. The findings emphasize the necessity for clinicians to maintain a high index of suspicion for drug-induced skin reactions, even with medications considered safe and routinely used. This case serves as a critical reminder of the importance of thorough medication history assessments and the potential implications of drug interactions in dermatological care.

Macrophage manufacturing and engineering with 5'-Cap1 and N1-methylpseudouridine-modified mRNA.

Macrophage-based cell therapeutics is an emerging modality to treat cancer and repair tissue damage. A reproducible manufacturing and engineering process is central to fulfilling their therapeutic potential. Here, we establish a robust macrophage-manufacturing platform (Mo-Mac) and demonstrate that macrophage functionality can be enhanced by N1-methylpseudouridine (m1Ψ)-modified mRNA. Using single-cell transcriptomic analysis as an unbiased approach, we found that >90% cells in the final product were macrophages while the rest primarily comprised T cells, B cells, natural killer cells, promyelocytes, promonocytes, and hematopoietic stem cells. This analysis also guided the development of flow-cytometry strategies to assess cell compositions in the manufactured product to meet requirements by the National Medical Products Administration. To modulate macrophage functionality, as an illustrative example we examined whether the engulfment capability of macrophages could be enhanced by mRNA technology. We found that efferocytosis was increased in vitro when macrophages were electroporated with m1Ψ-modified mRNA encoding CD300LF (CD300LF-mRNA-macrophage). Consistently, in a mouse model of acute liver failure, CD300LF-mRNA-macrophages facilitated organ recovery from acetaminophen-induced hepatotoxicity. These results demonstrate a GMP-compliant macrophage-manufacturing process and indicate that macrophages can be engineered by versatile mRNA technology to achieve therapeutic goals.

Fibroblast growth factor 21 alleviates acetaminophen induced acute liver injury by activating Sirt1 mediated autophagy.

BACKGROUND AND AIMS: Acetaminophen (APAP) is the main cause of acute liver injury (ALI) in the Western. Our previous study has shown that fenofibrate activated hepatic expression of fibroblast growth factor 21 (FGF21) can protect the liver form APAP injuries by promoting autophagy. However, the underlying mechanism involved in FGF21-mediated autophagy remains unsolved. METHODS: The ALI mice model was established by intraperitoneal injection of APAP. To investigate the influence of FGF21 on autophagy and Sirt1 expression in APAP-induced ALI, FGF21 knockout (FGF21KO) mice and exogenously supplemented mouse recombinant FGF21 protein were used. In addition, primary isolated hepatocytes and the Sirt1 inhibitor EX527 were used to observe whether FGF21 activated autophagy in APAP injury is regulated by Sirt1 at the cellular level. RESULTS: FGF21, Sirt1, and autophagy levels increased in mice with acute liver injury (ALI) and in primary cultured hepatocytes. Deletion of the FGF21 gene exacerbated APAP-induced liver necrosis and oxidative stress, and decreased mitochondrial potential. It also reduced the mRNA and protein levels of autophagy-related proteins such as Sirt1, LC3-II, and p62, as well as the number of autophagosomes. Replenishment of FGF21 reversed these processes. In addition, EX527 partially counteracted the protective effect of FGF21 by worsening oxidative damage, mitochondrial damage, and reducing autophagy in primary liver cells treated with APAP. CONCLUSION: FGF21 increases autophagy by upregulating Sirt1 to alleviate APAP-induced injuries.

Role of DNase I in DNA degradation and cell-free DNA generation after acetaminophen-induced hepatic injury.

Cell-free DNA (cfDNA), the DNA in the blood circulation, is a useful marker for diagnosing hereditary diseases and tumors. However, the mechanisms underlying the generation of cfDNA are not completely understood. We previously studied DNases [Caspase-activated DNase (CAD), DNase1L3, and DNase I] and reported that in acetaminophen-induced liver necrosis, DNase1L3 was the main endonuclease generating cfDNA, with CAD playing a supporting role. In this study, we generated triple-gene knockout (TKO) mice, Cad -/-DNase1L3 -/-DNase1 -/-, and found that DNase I also contributed to cfDNA generation. Given that a defect in DNase1L3 or DNase I is involved in autoimmune diseases, TKO mice would be useful as a disease model and tool for identifying the in vivo roles of endonucleases.

Differentiating Ischemic Hepatitis from Acetaminophen Overdose in Acute Liver Failure: Role of Acetaminophen Adducts-Ischemic Hepatitis vs Acetaminophen Overdose.

BACKGROUND AND AIMS: Acetaminophen (APAP) hepatotoxicity and ischemic hepatic injury (IH) demonstrate remarkably similar biochemical patterns. Deciding between these two etiologies in the setting of acute liver failure (ALF) can be challenging. We reviewed all cases in the Acute Liver Failure Study Group (ALFSG) registry where these diagnoses were considered, to determine reasons for, and frequency of, difficulties making these diagnoses. We hypothesized that the newly developed APAP-CYS adduct assay could help in discerning the correct diagnosis. METHODS: Among 3364 patients with ALF or acute liver injury (ALI: INR ≥ 2.0 but without encephalopathy) between 1998 and 2019, 1952 (58%) received a final diagnosis of either APAP (1681) or IH (271). We utilized a review committee of senior hepatologists as well as the APAP-CYS assay (where sera were available), measuring the presence of toxic by-products of APAP injury to optimize adjudication. RESULTS: With these methods, a total of 575 adduct positive APAP cases included 488 recognized APAP, as well as an additional 87 patients previously diagnosed as other etiologies. Nine cases initially attributed to IH were deemed combination APAP-IH injuries. Conversely, 215 of the 280 IH subjects tested for adducts disclosed 173 confirmed as IH with adduct testing below the toxicity threshold, while 9 cases were revised from APAP to the IH-APAP combination phenotype, where both hypotension and APAP likely played a role. CONCLUSIONS: Discerning APAP from IH can be difficult-in rare cases, combined injury is observed (18/1952). APAP-CYS testing resulted in revising the diagnosis in 14.6% of cases.

Evaluating the use of paracetamol to prevent fasting headache during the first week of Ramadan: A randomized, open-label, clinical trial.

BACKGROUND: Fasting headaches frequently occur during the first few days of Ramadan, and treatment is challenging because of fasting. OBJECTIVE: This study aimed to evaluate the effect of extended-release paracetamol on preventing fasting headaches. METHODS: A randomized, open-label clinical trial investigated the efficacy of extended-release paracetamol at a daily dose of 1330 mg in preventing fasting headache. Adults aged 18 years and older were recruited through the Clinical Trial Unit at the King Saud University Medical City. The eligible participants in the study fasted 13.5 h daily during the first week of Ramadan. Participants in the treatment and control arms were followed up to investigate the occurrence, severity, and timing of headache symptoms via self-reporting using a standardized headache diary scale with a daily online link or phone call. The primary outcome was the frequency of headache episodes while fasting during the first week of Ramadan. RESULTS: A total of 238 participants were enrolled and randomized. Of these, 173 followed the protocol (80 treated, 93 control) for at least the first day and were included in the analysis. Most participants were young and healthy, with a mean age of 32.2 ± 10.2 years. More men were included in the study (102/173; 59.0%), a small proportion of participants were smokers (31/173; 17.9%), and almost all participants reported being coffee drinkers (165/173; 95.4%); nonetheless, these characteristics were evenly distributed between the two groups in the study. The overall incidence of headache episodes was 33.0% (57/173) on day 1 and decreased to 11.3% (18/159) on day 7. On average over the 7 days, no significant effect was observed for the treatment on the incidence of headache, as the findings from the generalized estimating equation model indicated (ß = -0.398, p = 0.084; odds ratio = 0.67, 95% confidence interval [CI] 0.42-1.06). Moreover, there was initially no significant difference in the incidence of headache episodes between the treatment and control groups. However, the treatment group had significantly fewer headache episodes during fasting than the control group on day 3 (4/72 [5.6%] vs. 15/91 [16.5%], p = 0.031; relative risk [RR] = 0.34, 95% CI 0.12-0.97) and day 6 (5/69 [7.2%] vs. 20/90 [22.2%], p = 0.010; RR = 0.33, 95% CI 0.13-0.82). No adverse effects were observed during the study period. CONCLUSION: No significant differences were observed in the occurrence of fasting headaches between the two groups on most days during the study period. Additional studies are required to address fasting headaches during the first week of Ramadan.

Perioperative pain management intervention in older patients with hip fracture in an orthogeriatric unit. A controlled before/after study assessing an audit and feedback intervention (PAIN-AGE).

BACKGROUND: Postoperative pain delays ambulation, extends hospital stay, reduces the probability of recovery, and increases risk of long-term functional impairment. Pain management in hip fractured patients poses a challenge to the healthcare teams. Older adults are more vulnerable to opioid-associated side effect and it is primordial to minimize their exposure to opioids. Acetaminophen is associated with reduced opioid use so we need to focus on acetaminophen use in first-line analgesia. METHODS: We conducted a controlled before/after study to assess the ability of an audit and feedback (A&F) intervention built with nurses to improve the quality of perioperative pain management in older patients hospitalized for hip fracture in an orthogeriatric unit (experimental group) versus a conventional orthopedic unit (no A&F intervention). The primary endpoint was the percentage of patients who received 3 g/day of acetaminophen during the three postoperative days, before and after the A&F intervention. Secondary endpoints included nurses' adherence to medical prescriptions, clinical data associated with patients and finally factors associated with intervention. The significative level was set at 0.05 for statistical analysis. RESULTS: We studied data from 397 patients (mean age 89 years, 75% female). During the postoperative period, 16% of patients from the experimental group received 3 g/day of acetaminophen before the A&F intervention; the percentage reached 60% after the intervention. The likelihood of receiving 3 g/day of acetaminophen during the postoperative period and adhering to the medical prescription of acetaminophen were significantly increased in the experimental group as compared with the control group. The patient's functional status at discharge (assessed by Activities of Daily Living scores) was significantly better and the length of hospital stay significantly reduced after the A&F intervention. CONCLUSION: Our controlled before/after study showed that an A&F intervention significantly improved perioperative pain management in older adults hospitalized for hip fracture. Involving teams in continuous education programs appears crucial to improve the quality of pain management and ensure nurses' adherence to medical prescriptions.

Gene Therapy in the Light of Lifestyle Diseases: Budesonide, Acetaminophen and Simvastatin Modulates rAAV Transduction Efficiency.

Recombinant AAV (rAAV) vectors are increasingly favored for gene therapy due to their useful features of vectorology, such as transfection of dividing and nondividing cells, the presence of tissue-specific serotypes, and biosafety considerations. This study investigates the impact of commonly used therapeutic drugs-acetaminophen, budesonide, and simvastatin-on rAAV transduction efficiency in HEK-293 cells. Cells were transduced with an AAV mosaic vector under the control of a cytomegalovirus (CMV) promoter encoding green fluorescent protein (GFP). Transduction efficiency was assessed by qPCR and fluorescent microscopy. Analysis of functional interactions between genes potentially involved in rAAV transduction in drug-exposed cells was also performed. This study showed a clear effect of drugs on rAAV transmission. Notably, acetaminophen enhanced transduction efficiency by 9-fold, while budesonide and simvastatin showed 2-fold and 3-fold increases, respectively. The gene analysis illustrates the possible involvement of genes related to cell membranes in the potentiation of rAAV transduction induced by the drugs under investigation. Attention should be paid to S100A8, which is a common drug-modified gene for drugs showing anti-inflammatory effects (budesonide and simvastatin), demonstrating an interaction with the gene encoding the receptor for AAV (HGFR). This study underscores the significance of assessing rAAV pharmacokinetics/pharmacodynamics (PKs/PDs) and drug-gene therapy interactions in optimizing gene therapy protocols.

Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase-both of which are vital for maintaining cellular redox balance-combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury.