High-dose Treatment Research Articles

Abstract 4136116: Metformin Therapy for Reperfusion Injury Consolidates Cardioprotection in the High-Risk Elderly Heart

Introduction: Metformin (MET), a first-line diabetes therapy, exhibits cardioprotective effects during acute ischemia and reperfusion (I/R). Cardiac injury is enhanced in the aging heart in murine and humans. Acute, high dose MET treatment at the onset of reperfusion (R) markedly reduced infarct size (MI) in the high risk aged heart via modulation of mitochondrial complex I. However, the effect of subsequent chronic, standard dose MET to consolidate and possibly enhance cardioprotection and survival following I/R in the aged heart remains unknown. Hypothesis: Administration of chronic standard dose of MET will ameliorate mortality and morbidity following MI through rescuing an impaired adaptive metabolic remodeling. Methods: Aged (22-24 month) C57BL6/J mice were subjected to sham operations or 45 min of ischemia by LAD ligation followed by R. All mice received acute, high dose MET (2 mM, i.v.) at the onset of R followed by randomization to chronic MET (300 mg/kg/day) in drinking water versus vehicle (VEH) administered for 14 days. Cardiac function was determined by echocardiography weekly. IonOptix Myocyte Calcium and Contractility System measured the contractile functions and transient calcium signaling of isolated cardiomyocytes. Results: The Kaplan-Meier survival analysis showed that chronic MET treatment following acute treatment at the onset of R significantly reduced mortality compared to VEH group. Although chronic MET treatment did not further reduce MI size, echo and histology showed that chronic MET preserved diastolic function, prevented left ventricular hypertrophy and reduced collagen deposition following I/R in aging. Moreover, isolated cardiomyocytes from MET treated hearts showed improvements in contractile function, transit calcium signaling, and the coupling between contractility and calcium levels as compared to the cardiomyocytes from VEH group hearts. Immunoblotting results showed that Sens2/AMPK metabolic signaling was significantly upregulated by chronic MET post-MI, indicating the metabolic homeostasis modulated by MET is a critical factor involved in the beneficial effects of chronic MET on limiting I/R-induced myocardial damage that leads to deleterious remodeling in aging. Conclusions: The mortality and morbidity of MI in the high risk aged heart is attenuated with acute, high dose of MET treatment followed by chronic standard dose MET treatment to consolidate protection via rescuing the impaired adaptive metabolic response in aging.

RADT-48. ANALYSIS OF PROTON RADIATION THERAPY INDUCED CONTRAST ENHANCEMENT: A SINGLE INSTITUTION, RETROSPECTIVE STUDY

Abstract Proton radiotherapy (PRT) has superior physical dose distribution with a lesser integral off target radiation dose exposure compared with standard photon radiotherapy resulting in reduced toxicity of uninvolved normal tissues. However, there may be toxicity in areas targeted for high dose treatment as a result of uncertainty about the relative radiobiologic effect (RBE) of proton radiotherapy compared with photon radiotherapy and the potential for localized high doses at the end of the proton beam range (Bragg peak). This may result in radiation-induced contrast enhancement (RICE) reflecting transient toxicity or permanent injury, particularly when associated with concurrent chemotherapy. We analyzed 150 consecutive adult patients, with a histopathologic diagnosis of CNS malignancy, who underwent only PRT at Johns Hopkins Hospital between 2019 – 2023 with least 1 year of follow-up imaging. RICE was defined as a new post-treatment contrast enhancement on MRI within the radiation field. The determination of disease progression or RICE was confirmed with additional follow-up MRI or pathology. RICE was identified in 14 cases (9.3%). The median age was 48 y (range 19 – 72 years), sex 50% female. Diagnosis was 5 astrocytoma, 3 meningioma, 2 glioblastoma, 1 medulloblastoma, 2 oligodendroglioma, 1 tectal glioma. 4/5 astrocytoma patients were grade 2, 2/3 meningioma was grade 1, 1/3 was grade 2, 2/2 oligodendroglioma was grade 2. The median time since completing PRT to development of RICE was 3.5 months. The median radiation dose was 52.20 Gye (range 23.40 - 60.06). Dexamethasone was used in 11 patients (78 %) and in bevacizumab was used 2. Chemotherapy with temozolomide 7 (50%), PCV 1, and none in 5. 12 (85%) patients were still alive. PRT can also be associated with radiation injury in the target, and more information is needed about the incidence, natural history, and associations with localized dosimetry.

Corticosteroid Effect in Acute Spinal Cord Injury in the Rural Area

Spinal cord injuries (SCI) are devastating traumatic events in the lives of patients, often resulting in severe and/or permanent neurologic disabilities. Nearly half a million people are living permanently disabled in the United States due to traumatic SCI and 12,000–15,000 patients per year incur new injuries. A 78-year-old male patient came to the emergency room with a history of falling from a height with a pelvic position below exposed to trees 30 hours before admission, found weakness in the lower limbs, unable to urinate since yesterday. On radiologic examination, a burst fracture was found in the collumna of the 1st lumbar vertebra. The patient could not be examined for MRI due to limitations and unavailability of equipment at the hospital. The patient was given high dose of Methylprednisolone treatment for 3 days and there was no motoric improvement in the patient. Acute spinal cord injury is a very dangerous disease because it can cause patients both psychological and non psychological disorders. In areas that are left behind and do not have very good facilities and medical personnel to carry out this treatment. There is no treatment option other than using corticosteroids. However, the effect of corticosteroids still needs to be further developed and researched.

Metabolic stress in patients with acute severe ulcerative colitis - a single-center cohort study

Background and aimsAcute severe ulcerative colitis (ASUC) is characterized by systemic inflammation, which may initiate an acute-phase response leading to hypercatabolism. Patients with ASUC are usually treated with high-dose steroids that may further accelerate the metabolic response and lead to hyperglycemia and insulin resistance. Nevertheless, the degree of synergy between inflammation and steroid treatment and their influence on the insulin resistance remains unknown. We aimed to measure the degree of metabolic stress including insulin resistance in patients with ASUC during admission and three weeks after discharge.MethodsThis single-center cohort study was conducted in adult patients with ASUC, defined and assessed by Truelove and Witt’s criteria. Indirect calorimetry, bioelectrical impedance analysis, and the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were applied at baseline and at follow-up three weeks after discharge.ResultsAmong the 22 patients admitted during the project period, 15 provided consent for participation in the study. Median C-reactive protein at inclusion was 37.6 [4; 154.7]. Both median HOMA-IR and fasting plasma glucose were markedly increased at inclusion (median 8.6 [3.8; 14.1] and 7.1 [6; 8.7], respectively), and both had decreased significantly three weeks after discharge (p=0.0036 and p=0.0039, respectively). No significant differences were observed in resting energy expenditure or anthropometric measurements from baseline to follow-up.ConclusionPatients with ASUC presented with marked insulin resistance, indicating that the days following admission and high-dose steroid treatment are particularly vulnerable. Despite improvement at three-week follow-up, patients still exhibited insulin resistance compared with relevant control groups.Clinical trial registrationClinicalTrials.gov, identifier NCT0527183.

Potential Disease-Modifying Effects of Ganglioside GM1 Pulse Treatment on Spinocerebellar Ataxia Type 3, a Parallel-Group, Double-Blind, Randomized, Controlled Trial.

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited neurodegenerative disorder for which there is currently no cure, nor effective treatment strategy. Our aim was to investigate the safety and efficacy of high-dose ganglioside GM1 (ganglioside-monosialic acid) pulse treatment in patients with SCA3. Patients were randomly allocated to receive either high-dose GM1 (400 mg on the first day followed by 200 mg/day), low-dose GM1 (40 mg/day), or placebo (normal saline) for 4 weeks. The primary outcome, assessed by measuring the change in the Scale for the Assessment and Rating of Ataxia (SARA) scores from baseline to 12 weeks post-treatment, is central to evaluating treatment efficacy. Secondary outcomesincluded changes in the International Cooperative Ataxia Rating Scale (ICARS) score, Barthel Index of Activities of Daily Living (ADL), and plasma and cerebrospinal fluid (CSF) GABA levels. Safety was assessed in all treated patients. A total of 48 patients with SCA3 were enrolled in this study. After 12 weeks, data from 43 patients were included in the efficacy analysis (intention-to-treat analysis). The least-squares mean change in the SARA score from baseline to 12 weeks post-treatment was -3.80 (standard error [SE], 0.39; 95% confidence interval [CI], -4.58 to -3.02) in the high-dose GM1 group, 0.34 (SE, 0.40; 95% CI, -0.46 to 1.13) in the low-dose GM1 group, and 0.73 (SE, 0.40; 95% CI, -0.07 to 1.52) in the placebo group, respectively. Secondary outcomes showed improvements in the ICARS score, Barthel Index of ADL, and plasma and CSF GABA levels in the high-dose GM1 group compared to the low-dose GM1 and placebo groups. All treatments were well-tolerated and safe. High-dose GM1 treatment significantly ameliorated ataxic symptoms in patients with SCA3. © 2024 International Parkinson and Movement Disorder Society.

Video Head Impulse Test Coherence Predicts Vertigo Recovery in Sudden Sensorineural Hearing Loss with Vertigo.

The labyrinthitis poses inferior quality of life with prolonged vestibular symptoms in patients with sudden sensorineural hearing loss with vertigo (SSNHLV). This study utilized a novel coherence analysis in video head impulse test (vHIT) to investigate vertigo outcomes in SSNHLV patients. A retrospective review included 48 SSNHLV patients completing high-dose steroid treatment between December 2016 and April 2023, and 38 healthy volunteers were prospectively enrolled between November 2022 and April 2023 in our academic tertiary referral center. Magnitude-squared wavelet coherence was measured between eye and head velocities in vHIT to represent the degree of correlation across different frequency bands. Vertigo recovery, assessed by visual analog scale equal to zero at 2 weeks and 2 months, was analyzed using a multivariable Cox regression model. The VAS among patients with SSNHLV was 5.73 ± 2.45 (mean ± standard deviation). Higher coherent frequencies in the horizontal semicircular canal (SCC), posterior SCC, mean, and minimal coherent frequencies of all three SCCs combined were significantly associated with early complete vertigo remission at two weeks post-treatment. In the multivariate analysis, the minimal coherent frequency among the three SCCs emerged as an independent factor (hazard ratio [HR] 2.040, 95% confidence interval [CI] 1.776-2.304). At two months post-treatment, in addition to the previously significant parameters, vestibulo-ocular reflex (VOR) abnormality in the posterior SCC, gains in the horizontal and posterior SCCs, total and overt saccades in the horizontal SCC, coherent frequency in the anterior SCC, and mean VOR gain of all three SCCs combined were also statistically significantly related to total vertigo relief. The greater minimal coherent frequency among the three SCCs was a strong factor contributing to earlier relief of vertigo in patients with SSNHLV. Coherence analysis in vHIT may be more sensitive than time series analysis for evaluating vertigo prognosis prediction.

Efficacy and safety assessment of probiotic Bacillus coagulans (Heyndrickxia coagulans) BCP92 for treatment of diarrhea

Abstract Objective: Probiotics offer a potentially new therapeutic approach for the treatment of diarrhea. This study aimed to determine the anti-diarrheal activity of Bacillus coagulans BCP92 (MTCC 25460) and its safety assessment (acute and sub-acute toxicity studies) in animal models and cell lines. Methods: The antidiarrheal activity was studied in mice using a castor oil-induced diarrhea model. In the acute toxicity study, the rats were orally fed 2000 mg/kg (4 × 1011 CFU/g) of B. coagulans BCP92 (MTCC 25460) as a single dose, and for sub-acute toxicity study rats received 250, 500, and 1,000 mg/kg/day for 28 days. At the end of the treatment, body weight, organ weight, food intake, biochemical parameters, hematological parameters, and histopathology were studied. B. coagulans BCP92 is effective against diarrhea by reducing the onset of diarrhea (latency), frequency of defecation, total fecal weight, and percentage of defecation. In-vitro MTT assay was performed on Vero cell lines. Results: In-vitro MTT assay showed a cytoprotective effect. In acute toxicity study, 2000 mg/kg dose did not cause any alteration in clinical signs, morbidity, or mortality. The findings of the subacute toxicity study showed no alterations in physical appearance and behavioral patterns. Moreover, no significant variations were found in organ weights and hematological and biochemical parameters of the treated groups in the control group. Furthermore, no visible histological changes were observed in the heart, lung, liver, and kidney of the high-dose treatment groups. Conclusion: Thus, the results of the present study conclude that B. coagulans BCP92 is safe for human use in the treatment of diarrhea.

A case with recurrent idiopathic anaphylaxis episodes starting soon after COVID-19 mRNA vaccination

Introduction: A patient was presented with a history of idiopathic recurrent anaphylaxis after administration of Pfizer BioNTech mRNA vaccine, and the attacks were controlled with omalizumab. To our knowledge, this is the first reported case of recurrent idiopathic anaphylaxis (IA) after administration of Pfizer BioNTech mRNA vaccine. Case Presentation: A 52-year-old man with recurrent episodes of IA after COVID-19 vaccination presented to our adult Allergy and Immunology Clinic. In the patient, urticaria and anaphylaxis episodes could not be controlled with high-dose antihistamine and systemic steroid treatment, and complete control was achieved with omalizumab treatment and anaphylaxis attacks completely regressed. Conclusion: In cases of unexplained or recurrent anaphylaxis in adult patients, COVID-19 vaccination and timing should be questioned, and its association with anaphylaxis might be considered.

Zhuangyao Jianshen Wan ameliorates senile osteoporosis in SAMP6 mice through Modulation of the GCN5L1-mediated PI3K/Akt/wnt signaling pathway

BackgroundSenile osteoporosis (SOP) is a systemic bone disease characterized by increased susceptibility to fractures. However, there is currently no effective treatment for SOP. The Zhuangyao Jianshen Wan (ZYJSW) pill is traditionally believed to possess kidney-nourishing and bone-strengthening effects, demonstrating efficacy in treating fractures. Despite this, its effectiveness and mechanism in SOP remain unclear. This study aims to investigate the therapeutic potential of ZYJSW in treating SOP in senescence accelerated mouse prone 6 (SAMP6, P6) mice, and elucidate the underlying mechanisms. MethodsFour-month-old SAMP6 mice were categorized into six groups: the model group (SAMP6), low, medium, and high-dose ZYJSW treatment groups, calcitriol treatment (positive control 1) group, and metformin treatment (positive control 2) group. Gastric administration was carried out for 15 weeks, and a normal control group comprising four-month-old Senescence-Accelerated Mouse Resistant 1 (SAMR1) mice. Changes in body weight, liver and kidney function, bone protective effects, and muscle quality were evaluated using various assays, including H&E staining, Goldner staining, bone tissue morphology analysis, Micro-CT imaging, and biomechanical testing. Qualitative analysis and quality control of ZYJSW were performed via LC-MS/MS analysis. To explore mechanisms, network pharmacology and proteomics were employed, and the identified proteins were validated by Western blotting. ResultsOral administration of ZYJSW to P6 mice exerted preventive efficacy against osteopenia, impaired bone microstructure, and poor bone and muscle quality. ZYJSW attenuated the imbalance in bone metabolism by promoting bone formation, as evidenced by the upregulation of key factors such as Runt-related transcription factor 2 (RUNX2), Bone Morphogenetic Protein (BMP2), Osteoprotegerin (OPG) and Osteocalcin (OCN), while simultaneously inhibiting bone resorption through the downregulation of TNF receptor associated factor 6 (TRAF6), Tartrate resistant acid phosphatase (TRAP), Receptor activator for nuclear factor-κB ligand (RANKL) and Cathepsin K (CTSK). Additionally, ZYJSW enhanced muscle structure and function by counteracting the elevation of Ubiquitin (Ub), Muscle RING-finger protein-1 (Murf-1), F-Box Protein 32 (FBOX32), and Myogenin (Myog). Network pharmacology predictions, proteomics analysis corroborated by published literature demonstrated the role of ZYJSW involving in safeguarding mitochondrial biogenesis. This was achieved by suppressing GCN5L1 expression, contributing to the heightened expression of TFAM, PGC-1α, and nuclear respiratory factor-1 (NRF-1) proteins. ZYJSW also positively modulated Wnt signaling pathways responsible for bone formation, due to regulating expressions of key components like β-catenin, GSK-3β, and LRP5. In addition, ZYJSW causes the downregulation of the PI3K/Akt pathway by inhibiting the phosphorylation of both PI3K and Akt. ConclusionsThe study highlights the significance of ZYJSW in preserving the health of both bone and muscle in P6 mice, potentially through the regulation of the GCN5L1-mediated PI3K/Akt/Wnt signaling pathway. The translational potential of this articleOur research provides evidence and a mechanistic rationale for ZYJSW as a candidate for SOP treatment, offering insights for further exploration and strategy development.

Longer duration of high-dose corticosteroids provides benefit for hospitalized COVID-19 patients with high oxygen requirement

The optimal corticosteroids dose in patients with coronavirus disease 2019 (COVID-19) requiring high oxygen remains unknown. In this retrospective study of patients with COVID-19 requiring high oxygen and receiving corticosteroids, the efficacy, safety, and duration of high-dose treatment were evaluated. The primary outcome was all-cause mortality during follow-up. Safety outcomes included infection, gastrointestinal bleeding, and venous thromboembolic events. 210 patients were included, with 126 in Group A (corticosteroids at a equivalent dose <1 mg/kg/d prednisone), 44 in Group B (corticosteroids at a equivalent dose ≥1 mg/kg/d prednisone for ≤5 days), and 40 in Group C (corticosteroids at a equivalent dose ≥1 mg/kg/d prednisone for >5 days). The all-cause mortality risk was lower in Group C but higher in Group B than in Group A. Safety outcomes did not differ significantly, except for Group C, which had the highest venous thromboembolism rate. Our results suggest that high-dose corticosteroids for a longer course decrease mortality with comparable safety outcome.

The high-dose statin treatment reduces neutrophil extracellular traps formation in patients with coronary artery disease

Abstract Background Neutrophil extracellular traps formation (NETosis) is currently considered as an important mediator in atherosclerosis and atherothrombosis. However, the impact of high-dose statin treatment, as potent cholesterol-lowering agents with pleiotropic effects, on NETosis in coronary artery disease (CAD) has been poorly described. Purpose We sought to assess whether in CAD patients the recommended statin treatment intensification is associated with changes in NETs-related markers and if such changes can alter fibrin clot properties. Methods 130 patients with advanced CAD, who did not achieve the target low-density lipoprotein cholesterol (LDL-C) were included. Before and at least 6 months after initiation of high-dose statin therapy (rosuvastatin 40 mg/d or atorvastatin 80 mg/d) citrullinated histone H3 (H3cit), myeloperoxidase (MPO) and neutrophil elastase (NE) as markers associated with NETosis were assessed in relation to C-reactive protein (CRP), thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis proteins. Results At baseline, NETosis did not differ depending on gender and cardiovascular risk factors but H3cit correlated with MPO (R=0.543, P&amp;lt;0.001) and CRP (R=0.540, P&amp;lt;0.001). All NETosis markers were inversely correlated with Ks. Median LDL-C reduction by 25% (P&amp;lt;0.001) on high-dose statin treatment was independent from H3cit reduction by 30.4%, MPO by 28.1%, and NE by 25.5% (in all P&amp;lt;0.001, Figure 1). The ΔH3cit and ΔMPO, but not ΔNE were associated with ΔCRP (R=0.855, P&amp;lt;0.001; R=0.250, P=0.004, respectively), Δthrombin activatable fibrinolysis inhibitor (TAFI) (R=0.385, P&amp;lt;0.001; R=0.245, P=0.005), and inversely with ΔKs (R=-0.315, P&amp;lt;0.001; R=-0.395, P=0.001). In multivariable analysis the H3cit decrease was independently associated with ΔCRP (β=0.771, P&amp;lt;0.001), ΔTAFI (β=0.125, P=0.013) and Δfibrinogen (β=0.106, P=0.034) but not with ΔLDL-C. Conclusions As has been shown for the first time high-dose statin treatment reduces levels of NETs-related markers, regardless of lipid-lowering effect in CAD patients.

Semaglutide improves contractile function in isolated human atrium

Abstract Background Recently, the results of the STEP-HFpEF trial were announced, in which high-dose treatment with the antidiabetic glucagon-like-peptide 1 agonist semaglutide resulted in a significant improvement of HFpEF-associated symptoms and reduction of NT-proBNP levels. Interestingly, treatment effects were independent of initial body weight and left-ventricular ejection fraction, sparking interest regarding the precise mechanism of action. Purpose We tested the effects of acute semaglutide treatment in isolated human right-atrial trabeculae. Methods Trabeculae were prepared from right atrial appendage biopsies from 32 patients undergoing elective coronary artery bypass grafting and/or valve surgery. Regular contractions were elicited by electrical field stimulation (1Hz, 5V/50ms, 37°C). Paired experiments were performed simultaneously per patient with a control group and one exposed to semaglutide (100 or 300nM). Developed tension was analysed at steady state after 30 min. Arrhythmias were defined as deviations from baseline not arising from electrical stimulation. L-type calcium channel blockade was achieved with nifedipine (2µM) in some experiments. Rapid cooling contraction was elicited to assess sarcoplasmic reticulum Ca2+ content (RCC1) by rapidly superfusing the trabeculae with chilled solution (2°C). After a short rewarming period of 10s to 37°C, RCC was repeated to assess the Na+/Ca2+ exchanger function (RCC2). Statistical analysis was conducted using paired t-test or Wilcoxon test as appropriate (for 2 groups) and one-way ANOVA with test for trend (for &amp;gt;2 groups). Results Exposure to semaglutide increased developed tension by over 3-fold in human atrial trabeculae in a dose-dependent manner: from 3.14±1.14 for control to 5.43±2.35mN/mm2 for 100nM semaglutide (p=0.03 vs. control) to 12.5±3.53 for 300nM semaglutide (p=0.004 vs. control, mean±SEM, fig. A-D, p=0.005 for linear trend). L-type calcium channel blockade with nifedipine blunted developed tension overall but did not abolish the effect of semaglutide (fig. E, p=0.02). In contrast, the developed tensions upon RCC1 and RCC2 were increased by semaglutide (300nM) compared to control, while the ratio of RCC2:RCC1 was elevated by semaglutide, indicating both increased SR Ca2+ reuptake and less external Ca2+ removal in the presence of semaglutide (fig. H-J). Relaxation time to 50% of baseline was unaltered (not shown), while relaxation time to 90% of baseline was mildly prolonged by semaglutide at 300 nM (fig. F). No increase in the rate of arrhythmias was observed by semaglutide treatment (fig. G). Conclusion Acute exposure of human atrial trabeculae to semaglutide results in a strong positive inotropic effect in a dose-dependent manner without increasing the propensity for arrhythmias. This effect is most likely due to increased SR Ca2+ reuptake. Treatment of heart failure patients with high-dose semaglutide can improve atrial function, which may ameliorate symptoms.

Unleashing the Power of Cold Atmospheric Plasma: Inducing Mitochondria Damage-Mediated Mitotic Catastrophe.

Despite the promise of cold atmospheric plasma (CAP) for cancer treatment, the challenges associated with the treatment of solid tumors and penetration depth limitations remain, restricting its clinical application. Here, biological evidence is provided that the killing effect of CAP treatment is confined to less than 500µm subcutaneously and the actual biological dose decreased gradually with depth for the first time, indicating that the limited penetration depth has become an urgent problem that demands immediate solutions. Significantly, it is showed that different from high-dose treatments, CAP decreased the doses to the low-dose range but still exhibited anti-tumor effects via mitotic catastrophe. Unlike radiotherapy or chemotherapy, low-dose CAP treatment induces mitochondrial structural damage and dysfunction, disrupts energy metabolism and redox balance, and results in mitotic catastrophe. Collectively, these findings suggest that better understanding and taking full advantage of the dose-response gradient effect of CAP is a potential strategy to prompt its clinical application beyond improving CAP penetration.

Gardenia jasminoides extract mitigates acetaminophen-induced liver damage in mice

BackgroundAcetaminophen (APAP)-induced hepatotoxicity is a potentially life-threatening condition. Gardenia jasminoides fruit extract (GJE), which contains geniposide (Gen) as its major active constituent, possesses anti-inflammatory and antioxidant properties and may help address the underlying pathogenesis of APAP-induced hepatotoxicity. This study aimed to evaluate the effects of GJE in a mouse model of APAP-induced hepatotoxicity.MethodsTwenty-four male ICR mice were divided into 4 groups (n = 6/group): [1] Control group, mice were given distilled water; [2] APAP group, mice received a single dose of 600 mg/kg APAP; [3] APAP + low-dose GJE group, mice received APAP followed 30 min later by 2 doses of low-dose GJE (0.44 g/kg/dose, containing Gen 100 mg/kg/dose) 8 h apart; [4] APAP + high-dose GJE group, mice received APAP followed by 2 doses of high-dose GJE (0.88 g/kg/dose, containing Gen 200 mg/kg/dose). All mice were euthanized 24 h after APAP administration. Liver tissue was used for histological examination and to measure glutathione (GSH) and malondialdehyde (MDA) levels. Serum was used to determine levels of ALT and inflammatory cytokines (tumor necrosis factor- α (TNF-α) and interleukin-6 (IL-6)).ResultsLiver histopathology showed moderate to severe hepatic necroinflammation in the APAP group, whereas only mild necroinflammation was observed in both treatment groups. Serum ALT levels were significantly elevated in the APAP group compared to the control group but were significantly reduced after low- and high-dose GJE treatment. Serum TNF- α levels were significantly higher in the APAP group than in the control group and were significantly lower after high-dose GJE treatment (135.5 ± 477.2 vs. 35.5 ± 25.8 vs. 74.7 ± 47.2 vs. 41.4 ± 50.8 pg/mL, respectively). Serum IL-6 followed a similar pattern. Hepatic GSH levels were significantly lower in the APAP group compared to the control group but significantly increased after both low- and high-dose GJE treatment (19.9 ± 4.5 vs. 81.5 ± 12.4 vs. 71.4 ± 7.8 vs. 82.6 ± 6.6 nmol/mg protein, respectively). Conversely, hepatic MDA levels were significantly elevated in the APAP group compared with the control group but significantly decreased after high-dose GJE treatment (108.6 ± 201.5 vs. 40.5 ± 18.0 vs. 40.5 ± 16.8 nmol/mg protein, respectively).ConclusionsTreatment with G. jasminoides fruit extract can alleviate APAP-induced hepatotoxicity, likely through its anti-inflammatory and antioxidant properties.

Progression of cyclosporine A-blood levels in experimental cats receiving a high-dose treatment protocol.

Cyclosporine A (CsA) is used as a steroid-sparing or alternative immunosuppressing agent in cats with various immune-mediated diseases such as immune-mediated hemolytic anemia. Daily treatment dosages of 5-20 mg/kg have been described. Interindividual variations in CsA blood levels are known to occur. To determine when steady-state conditions are reached and thus the earliest advisable time for monitoring CsA blood levels during the course of treatment, a prospective experimental study was conducted in six healthy adult Domestic Shorthair cats. Cats were treated with an oral dosage of 7 mg/kg CsA q 12 h for 10 days. On days 1, 2, 3, 5, 7, and 10 after the start of CsA administration (i.e., after 1, 3, 5, 9, 13, and 19 CsA administrations), EDTA blood was collected to measure the CsA level 12 h after the CsA administration (trough values) using high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS/MS). Statistical analysis revealed a significant increase in mean CsA blood levels up to day 5 (2,050 ± 964.2 ng/mL [mean ± SD], 832-3,203 ng/mL [minimum-maximum]; repeated-measures ANOVA: p = 0.0021), while values on days 5 and 7 did not differ significantly from CsA concentrations on day 10. CsA concentrations showed markedly interindividual variability. Cyclosporine A blood levels reached a steady state on day 5 of high dosages of CsA q 12 h (i.e., after nine CsA administrations), indicating that this time point is suitable for monitoring blood levels in clinical patients. Results confirmed the well-known remarkable interindividual variability of CsA, indicating the need for treatment monitoring. The assessed treatment regime resulted in significantly higher mean CsA trough levels than the target range for immunosuppressive therapy (200-600 ng/mL).

Acupuncture Treatment for Chronic Post-Traumatic Headache in Individuals with Mild Traumatic Brain Injury: A Pilot Study.

Chronic post-traumatic headache (CPTH) after a mild traumatic brain injury (mTBI) has been reported in up to 60% of patients and can be extremely debilitating. While pharmacological treatments are typically used for CPTH, they frequently cause side effects and have limited effectiveness, leading individuals with CPTH to be unsatisfied with current treatment options and to seek nonpharmacological options. Acupuncture has been identified as a potential treatment option; however, the evidence in this population remains limited. The overall goal of this study was to examine the effect of a once weekly (e.g., low dose) versus twice weekly (e.g., high dose) of acupuncture treatment on CPTH in individuals with mTBI. Thirty-eight individuals were randomized to receive either 5 or 10 acupuncture treatments using a standard protocol over 5 weeks. The protocol consisted of 14 points using traditional acupuncture and 4 points using electroacupuncture. Headache outcomes, safety, treatment adherence, sleep quality, and quality of life (QOL) were assessed. The results showed that while there were no differences between dose groups for any of the outcomes assessed, acupuncture significantly reduced the number of headache days and headache pain intensity in individuals with CPTH. There were no significant changes in acute medication use or sleep quality. While there were some QOL improvements identified, these results should be interpreted with caution. Overall, acupuncture was shown to be safe and well-tolerated in people with CPTH after mTBI, and five acupuncture treatments using a standardized protocol shows promise in providing headache relief for this population.

Elevated plasma and CSF neurofilament light chain concentrations are stabilized in response to mutant huntingtin lowering in the brains of Huntington’s disease mice

BackgroundTherapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD.MethodsLongitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild-type (WT) littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting the mutant HTT transgene (HTT ASO), at ages both before and after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology.ResultsPlasma and CSF NfL concentrations were significantly elevated in YAC128 compared to WT littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in a dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high-dose HTT ASO treatment for up to 6 months. Lowering of brain mHTT prior to the onset of regional brain atrophy and HD-like motor deficits in this model had minimal effect on plasma NfL at either dose, but led to a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF.ConclusionsOur data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD.

Protective effect of evodiamine on acetic acid-induced gastric ulcers in rats through regulation of ROS/ICAM1/Nrf2 signaling pathway

Purpose: To study the effect of evodiamine on the signaling pathway of ROS/ICAM-1/Nrf2 in rats with acetic acid-induced stomach ulcers. Methods: The rats were randomly assigned to five groups containing 10 rats each. Prior to acetic acidinduction of gastric ulcers, omeprazole (4.0 mg/kg/day), low-dose evodiamine (L-EVD, 20 mg/kg/day), and high-dose evodiamine (H-EVD, 40 mg/kg/day) were orally administered to the respective groups for 15 days. Following ulcer induction, the same treatments continued for an additional 7 days, for a total treatment duration of 22 days. The control (0.9 % saline) and acetic acid (model) groups were administered 0.9 % sodium chloride solution (10 mL/kg) for the same period. Thereafter, oxidative stress, inflammatory markers, macroscopic and microscopic evaluations were conducted on the gastric mucosa. Results: The acetic acid group showed significantly higher levels of oxidative and inflammatory markers, as well as damage and degeneration of the gastric mucosa when compared to control group (p &lt; 0.05). However, both low-dose and high-dose evodiamine treatment groups demonstrated significant gastric healing. Administration of low-dose and high-dose evodiamine resulted in significantly lower levels of malondialdehyde (MDA), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), myeloperoxidase (MPO) and intracellular adhesion molecule-1 (ICAM-1, p &lt; 0.05). Furthermore, evodiamine treatment led to significantly increased levels of glutathione (GSH) and nuclear facterythroid factor 2 (Nrf2). Conclusion: Evodiamine reduces oxidative stress, suppresses inflammatory reactions, and exerts an anti-ulcer effect on acetic acid-induced gastric ulcers in rats by modulating ROS/ ICAM-1/Nrf2 signaling pathway. More studies into the integration of evodiamine into conventional pharmaceutical treatments for gastric ulcers should be conducted.

Metabolomics Revealed the Effects of Momordica charantia L. Saponins on Diabetic Hyperglycemia and Wound Healing in Mice.

Momordica charantia L. saponins (MCS) may promote wound-healing properties but the underlying mechanisms are unclear. This study aimed to examine the effects and mechanisms of MCS on diabetic wounds. The results have shown that higher MCS intake lowered fasting blood glucose levels, serum lipids, and lipopolysaccharides in diabetic mice. MCS-treated diabetic mice exhibited faster wound healing than the diabetic control groups. After three days, the diabetic control groups exhibited a wound area reduction of only 19.3%, while a 39.75% reduction was observed following high-dose MCS treatment. Five potential biomarkers were screened in the metabolomics study. The results revealed that MCS mainly regulated glycerophospholipid metabolism, fructose and mannose metabolism, steroid hormone biosynthesis, pyrimidine metabolism, and the Krebs cycle, thus affecting wound healing. Overall, MCS could not only exert a hypoglycemic effect but also promote diabetic wound healing, making it a potential treatment option for diabetes-related wounds.

Semaglutide treatment for PRevention Of Toxicity in high-dosE Chemotherapy with autologous haematopoietic stem-cell Transplantation (PROTECT): study protocol for a randomised, double-blind, placebo-controlled, investigator-initiated study

IntroductionCancer treatment with high-dose chemotherapy damages the mucosal barrier of the gastrointestinal (GI) tract and is associated with severe toxicity involving mucositis, severe inflammation and organ dysfunction. Currently, there is...