Magnesium Sulfate Mitigates the Progression of Monocrotaline Pulmonary Hypertension in Rats.

We investigated whether magnesium sulfate (MgSO4) mitigated pulmonary hypertension progression in rats. Pulmonary hypertension was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg). MgSO4 (100 mg/kg) was intraperitoneally administered daily for 3 weeks, from the seventh day after monocrotaline injection. Adult male rats were randomized into monocrotaline (MCT) or monocrotaline plus MgSO4 (MM) groups (n = 15 per group); control groups were maintained simultaneously. For analysis, surviving rats were euthanized on the 28th day after receiving monocrotaline. The survival rate was higher in the MM group than in the MCT group (100% versus 73.3%, p = 0.043). Levels of pulmonary artery wall thickening, α-smooth muscle actin upregulation, right ventricular systolic pressure increase, and right ventricular hypertrophy were lower in the MM group than in the MCT group (all p < 0.05). Levels of lipid peroxidation, mitochondrial injury, inflammasomes and cytokine upregulation, and apoptosis in the lungs and right ventricle were lower in the MM group than in the MCT group (all p < 0.05). Notably, the mitigation effects of MgSO4 on pulmonary artery wall thickening and right ventricular hypertrophy were counteracted by exogenous calcium chloride. In conclusion, MgSO4 mitigates pulmonary hypertension progression, possibly by antagonizing calcium.

Platonin mitigates vascular hyporeactivity of thoracic aorta in septic rats.

BACKGROUND: Vascular hyporeactivity contributes to hemodynamic alterations and circulatory failure in severe sepsis. Among the identified mechanisms, inflammation and oxidative stress are the most crucial ones in mediating the development of vascular hyporeactivity induced by sepsis. Platonin, a photosensitive dye and an antioxidant, possesses potent antiinflammation effects. We elucidated whether platonin could mitigate vascular hyporeactivity of thoracic aorta in septic rats. MATERIAL AND METHODS: Adult male Sprague-Dawley rats were randomized to receive sham operation (Sham), Sham plus platonin (100 µg/kg), cecal ligation and puncture (CLP), or CLP plus platonin (10, 50, or 100 µg/kg) and designated as the Sham, P, CLP, CLP + P(10), CLP + P(50), and CLP + P(100) group, respectively (n = 6 in each group). After maintaining for 12 hours, surviving rats were euthanized and thoracic aorta was isolated and vascular reactivity of aortic rings was determined. RESULTS: Vascular reactivity induced by vasoconstrictors phenylephrine and angiotensin II of the Sham and the P groups (n = 6 in both groups) were similar, whereas vascular reactivity of the CLP group (n = 5) were significantly lower than those of the Sham group (both P < 0.001). Of note, vascular reactivity induced by phenylephrine and angiotensin II of the CLP + P(10) group (n = 5) and the CLP group were not significantly different. In contrast, vascular reactivity induced by phenylephrine and angiotensin II of the CLP + P(50) and the CLP + P(100) groups (n = 6 in both groups) were significantly higher than those of the CLP group (phenylephrine: P = 0.024 and 0.017; angiotensin II: P = 0.031 and 0.036). CONCLUSION: Platonin could mitigate vascular hyporeactivity of thoracic aorta in septic rats.

Oral Dexmedetomidine Achieves Superior Effects in Mitigating Emergence Agitation and Demonstrates Comparable Sedative Effects to Oral Midazolam for Pediatric Premedication: A Systematic Review and Meta-Analysis of Randomized Controlled Studies.

Background: Oral midazolam is the most commonly used sedative premedication agent in pediatric patients. While effective, oral midazolam cannot reduce the incidence of emergence agitation. Oral dexmedetomidine may be effective in providing satisfactory sedation and reduce the incidence of emergence agitation, although the results of different randomized controlled trials are conflicting. Methods: This study enrolled randomized controlled trials (RCTs) examining premedication with oral dexmedetomidine versus oral midazolam in pediatric patients undergoing general anesthesia. PubMed, the Cochrane Library, Embase, and the Web of Science database were searched from their inception until June 2023. The outcomes were the incidence of satisfactory preoperative sedation, satisfactory sedation during separation from parents, satisfactory sedation during anesthesia induction using an anesthesia mask, and the incidence of emergence agitation. Results: A total of 9 RCTs comprising 885 patients were analyzed. Our data revealed comparable effects of dexmedetomidine and midazolam with respect to satisfactory preoperative sedation and a satisfactory incidence of sedation during parental separation and mask acceptance before anesthesia induction. Notably, our data revealed that the rate of emergence agitation was significantly lower in pediatric patients receiving dexmedetomidine (n = 162) than in those receiving midazolam (n = 159) (odds ratio = 0.16; 95% confidence interval: 0.06 to 0.44; p < 0.001; I2 = 35%). Conclusions: Data from this meta-analysis revealed comparable effects for premedication with oral dexmedetomidine or oral midazolam with respect to satisfactory sedation; furthermore, premedication with oral dexmedetomidine more effectively mitigated emergence agitation in pediatric patients receiving general anesthesia compared with oral midazolam.

High-Fructose/High-Fat Diet Downregulates the Hepatic Mitochondrial Oxidative Phosphorylation Pathway in Mice Compared with High-Fat Diet Alone.

Both high-fat diet (HFD) alone and high-fructose plus HFD (HFr/HFD) cause diet-induced non-alcoholic fatty liver disease in murine models. However, the mechanisms underlying their impacts on inducing different levels of liver injury are yet to be elucidated. This study employed a proteomic approach to elucidate further on this issue. Adult male C57BL/6J mice were allocated to the HFD or the HFr/HFD group. After feeding for 12 weeks, all mice were euthanized and samples were collected. The proteomic profiles in liver tissues were analyzed using liquid chromatography-tandem mass spectrometry followed by canonical pathway analysis. We demonstrated that the mitochondrial oxidative phosphorylation (OXPHOS) pathway was the most significantly downregulated canonical pathway in the HFr/HFD group when compared with the HFD group. Within the OXPHOS pathway, the HFr/HFD group demonstrated significant downregulation of complexes I and III and significant upregulation of complex IV when compared with the HFD group. Moreover, the HFr/HFD group had lower protein levels of NADH: ubiquinone oxidoreductase subunits S3, S6, A5, and A12 in complex I (p < 0.001, =0.03, <0.001, and <0.001, respectively), lower protein level of cytochrome C in complex III (p < 0.001), and higher protein level of cytochrome C oxidase subunit 2 in complex IV (p = 0.002), when compared with the HFD group. To summarize, we have demonstrated that the hepatic mitochondrial OXPHOS pathway is significantly downregulated in long-term HFr/HFD feeding when compared with long-term HFD feeding. These data support the concept that the hepatic mitochondrial OXPHOS pathway should be involved in mediating the effects of HFr/HFD on inducing more severe liver injury than HFD alone.

Tumor Necrosis Factor-α Mediates Lung Injury in the Early Phase of Endotoxemia.

Endotoxemia induces lung injury. We assessed the therapeutic efficacy between triple cytokine (tumor necrosis factor-α [TNF-α], interleukin-1ß [IL-1ß], and IL-6) inhibition (mediated by KCF18 peptide) and single cytokine (TNF-α) inhibition (mediated by SEM18 peptide) on alleviating lung injury in the early phase of endotoxemia. Mice receiving endotoxin (Endo group), endotoxin plus KCF18 (EKCF group), or endotoxin plus SEM18 (ESEM) were monitored and euthanized at 24 h after endotoxin. Our data demonstrated altered lung function (decreases in tidal volume, minute ventilation, and dynamic compliance; and by contrast, increases in airway resistance and end expiration work) and histology (increases in injury scores, leukocyte infiltration, vascular permeability, and tissue water content) in the Endo group with significant protection observed in the EKCF and ESEM groups (all p < 0.05). Levels of inflammation (macrophage activation and cytokine upregulations), oxidation (lipid peroxidation), necroptosis, pyroptosis, and apoptosis in EKCF and ESEM groups were comparable and all were significantly lower than in the Endo group (all p < 0.05). These data demonstrate that single cytokine TNF-α inhibition can achieve therapeutic effects similar to triple cytokines TNF-α, IL-1ß, and IL-6 inhibition on alleviating endotoxin-induced lung injury, indicating that TNF-α is the major cytokine in mediating lung injury in the early phase of endotoxemia.

Testicular torsion-detorsion causes dysfunction of mitochondrial oxidative phosphorylation.

BACKGROUND: Semen quality impairment is a serious consequence of testicular torsion-detorsion. Adequate germ-cell mitochondrial oxidative phosphorylation plays a crucial role in male fertility. Changes in cellular oxidative phosphorylation in testicular tissues after testicular torsion-detorsion remain unclear. OBJECTIVES: This study investigated whether testicular torsion-detorsion induces alternations of mitochondrial oxidative phosphorylation in testicular tissues. MATERIALS AND METHODS: BALB/c male mice were divided into a Sham group and a testicular torsion-detorsion group. At the end of the procedure, the mice were euthanized, and their bilateral testicles were removed. Mitochondria morphology was evaluated through transmission electron microscopy. The cellular respiratory functions of germ cells were evaluated using a Seahorse analyzer assay. The proteome profiles in testicular tissues were analyzed using liquid chromatography-tandem mass spectrometry. The differences in the expression levels of each component in the oxidative phosphorylation were revealed using Ingenuity Pathways Analysis. RESULTS: Inner mitochondrial membrane disruption was found in ipsilateral twisted testicular mitochondria in the torsion-detorsion group but not in contralateral untwisted testes. The cellular respiratory function in germ cells was significantly decreased after testicular torsion-detorsion in ipsilateral twisted testes but not in contralateral untwisted testes. Liquid chromatography-tandem mass spectrometry analysis of ipsilateral twisted testicular tissue revealed that mitochondrial proteins were differentially expressed after testicular torsion-detorsion. Testicular torsion-detorsion induced downregulation of oxidative phosphorylation and revealed alternations of specific proteins in the oxidative phosphorylation complexes. DISCUSSION AND CONCLUSION: Testicular torsion-detorsion produced mitochondria injury and dysregulation of mitochondrial oxidative phosphorylation in ipsilateral twisted testes. Different protein expressions were identified in the mitochondrial oxidative phosphorylation complexes with testicular torsion-detorsion; new therapeutic targets may be identified to restore the oxidative phosphorylation function of germ cells.

Let-7i-5p Mediates the Therapeutic Effects of Exosomes from Human Placenta Choriodecidual Membrane-Derived Mesenchymal Stem Cells on Mitigating Endotoxin-Induced Mortality and Liver Injury in High-Fat Diet-Induced Obese Mice.

Obesity complicates sepsis and increases the mortality of sepsis. We examined the effects of exosomes (from human placenta choriodecidual membrane-derived mesenchymal stem cells, pcMSCs) on preventing sepsis in obesity and the mitigating role of hsa-let-7i-5p microRNA. Obese mice (adult male C57BL/6J mice fed a high-fat diet for 12 weeks) received normal saline (HFD), endotoxin (10 mg/kg, intraperitoneal (ip); HFDLPS), endotoxin with exosomes (1 × 108 particles/mouse, ip; HLE), or endotoxin with let-7i-5p microRNA inhibitor-pretreated exosomes (1 × 108 particles/mouse, ip; HLEi). Our data demonstrated that the 48-h survival rate in the HLE (100%) group was significantly higher than in the HFDLPS (50%) and HLEi (58.3%) groups (both p < 0.05). In the surviving mice, by contrast, levels of liver injury (injury score, plasma aspartate transaminase and alanine transaminase concentrations, tissue water content, and leukocyte infiltration in liver tissues; all p < 0.05), inflammation (nuclear factor-κB activation, hypoxia-inducible factor-1α activation, macrophage activation, and concentrations of tumor necrosis factor-α, interleukin-6, and leptin in liver tissues; all p < 0.05), and oxidation (malondialdehyde in liver tissues, with p < 0.001) in the HLE group were significantly lower than in the HFDLPS group. Levels of mitochondrial injury/dysfunction and apoptosis in liver tissues in the HLE group were also significantly lower than in the HFDLPS group (all p < 0.05). Inhibition of let-7i-5p microRNA offset the effects of the exosomes, with most of the aforementioned measurements in the HLEi group being significantly higher than in the HLE group (all p < 0.05). In conclusion, exosomes mitigated endotoxin-induced mortality and liver injury in obese mice, and these effects were mediated by let-7i-5p microRNA.

Beneficial effects of preoperative oral nutrition supplements on postoperative outcomes in geriatric hip fracture patients: A PRISMA-compliant systematic review and meta-analysis of randomized controlled studies.

BACKGROUND: Geriatric hip fracture patients often present malnutrition during admission, which leads to higher morbidity and mortality. Protein-based oral nutrition supplements may improve nutritional status. We conducted this systematic review and meta-analysis of randomized controlled trials (RCTs) according to the PRISMA guidelines to elucidate whether preoperative nutrition supplements can improve postoperative outcomes in geriatric hip fracture patients. METHODS: Only RCTs conducted to compare postoperative outcomes between geriatric hip fracture patients (>60 years old) receiving preoperative oral protein-based nutrition supplement (ONS group) and those who receiving regular diet (Control group) were included. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched from inception until August, 2021. Postoperative outcomes, including complications, length of hospital stay, and in-hospital mortality, were assessed. RESULTS: A total of 5 RCTs with 654 geriatric hip fracture patients (ONS group: 320 subjects; Control group 334 subjects) were included. Our data revealed that postoperative complications risk in the ONS group was significantly lower than in the Control group (odd's ratio: 0.48, 95% confidence intervals [CI]: 0.26-0.89, P = .02, I2 = 64%). However, no significant differences in the length of hospital stay (standardized mean difference: -0.35 days, 95% CI: -1.68 to 0.98 days, P = .61, I2 = 0%) and the risk of having postoperative in-hospital mortality (odd's ratio: 1.07, 95% CI: 0.43-2.63, P = .89, I2 = 54%) between these 2 groups were observed. Quality assessment revealed high risk of bias and significant data heterogeneity (I2>50%) in most included RCTs. CONCLUSION: Preoperative protein-based oral nutrition supplements exert beneficial, but limited, effects on postoperative outcomes in geriatric patients with hip fracture undergoing surgery.

Different impacts of various tocolytic agents on increased risk of postoperative hemorrhage in preterm labor women undergoing Cesarean delivery: A population-based cohort study.

Tocolytic agents, commonly used for inhibiting preterm labor, pose the risk of uterine atony, leading to postpartum hemorrhage. This study elucidated the effects of different tocolytic agents on postoperative hemorrhage among women in preterm labor undergoing Cesarean delivery (CD). Data from Taiwan National Health Insurance Research Database were analyzed. The risk (adjusted hazard ratio [aHR] and 95% confidence intervals [CI]) of postoperative hemorrhage in CD women with preterm labor diagnosis using tocolytic agents (Tocolysis group) comparing to CD women not using tocolytic agents (Control group) were determined. Impacts of different tocolytic agents in this regard were also investigated. Our data revealed that the incidence (11.7% vs 2.6%, P < .001) and risk (aHR: 1.21, 95% CI: 1.12-1.31, P < .001) of postoperative hemorrhage were significantly higher in the Tocolysis group (n = 15,317) than in the Control group (n = 244,096). Ritodrine was the most frequently used tocolytic agent (80.5%), followed by combination therapy (using more than one tocolytic agents) (8.5%), magnesium sulfate (MgSO4, 4.6%), calcium channel blockers (3.8%), betamimetics other than ritodrine (1.9%), prostaglandin synthase inhibitors (0.5%), and nitrates (0.1%). Barring those using calcium channel blockers and combination therapy, the use of MgSO4 (aHR: 1.43, P = .001), betamimetics other than ritodrine (aHR: 1.71, P < .001), prostaglandin synthase inhibitors (aHR: 2.67, P < .001) and nitrates (aHR: 3.30, P = .001) was associated with higher risks of postoperative hemorrhage compared with ritodrine. In conclusion, CD women with preterm labor diagnosis using tocolytic agents exhibit an increased risk of postoperative hemorrhage and that this risk varies with the use of different tocolytic agents.

Spotlight on Bortezomib: potential in the treatment of hepatocellular carcinoma.

INTRODUCTION: This study reviews the evidence for the use of Bortezomib (BZB), a first-in-class proteasome inhibitor in advanced Hepatocellular carcinoma (HCC). This review aims to delineate the role of BZB within the management of non-surgical and metastatic HCC, either as an alternative or as an adjunct to the current treatment paradigm. AREAS COVERED: In addition to BZB pharmacology and mechanism of action, safety and tolerance profiles of the drug obtained from clinical trials are explored. The utility of BZB as a therapeutic agent either alone or in combination with other therapies against HCC, including its application in both preclinical and clinical settings has been reviewed. In particular, we highlight the importance of preclinical evaluation of BZB as a combinatorial agent in synergism with other therapies for the use in the management of HCC. EXPERT OPINION: There has been much interest surrounding the use of BZB, a first-in-class proteasome inhibitor for HCC therapy. The discernment of outcomes of BZB clinical trials for HCC need to take into consideration the disease-specific factors that can affect survival outcomes including patient selection and aetiological differences. Further preclinical testing of BZB in combination with other therapeutic modalities can be important for eliciting enhanced anti-HCC effects.

Murine hepatocellular carcinoma derived stem cells reveal epithelial-to-mesenchymal plasticity.

AIM: To establish a model to enrich and characterize stem-like cells from murine normal liver and hepatocellular carcinoma (HCC) cell lines and to further investigate stem-like cell association with epithelial-to-mesenchymal transition (EMT). METHODS: In this study, we utilized a stem cell conditioned serum-free medium to enrich stem-like cells from mouse HCC and normal liver cell lines, Hepa 1-6 and AML12, respectively. We isolated the 3-dimensional spheres and assessed their stemness characteristics by evaluating the RNA levels of stemness genes and a cell surface stem cell marker by quantitative reverse transcriptase-PCR (qRT-PCR). Next, we examined the relationship between stem cells and EMT using qRT-PCR. RESULTS: Three-dimensional spheres were enriched by culturing murine HCC and normal hepatocyte cell lines in stem cell conditioned serum-free medium supplemented with epidermal growth factor, basic fibroblast growth factor and heparin sulfate. The 3-dimensional spheres had enhanced stemness markers such as Klf4 and Bmi1 and hepatic cancer stem cell (CSC) marker Cd44 compared to parental cells grown as adherent cultures. We report that epithelial markers E-cadherin and ZO-1 were downregulated, while mesenchymal markers Vimentin and Fibronectin were upregulated in 3-dimensional spheres. The 3-dimensional spheres also exhibited changes in expression of Snai, Zeb and Twist family of EMT transcription factors. CONCLUSION: Our novel method successfully enriched stem-like cells which possessed an EMT phenotype. The isolation and characterization of murine hepatic CSCs could establish a precise target for the development of more effective therapies for HCC.