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Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aβ plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aβ clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

Background: Upper gastrointestinal bleeding (UGIB) is a common medical emergency and early assessment of its outcomes is vital for treatment decisions., Aim: To develop a new scoring system to predict its prognosis., Methods: In this retrospective study, 692 patients with UGIB were enrolled from two centers and divided into a training ( n = 591) and a validation cohort ( n = 101). The clinical data were collected to develop new prognostic prediction models. The endpoint was compound outcome defined as (1) demand for emergency surgery or vascular intervention, (2) being transferred to the intensive care unit, or (3) death during hospitalization. The models' predictive ability was compared with previously established scores by receiver operating characteristic (ROC) curves., Results: Totally 22.2% (131/591) patients in the training cohort and 22.8% (23/101) in the validation cohort presented poor outcomes. Based on the stepwise-forward Logistic regression analysis, eight predictors were integrated to determine a new post-endoscopic prognostic scoring system (MH-STRALP); a nomogram was determined to present the model. Compared with the previous scores (GBS, Rockall, ABC, AIMS65, and PNED score), MH-STRALP showed the best prognostic prediction ability with area under the ROC curves (AUROCs) of 0.899 and 0.826 in the training and validation cohorts, respectively. According to the calibration curve, decision curve analysis, and internal cross-validation, the nomogram showed good calibration ability and net clinical benefit in both cohorts. After removing the endoscopic indicators, the pre-endoscopic model (pre-MH-STRALP score) was conducted. Similarly, the pre-MH-STRALP score showed better predictive value (AUROCs of 0.868 and 0.767 in the training and validation cohorts, respectively) than the other pre-endoscopic scores., Conclusion: The MH-STRALP score and pre-MH-STRALP score are simple, convenient, and accurate tools for prognosis prediction of UGIB, and may be applied for early decision on its management strategies., Competing Interests: Conflict-of-interest statement: Dr. Zeng has nothing to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The clinical characteristics, auxiliary examinations, skin and neuropathological features of 7 patients who had reticular cyanosis with peripheral neuropathy from the Department of Neurology, Huashan Hospital, Fudan University from January 2019 to December 2022 were retrospectively analyzed. Among the 7 patients, 5 were female and 2 were male.The age of onset of peripheral neuropathy was (39.8±21.3) years and the disease duration of peripheral neuropathy was (2.7±2.3) years. Three patients had acute onset and 4 patients had chronic onset. All the patients had limb numbness, with limb weakness in 6 patients and pain in 5 cases. Neuroelectrophysiological examination revealed 1 case of mononeuropathy, 2 cases of polyneuropathy, 2 cases of peripheral neuropathy, and 2 cases of sensory neuron neuropathy. Skin biopsy was performed in 3 patients, which presented hyperplasia and expansion of blood vessels in the dermis with lymphocyte infiltration. Nerve biopsy was performed in 3 patients, indicating axonal damage. Reticular cyanosis with peripheral neuropathy characterizes with numbness and weakness of limbs, most of which were accompanied by pain. Electrophysiological changes are in various forms. The pathological changes are dominated by the damage of axonal.

Rationale: Tuberculosis (TB) and post-transplant lymphoproliferative disorder are serious complications affecting the long-term survival of kidney transplant recipients (KTRs). Both of complications have overlapping clinical symptoms, signs, and high similar imaging presentation, which make early clinical diagnosis challenging. In this paper, we reported a rare case of post-transplant pulmonary TB combined with Burkitt lymphoma (BL) in KTR., Patient Concerns: A 20-year-old female KTR presented to our hospital with abdominal pain and multiple nodules throughout the body., Diagnoses: TB is diagnosed based on the lung histopathology showed fibrous connective tissue hyperplasia with number of chronic inflammatory changes, localized necrosis, granuloma formation and multinucleated giant cells were seen in the lung tissue. Moreover, lung histopathology specimen tested positive for TB gene. TB The culture for tuberculosis was positive. BL was diagnosed as metastatic after completion of liver and bone marrow biopsy., Interventions: After an early diagnosis of TB, the patient received intensification of anti-tubercular therapy. Because the patient was diagnosed with BL, rituximab, cardioprotection, hepatoprotection and alkalinization of urine were added., Outcomes: After an early diagnosis of TB, the patient received anti-tubercular therapy and her clinical symptoms and imaging manifestations improved. After the diagnosis of BL was made, the patient's condition progressed rapidly, followed by multi-organ damage and died 3 months later., Lessons: Therefore, in organ transplant patients, who present with multiple nodules and normal tumor markers, they should be alerted to the possibility of concurrent TB and post-transplant lymphoproliferative disorder, and perfect tests such as Epstein-Barr virus, β2-microglobulin, lactate dehydrogenase, γ-interferon release test and Xpert Mycobacterium TB/rifampicin test and perform early lesion site biopsy to clarify the diagnosis with a view to improving the prognosis., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: In recent years, many extrapedicular puncture methods have been applied to percutaneous kyphoplasty (PKP) in the treatment of osteoporotic vertebral compression fractures (OVCFs). However, these techniques were generally complex and had the risk of some puncture-related complications, which greatly limited the wide applications in PKP. Finding a safer and more feasible extrapedicular puncture method was rather important., Objectives: To evaluate the treatment effect of modified unilateral extrapedicular PKP in patients with lumbar OVCFs clinically and radiologically., Study Design: Retrospective study., Setting: Department of Orthopedic Surgery, an affiliated hospital of a medical university., Methods: Patients who were treated by modified unilateral extrapedicular PKP in our institution, from January 2020 to March 2021, were retrospectively enrolled. The degree of pain relief and functional recovery were evaluated by the Visual Analog Scale (VAS) and the Oswestry Disability Index (ODI), respectively. Radiologic results were assessed including anterior vertebral height (AVH) and kyphotic angle. In addition, volumetric analysis was performed to evaluate bone cement distribution. And the intraoperative data and complications were also recorded., Results: A total of 48 patients with lumbar OVCFs were successfully treated by modified unilateral extrapedicular PKP. All patients experienced a significant decrease in VAS and ODI scores after surgery (P < 0.01) and maintained the statistical significance until the last follow-up (P < 0.01), as well as significant AVH restoration (P < 0.01) and kyphotic angle correction (P < 0.01) compared with preoperative corresponding values. Volumetric analysis showed that all cases of bone cement diffused across the midline of the vertebral body (VB), in which 43 patients (89.6%) presented optimal contralateral distribution with good or excellent bone cement spread. In addition, 8 patients (16.7%) experienced asymptomatic cement leakage, and no other severe complications, such as injuries to segmental lumbar arteries and nerve roots, were found., Limitations: A noncontrol study with a small patient population and short follow-up duration., Conclusions: Modified unilateral extrapedicular PKP, in which the puncture trajectory was advanced through the bottom of Kambin's triangle to or across the midline of VB for proper bilateral cement distribution, greatly alleviated back pain and restored the morphology of fractured vertebrae. It seemed to be a safe and effective alternative applied to treat lumbar OVCFs with appropriate patient selection.

The aim of this study was to clarify the anti-fatigue effect of peanut oligopeptides (POPs) in mice and to investigate its possible underlying mechanism. A total of 150 male ICR mice were randomly assigned into five groups: control, whey protein (0.50 g/kg·bw), and three peanut peptide groups (0.25, 0.50, and 1.00 g/kg·bw). All the mice were treated with intra-gastric administration for 30 days. Following the intervention, a weight-loaded swimming test, blood lactate concentration, glycogen content, the activities of antioxidant factors and energy metabolism enzymes, and the function of mitochondria in the skeletal muscle were examined. The results show that POP intervention significantly prolonged the exhaustive swimming time, decreased blood lactate concentration levels, regulated the process of energy metabolism, and increased the level of antioxidant enzymes, muscle glycogen, and expressions of mtTFA and NRF-1 in the mitochondria of the gastrocnemius muscle. The results suggest that POPs produce an anti-fatigue effect in the animals, and they may exert this effect through the mechanism of improving the animals' antioxidant capacity to reduce oxidative damage levels and regulating the process of energy metabolism.

The production and application of nanoplastics has been increased during decades, and the enterotoxicity caused by their bioaccumulation has attracted vast attention. Maltol was proved to exert a protective effect on gut damage induced by carbon tetrachloride and cisplatin, indicating its confrontation with nanoplastics-induced intestinal toxicity. To explore the ameliorative effects of maltol on polystyrene nanoplastics (PS)-mediated enterotoxicity and the underlying mechanism, the mice were exposed to PS (100 mg/kg), combining with or without the treatment of maltol treatment at 50 and 100 mg/kg. We found PS exposure caused intestinal barrier damage and enterocyte apoptosis, while lysosomal dysfunction and autophagic substrate degradation arrest in enterocytes of mice were also observed. In addition, PS exacerbated the disturbance of the intestinal microbial community, affected the abundance of lysosome and apoptosis-related bacterial genes, and decreased the number of known short-chain fatty acid (SCFA) producing bacteria. However, those alterations were improved by the maltol treatment. Maltol also protected the human intestinal Caco-2 cells from PS-induce damages. Mechanistic studies showed maltol promoted TFEB nuclear translocation through the AMPK/mTOR signaling pathway to restore lysosomal function and reduce autophagy dependent apoptosis. The findings in the present work might help to elucidate the potential molecular mechanisms of PS-induced enterotoxicity. For the first time to our knowledge, the protective effect of maltol on PS-induced intestinal injury was studied from multiple perspectives, which provided a potential therapeutic approach for diseases caused by environmental pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The current antibacterial wound dressings with antibiotic substances or metal bactericidal agents may lead to severe multidrug resistance and poor biocompatibilities. Herein, we report an inherent antibacterial hydrogel constructed by only two naturally small molecules gallic acid (GA) and diammonium glycyrrhizinate (DG) for promoting Staphylococcus aureus (S. aureus)-infected wound healing. The resultant GAD hydrogel can be fabricated by co-assembly of these two materials through simple steps. Thanks to the incorporation of GA and DG, GAD hydrogel enabled a strong mechanical performance and great self-healing property with a sustained-release of drugs into skin wounds. Moreover, the cell viability assays showed that GAD hydrogel had good cytocompatibility by promoting cell proliferation and migration. In addition, GAD hydrogel had broad antibacterial efficiency against both Gram-positive and Gram-negative bacteria. Taken together, GAD hydrogel is a promising dressing to accelerate bacterial-infected wound healing through reconstructing an intact and thick epidermis without antibiotics or cytokines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: To identify risk factors for hospital-acquired pneumonia (HAP) in patients with aneurysmal subarachnoid hemorrhage (aSAH) and establish a predictive model to aid evaluation., Methods: The cohorts of 253 aSAH patients were divided into the HAP group ( n = 64) and the non-HAP group ( n = 189). Univariate and multivariate logistic regression were performed to identify risk factors. A logistic model (Model-Logit) was established based on the independent risk factors. We used risk factor categories to develop a model (Model-Cat). Receiver operating characteristic curves were generated to determine the cutoff values. Areas under the curves (AUCs) were calculated to assess the accuracy of models and single factors. The Delong test was performed to compare the AUCs., Results: The multivariate logistic analysis showed that the age [ p = 0.012, odds ratio (OR) = 1.059, confidence interval (CI) = 1.013-1.107], blood glucose (BG; >7.22 mmol/L; p = 0.011, OR = 2.781, CI = 1.263-6.119), red blood distribution width standard deviation (RDW-SD; p = 0.024, OR = 1.118, CI = 1.015-1.231), and Glasgow coma scale (GCS; p < 0.001, OR = 0.710, CI = 0.633-0.798) were independent risk factors. The Model-Logit was as follows: Logit( P ) = -5.467 + 0.057 * Age + 1.023 * BG (>7.22 mmol/L, yes = 1, no = 0) + 0.111 * RDW-SD-0.342 * GCS. The AUCs values of the Model-Logit, GCS, age, BG (>7.22 mmol/L), and RDW-SD were 0.865, 0.819, 0.634, 0.698, and 0.625, respectively. For clinical use, the Model-Cat was established. In the Model-Cat, the AUCs for GCS, age, BG, and RDW-SD were 0.850, 0.760, 0.700, 0.641, and 0.564, respectively. The AUCs of the Model-Logit were insignificantly higher than the Model-Cat (Delong test, p = 0.157). The total points from -3 to 4 and 5 to 14 were classified as low- and high-risk levels, respectively., Conclusions: Age, BG (> 7.22 mmol/L), GCS, and RDW-SD were independent risk factors for HAP in aSAH patients. The Model-Cat was convenient for practical evaluation. The aSAH patients with total points from 5 to 14 had a high risk for HAP, suggesting the need for more attention during treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Hu, Chen and Yu.)

Background: Epimedii Folium, as a natural botanical medicine, has been reported to have protective effects on intestinal diseases by modulating multiple signaling pathways. This study aimed to explore the potential targets and molecular mechanisms of Epimedii Folium extract (EFE) against cisplatin-induced intestinal injury through network pharmacology, molecular docking, and animal experiments. Methods: Network pharmacology was used to predict potential candidate targets and related signaling pathways. Molecular docking was used to simulate the interactions between significant potential candidate targets and active components. For experimental validation, mice were intraperitoneally injected with cisplatin 20 mg/kg to establish an intestinal injury model. EFE (100, 200 mg/kg) was administered to mice by gavage for 10 days. The protective effect of EFE on intestinal injury was analyzed through biochemical index detection, histopathological staining, and western blotting. Results: Network pharmacology analysis revealed that PI3K-Akt and apoptosis signaling pathways were thought to play critical roles in EFE treatment of the intestinal injury. Molecular docking results showed that the active constituents of Epimedii Folium, including Icariin, Epimedin A, Epimedin B, and Epimedin C, stably docked with the core AKT1, p53, TNF-α, and NF-κB. In verified experiments, EFE could protect the antioxidant defense system by increasing the levels of glutathione peroxidase (GSH-Px) and catalase (CAT) while reducing the content of malondialdehyde (MDA). EFE could also inhibit the expression of NF-κB and the secretion of inflammatory factors, including TNF-α, IL-1β, and IL-6, thereby relieving the inflammatory damage. Further mechanism studies confirmed that EFE had an excellent protective effect on cisplatin-induced intestinal injury by regulating PI3K-Akt, caspase, and NF-κB signaling pathways. Conclusion: In summary, EFE could mitigate cisplatin-induced intestinal damage by modulating oxidative stress, inflammation, and apoptosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xia, Hu, Wang, Cai, Ren, Wang, Lei and Li.)

Background: Cisplatin-induced cardiotoxicity severely limits its clinical application as an antitumor drug and increases the risk of cardiovascular disease. Icariin (ICA), the main flavonoid isolated from Epimedii Folium, has been demonstrated to have various beneficial effects on cardiovascular disease. However, the protective effect of ICA against cisplatin-induced cardiotoxicity remains unclear., Purpose: In present study, we explored the protective action of ICA against cisplatin-induced cardiotoxicity and its possible molecular mechanisms in vitro and in vivo., Methods: Mice were intraperitoneally injected with cisplatin 4 mg/kg every other day for 7 times to establish myocardial injury model. ICA (15, 30 mg/kg) was administered to mice by gavage for 21 days. H9c2 cells were treated with ICA (3, 6, 12 µM) in the presence or absence of cisplatin (40 µM), and then cell viability, oxidative stress, apoptosis, and mitochondrial function were evaluated., Results: Biochemical index detection and histopathological staining analysis showed that ICA had a good protective effect on cisplatin-induced cardiotoxicity. Cellular experiments showed that ICA inhibited cisplatin-induced oxidative stress in a dose-dependent manner by regulating the levels of glutathione peroxidase (GSH-Px), catalase (CAT), superoxide dismutase (SOD) and malondialdehyde (MDA). ICA could inhibit the expression of NF-κB and the secretion of inflammatory factors, thereby alleviating the inflammatory injury caused by cisplatin. In addition, ICA could alleviate cisplatin-induced myocardial injury by activating SIRT1 and PI3K/Akt signaling pathways and inhibiting MAPKs signaling pathway., Conclusion: These results suggest that ICA could attenuate cisplatin-induced cardiac injury by inhibiting oxidative stress, inflammation and apoptosis, laying a foundation for ICA to reduce chemotherapy-induced cardiotoxicity in clinical practice., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Genetic diversity plays important roles in maintaining population productivity. While the impact of genotypic richness on productivity has been extensively tested, the role of genotypic evenness has not been considered. Plant density can also affect population productivity, but its interaction with genotypic diversity has not been tested. We constructed experimental populations of the clonal plant Hydrocotyle vulgaris with either low or high richness (consisting of four vs. eight genotypes), either low or high evenness (each genotype had a different number vs. the same number of ramets), and either low or high density (consisting of 16 vs. 32 ramets) in a full factorial design. Total biomass of plant populations did not differ between four- and eight-genotype mixtures. When the initial plant density was low, total biomass of populations with high genotypic evenness was significantly greater than total biomass of those with low genotypic evenness. However, this difference disappeared when the initial plant density was high. Moreover, total biomass increased linearly with increasing plant density at harvest, but was negatively correlated to variation in leaf area. We conclude that genotypic evenness but not genotypic richness can benefit population productivity, and that plant density can alter the impact of genotypic evenness on population productivity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Yu, Hu, Sheng, Xue and Yu.)

1- O -Acetylbritannilactone (ABL) is a marker component of Inula britannica L. and is reported to exhibit multiple pharmacological activities, including antiaging, anti-inflammatory, and antidiabetic properties. Although the protective effect of Inula britannica L. on animal models of liver injury has been widely reported, the effect of ABL on alcohol-induced liver damage has not been confirmed. The present study was designed to investigate the protective effect of ABL against alcohol-induced LO2 human normal liver cell injury and to further clarify the underlying mechanism. Our results revealed that ABL at concentrations of 0.5, 1, and 2 μM could remarkably suppress the decreased viability of LO2 cells stimulated by alcohol. In addition, ABL pretreatment improved alcohol-induced oxidative damage by decreasing the level of reactive oxygen species (ROS) and the excessive consumption of glutathione peroxidase (GSH-Px), while increasing the level of catalase (CAT) in LO2 cells. Moreover, Western blotting analysis showed that ABL pretreatment activated protein kinase B (Akt) phosphorylation, increased downstream antiapoptotic protein Bcl-2 expression, and decreased the phosphorylation level of the caspase family including caspase 9 and caspase 3 proteins, thereby attenuating LO2 cell apoptosis. Importantly, we also found that ABL significantly inhibits the activation of the nuclear factor-kappa B (NF-κB) signaling pathway by reducing the secretion of proinflammatory factors including tumor necrosis factor-α (TNF-α) and interleukin (IL-1β). In conclusion, the current research clearly suggests that the protective effect of ABL on alcohol-induced hepatotoxicity may be achieved in part through regulation of the ROS/Akt/NF-κB signaling pathway to inhibit inflammation and apoptosis in LO2 cells. (The article path map has not been seen.)., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

The cholinergic anti-inflammatory pathway has been identified as an effective pathway to modify inflammatory responses. Here, we verified that delayed administration with a selective α7nAChR agonist GTS-21 enables a more efficient elimination of the offending pathogens, diminished inflammatory response and organ injury, and improved survival rates in the polymicrobial septic peritonitis model. We illustrated that the improved bacterial clearance upon GTS-21 stimulation was accompanied by enhanced recruitment of monocytes into the peritoneal cavity and simultaneously increased phagocytic activity and iNOS expression of these recruited monocytes. Mechanically, splenectomy prior to administration of GTS-21 attenuated the recruitment of monocytes into the peritoneal cavity and abolished the protective benefits of GTS-21 treatment. Meanwhile, GTS-21 administration accelerates the deployment of splenic monocytes during septic peritonitis. Collectively, these data suggested that appropriate selective pharmacological α7nAChR activation promotes monocytes trafficking in a spleen-dependent manner and upregulates the antibacterial activity of recruited monocytes during septic peritonitis, which may be utilized as a promising therapeutic modality for patients suffering from septic peritonitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Liu, Liu, Zhang, Chen, Zhao and Ma.)

Interface phonon modes that are generated by several atomic layers at the heterointerface play a major role in the interface thermal conductance for nanoscale high-power devices such as nitride-based high-electron-mobility transistors and light-emitting diodes. Here we measure the local phonon spectra across AlN/Si and AlN/Al interfaces using atomically resolved vibrational electron energy-loss spectroscopy in a scanning transmission electron microscope. At the AlN/Si interface, we observe various interface phonon modes, of which the extended and localized modes act as bridges to connect the bulk AlN modes and bulk Si modes and are expected to boost the phonon transport, thus substantially contributing to interface thermal conductance. In comparison, no such phonon bridge is observed at the AlN/Al interface, for which partially extended modes dominate the interface thermal conductivity. This work provides valuable insights into understanding the interfacial thermal transport in nitride semiconductors and useful guidance for thermal management via interface engineering., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

The purpose of this study is to construct a pH and redox sensitive nanoparticle to effectively deliver ginsenoside Rh 2 for the treatment of ulcerative colitis (UC). Herein, glycogen was modified by urocanic acid and α-lipoic acid (α-LA) to obtain an amphiphilic polymer (LA-UaGly). Such polymer LA-UaGly could self-assemble to form nanoparticles (Blank NPs) in water with excellent stability, which could also successfully encapsulated ginsenoside Rh 2 to form Rh 2 nanoparticles (Rh 2 NPs) with encapsulation efficiency of 74.36 ± 0.34%. DLS analysis indicated Rh 2 NPs were spherical with a particle size of 128.9 ± 0.3 nm. As expected, Rh 2 NPs exhibited typical pH and redox dual response release behaviour as well as the excellent in vivo safety. In vitro tests showed that Rh 2 NPs could effectively internalize and release Rh 2 into RAW264.7 cells, and protect cells from apoptosis (p < 0.05). More interestingly, Rh 2 NPs exhibited strong anti-inflammatory activity via significantly inhibiting the overproduction of nitric oxide (NO) and inflammatory cytokines (TNF-α, IL-1β and IL-6) (p < 0.05). In vivo experiments suggested that Rh 2 NPs significantly ameliorated the weight loss, colon length, disease activity index (DAI) score, and myeloperoxidase (MPO) activity in mice caused by dextran sulfate sodium salt (DSS) (p < 0.05). Simultaneously, pathological analysis proved that Rh 2 NPs could significantly reduce histological damage and inflammatory infiltration in mice. Rh 2 NPs could also effectively regulate the intestinal flora of mice by improving the species uniformity and abundance of the intestinal flora of mice and restoring the species diversity of the intestinal flora. In addition, both in vivo and in vitro experiments proved that Rh 2 NPs had stronger anti-inflammatory activity than Rh 2 . This study provides a promising strategy for the effective treatment of UC., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: We aim to evaluate the efficacy of 2 different 1-week quadruple therapies given back-to-back consecutive therapy in patients with difficult-to-treat Helicobacter pylori infection., Methods: Patients with proven H. pylori infection were recruited after >3 failed standard quadruple eradication. They received consecutive therapy consisting of esomeprazole 40 mg or rabeprazole 20 mg twice daily, amoxicillin 1,000 mg twice daily, tetracycline 500 mg 4 times daily, and furazolidone 100 mg 3 times daily for the first 7 days, followed by colloidal bismuth pectin 200 mg twice daily in place of furazolidone 100 mg for another 7 days. Eradication rates, treatment-emergent adverse events (TEAEs), and compliance were assessed., Results: Sixty-five patients were enrolled. The mean number of previous eradications was 3.6 (range: 3-7). The intention-to-treat and per-protocol eradication rates were 90.8% (59/65) and 95.1% (58/61). In total, 23.4% (15/64) of patients experienced drug-related TEAEs. No serious adverse events were observed. None of the patients required treatment for TEAEs, and 95.3% (61/64) showed good compliance. Overall, 51 patients (78.5%) were with the available antimicrobial susceptibility testing results. The resistance rates to clarithromycin, metronidazole, levofloxacin, and amoxicillin were 60.8% (31/51), 100% (51/51), 70.6% (36/51), and 2.0% (1/51), respectively. No resistance was detected to either furazolidone or tetracycline. However, in 54.9% of patients (28/51), H. pylori was resistant to 3 antibiotics (metronidazole, levofloxacin, and clarithromycin)., Discussion: Consecutive therapy, including amoxicillin, tetracycline, and furazolidone, achieved a good eradication rate (>90%), with desirable compliance and tolerability in difficult-to-treat H. pylori infection., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

This study investigated the antioxidant effects of whey protein peptide on learning and memory in aging C57BL/6N mice. A total of 72 SPF male C57BL/6N mice were used. Twelve mice were randomly selected as the control group, and the other mice were intraperitoneally injected with D-galactose (100 mg/kg body weight for 6 weeks), during which, the mice in the control group were intraperitoneally injected with the same amount of normal saline. After 6 weeks, the blood was taken from the epicanthus and the serum MDA level was measured, according to which, the mice were randomly divided into the model control group, the whey protein group (1.5 g/kg body weight), and three Whey protein peptide (WHP) intervention groups (0.3 g/kg body weight, 1.5 g/kg body weight, 3.0 g/kg body weight). The water solution of the test sample was administered by oral gavage every day. The intervention period was 30 days, during which, the model control group, the whey protein group, and the whey protein peptide group continued receiving intraperitoneal injections of D-galactose, while the control group continued receiving intraperitoneal injections of normal saline. After the intervention, behavioral experiments were conducted in the following order: open field test, water maze test, and new object recognition test. After the behavioral experiment, the morphology of hippocampal formation was observed by HE staining and TUNEL labeling. Oxidative stress-related indexes in the serum, liver, and brain were detected. Expression levels of the cholinergic system-related enzymes and proinflammatory cytokines in brain tissue were detected. Western blot was used to detect the expression of synaptic plasticity-related proteins in the mouse brain. The results showed that WHP could significantly improve the accumulation of MDA and PC, increase the activities of SOD and GSH-Px, resist oxidative stress injury, and enhance the potential of endogenous antioxidant defense mechanisms. WHP can significantly improve the decline of aging-related spatial exploration, body movement, and spatial and non-spatial learning/memory ability. Its specific mechanism may be related to reducing the degeneration of hippocampal nerve cells, reducing the apoptosis of nerve cells, improving the activity of AChE, reducing the expression of inflammatory factors (TNF-α and IL-1β) in brain tissue, reducing oxidative stress injury, and improving the expression of p-CaMKⅡ and BDNF synaptic plasticity protein. These results indicate that WHP can improve aging-related oxidative stress, as well as learning and memory impairment.

Although the abilities of the omentum to alleviate inflammation and prevent infection have been revealed over the past decades, the underlying mechanisms remain largely unelucidated. Here, we demonstrated that the mortality of mice exposed to cecal ligation and puncture (CLP) and omentectomy was remarkably increased compared to those treated with CLP alone. Moreover, the efficacy of the omentum was associated with an impairment in intraperitoneal bacterial clearance together with an increase in the expression of proinflammatory cytokines. Besides, in response to peritoneal infections, the size and quantity of the omental milky spots (MSs) were increased tremendously and they also support innate-like B1 cell responses and local IgM production in the peritoneal cavity. Furthermore, not only the migration but also the functional activities of neutrophils were diminished in the absence of the omentum. These data collectively show that the omentum contributes more to peritoneal immune responses during septic peritonitis than has heretofore been recognized. Thus, harnessing the function of MS-containing omentum to increase its protective effectiveness may exert important biological and therapeutic implications for the control of intra-abdominal infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Hu, Luo, Zhao, Liu, Ma and Yao.)

Radiation therapy is widely used in the treatment of tumor diseases, but it can also cause serious damage to the body, so it is necessary to find effective nutritional supplements. The main purpose of this study is to evaluate the protective effect of whey hydrolysate peptides (WHPs) against 60 Coγ radiation damage in mice and explore the mechanism. BALB/c mice were given WHPs by oral gavage administration for 14 days. Then, some mice underwent a 30-day survival test after 8 Gy radiation, and other mice received 3.5 Gy radiation to analyze the changes in body weight, hematology and bone marrow DNA after three and 14 days. In addition, through further analysis of the level of oxidative stress and intestinal barrier function, the possible mechanism of the radioprotective effect of WHPs was explored. The study found WHPs can prolong survival time, restore body weight, and increase the number of peripheral blood white blood cells and bone marrow DNA content in irradiated mice. In addition, WHPs can significantly improve the antioxidant capacity, inhibit pro-inflammatory cytokines and protect the intestinal barrier. These results indicate that WHPs have a certain radioprotective effect in mice, and the main mechanism is related to reducing oxidative damage.

Background: Cisplatin is one of the most common chemotherapeutic drugs. Cisplatin-induced toxicity gives rise to gastrointestinal cell damage, subsequent diarrhea and vomiting, leading to the discontinuation of its clinical application in long-term cancer chemotherapy. Panax quinquefolium L., also known as American ginseng, has many pharmacological activities such as improving immunity, anti-tumor, anti-radiation and blood sugar lowering., Purpose: Previously, our laboratory reported that American ginseng berry extract could alleviate chemotherapeutic agents-induced renal damage caused by cisplatin. Hence, this study further explored the protective effect of P. quinquefolium saponins (PQS) on cisplatin-induced intestinal injury in mice and the possible molecular mechanisms., Methods: Biochemical markers, levels of inflammatory factors, histopathological staining and western blotting were used to analyze intestinal injury based on various molecular mechanisms., Results: We demonstrated the destruction of the intestinal barrier caused by cisplatin exposure by detecting the activity of diamine oxidase (DAO) and the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin. Meanwhile, cisplatin exposure changed SOD and MDA levels in the small intestine, causing oxidative damage to the intestinal mucosa. The inflammation associated-intestinal damage was further explored by the measurement of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and analysis of nuclear factor-kappa B (NF-κB) inflammatory pathway protein expression. Moreover, apoptotic cells labeled with TUNEL staining-positive cells and activated caspase family proteins suggest that cisplatin induces intestinal apoptosis. Interestingly, PQS pretreatment significantly reversed these situations., Conclusion: These evidences clearly suggest that PQS can alleviate cisplatin-induced intestinal damage by inhibiting oxidative stress, reducing the occurrence of inflammation and apoptosis, and improving intestinal barrier function., (Copyright © 2020. Published by Elsevier GmbH.)

Cisplatin, as one of the most effective chemotherapeutic agents, its clinical use is limited by serious side effect of nephrotoxicity. Cisplatin-induced nephrotoxicity is closely related to apoptosis induction and activation of caspase. The present study aimed to explore the potential protective effect of ginsenoside Rk1 (Rk1), a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity and the underlying mechanisms in human embryonic kidney 293 (HEK-293) cells. Our results showed that the reduced cell viability induced by cisplatin could significantly recover by Rk1. Furthermore, glutathione (GSH) as an oxidative index, was elevated and the lipid peroxidation product malondialdehyde (MDA) was significantly decreased after Rk1 treatment compared to the cisplatin group. Additionally, Rk1 can also decrease the ROS fluorescence expression and increase the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) compared to the cisplatin group, which suggested a suppression of oxidative response. More importantly, the cisplatin-induced elevated protein levels of Bax, cleaved caspase-3, cleaved caspase-9, and decreased protein level of Bcl-2 were reversed after treatment with Rk1. Our results elucidated the possible protective mechanism of Rk1 for the first time, which may involve in its anti-oxidation and anti-apoptosis effects., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

The aim of this study is to review and discuss the literature on the utilization of magnetic resonance imaging (MRI) in investigating the structure and feasible function of the myodural bridge complex (MDBC) with relevant muscles, which will be useful to understand the function of the MDB. The myodural bridge (MDB) is a soft tissue connective bridge that provides a fascial continuity between the musculature/ligament and cervical spinal dura mater (SDM) in the suboccipital areas. All of these involved structures are referred to as the MDBC. It would transfer tensile forces effectively from involved suboccipital muscles/ligament to SDM during head movement. Despite present achievements, its anatomic and functional role is still unclear. MRI enables not only in vivo visualization of ligaments, musculature and spinal dura with conventional T 1 W, T 2 W and PDW imaging, but also functional evaluation of MDBC with relevant muscles, such as muscles' fatty infiltration, cross-sectional area changes and injuries. Though some functional MRI techniques have not been used for the MDBC with relevant muscles now, these techniques have great potential to better understand function of MDBC including its suspected clinical role. MRI is likely the most powerful tool to study MDBC and relevant muscles with only limited exploration so far., Competing Interests: The authors have no conflict of interest.

Background: Surgeon suturing technology plays a pivotal role in patient recovery after laparoscopic surgery. Intracorporal suturing and knot tying in minimally invasive surgery are particularly challenging and represent a key skill for advanced procedures. In this study, we compared the application of multidirectional stitching technology with application of the traditional method in a laparoscopic suturing instructional program., Methods: We selected forty residents within two years of graduation to assess the specialized teaching of laparoscopic suturing with laparoscopic simulators. The forty students were randomly divided into two groups, a control group and an experimental group, with twenty students in each group. The control group was scheduled to learn the traditional suture method, and the experimental group applied multidirectional stitching technology. The grades for suturing time, thread length, accuracy of needle entry, stability of the knot, tissue integrity, and tightness of the tissue before and after the training program were calculated., Results: There was no significant difference between the two groups before the learning intervention. After the program, both groups significantly improved in each subject. There were significant differences between the control group and the experimental group in suture time (P = 0.001), accuracy of needle entry and exit (P = 0.035), and whether the suture tissue had cracks (P = 0.030). However, the two groups showed non-significant differences in thread length (P = 0.093), stablity of the knot (P = 0.241), or tightness of the tissue (P = 0.367)., Conclusions: Multidirectional stitching technology improves the efficiency and effectiveness of traditional laparoscopic suture instructional programs. It might be a practicable, novel training method for acquiring proficiency in manual laparoscopic skills in a training setting.

Background: Vasculogenic mimicry (VM), defined as a capability of aggressive tumor Cells to mimic embryonic vasculogenic networks, caused poor prognosis in hepatocellular carcinoma (HCC). Rho kinases (ROCK), p21-activated kinase (PAK), hypoxia or epithelial-mesenchymal transition (EMT) contributed to the VM potential. However, the details underlying these biological behaviors have not been completely elucidated., Methods: Kaplan-Meier analysis was conducted to predict relationship with hypoxia Inducible factor (HIF-1α), EMT related markers: Vimentin and patient prognosis. CD34/periodic acid-Schiff (PAS) double staining was examined to differentiate VM-positive (VM+) and VM-negative (VM-) samples. Cells were cultured under controlled hypoxic environments (1% O2) or normoxic conditions. The effect of hypoxia on RhoA/ROCK, Rac1/PAK and EMT were evaluated by real time-qPCR and western blot. HIF-1α small interfering RNA (siRNA), overexpressed or short hairpin RNA (shRNA) of ROCK and kinase inhibitors were used to explore the effect of HIF-1α, RhoA/ROCK, Rac1/PAK and Vimentin on VM., Results: HIF-1α or Vimentin was upregulated in VM+ HCC tissues, compared to non-cancerous tissues (P < 0.01), and patients with high expression of HIF-1α or Vimentin had worse prognosis (P < 0.001). We showed hypoxia induced RhoA/ROCK and Rac1/PAK signaling transduction, and EMT could be repressed by HIF-1α siRNA. Notably, RhoA/ROCK or Rac1/PAK stabilized HIF-1α in hypoxia, whereas HIF-1α did not significantly altered RhoA/ROCK or Rac1/PAK signaling in hypoxia. Moreover, we found distinct roles of ROCK1, ROCK2 and PAK in regulating Vimentin phosphorylation., Conclusions: RhoA/ROCK and Rac/PAK signaling played crucial roles in hypoxia-induced VM via Ser72 and Ser56 Vimentin phosphorylation in HCC.

Objective: Invasive breast cancer (BRCA) is one of the prevalent types of invasive tumors with high mortality worldwide. Due to the lack of effective treatment to control the recurrence of distant metastases, the prognosis of BRCA is still very unsatisfactory. We aimed to find some biomarkers by bioinformatics analysis for survival prediction., Methods: Differentially expressed genes (DEGs) were screened out based on tumor group and normal group. Then, the weighted gene correlation network analysis (WGCNA) was employed to identify the clinically associated gene sets. Meanwhile, the enrichment analyses were performed for the functional annotation of the critical genes. The Kaplan Meier analysis calculated the essential genes' prognostic value., Results: After threshold screening, 1655 DEGs were obtained for subsequent analysis. 51 out of 1655 DEGs were significantly associated with BRCA patients' estrogen receptor status via WGCNA. Three genes (FABP7, CXCL3, and LOC284578) out of the 51 genes were associated with overall survival, and 3 genes were relapse-free survival associated. Finally, we obtained 5 essential prognostic associated genes (FABP7, CXCL3, LOC284578, CAPN6, and NRG2), which could be used as prognostic factors for BRCA., Conclusion: Our findings obtained a gene module associated with BRCA clinical trait and several key genes that acted as essential components in the prognostic of cancer, which may improve its treatment.

Background: Biomechanical studies have demonstrated that cortical bone trajectory (CBT) screw can provide a 30% increase in uniaxial yield pullout load than pedicle screw (PS). In addition, the insertion torque of CBT screw is 1.71 times higher than that of PS. A meta-analysis was conducted to evaluate clinical results between CBT screw technique and PS technique in lumbar fusion surgery., Methods: An extensive search of literature was performed in PubMed, Embase, the Cochrane library. The following outcomes were extracted: visual analog scale (VAS), Oswestry disabilities index (ODI), Japanese Orthopaedic Association (JOA) score, complications, fusion rates, hospital stay, incision length, blood loss, and operation time. Data analysis was conducted with RevMan 5.3 and STATA 12.0., Results: A total of 12 studies were included in the final analysis. The results indicated that CBT group with less blood loss [P < .01], less hospital stay [P < .01], and less incision length [P < .01] than PS group. There were no significant differences between 2 groups in other clinical parameters and outcomes., Conclusion: CBT technique provided similar clinical outcomes and fusion rates compared to PS technique in lumbar fusion surgery. However, CBT technique provided additional benefits of less blood loss, less hospital stay, and less incision length.

Vasculogenic mimicry (VM) results in the formation of an alternative circulatory system that can improve the blood supply to multiple malignant tumors, including hepatocellular carcinoma (HCC). However, the potential mechanisms of RhoC/ROCK in VM have not yet been investigated in HCC. Here, RhoC expression was upregulated in HCC tissues, especially the VM-positive (VM+) group, compared to noncancerous tissues (P < 0.01), and patients with high expression of RhoC had shorter survival times (P < 0.001). The knockdown of RhoC via short hairpin RNA (shRNA) in SK-Hep-1 cells significantly decreased VM formation and cell motility. In contrast, cell motility and VM formation were remarkably enhanced when RhoC was overexpressed in HepG2 cells. To further assess the potential role of ROCK1 and ROCK2 on VM, we stably knocked down ROCK1 or ROCK2 in MHCC97H cells. Compared to ROCK1 shRNA, ROCK2 shRNA could largely affect VM formation, cell motility and the key VM factors, as well as the epithelial-mesenchymal transition (EMT) markers in vitro and in vivo. Moreover, p-ERK, p-MEK, p-FAK, p-paxillin, MT1-MMP and MMP2 levels were clearly altered following the overexpression of RhoC, but ROCK2 shRNA had little effect on the expression of p-FAK, which indicated that RhoC regulates FAK/paxillin signaling, but not through ROCK2. In conclusion, our results show that RhoC/ROCK2 may have a major effect on VM in HCC via ERK/MMPs signaling and might be a potential therapeutic target for the treatment of HCC., (Copyright © 2018. Published by Elsevier B.V.)

Background: Frequent overdose of paracetamol (APAP) has become the major cause of acute liver injury. The present study was designed to evaluate the potential protective effects of ginsenoside Rk1 on APAP-induced hepatotoxicity and investigate the underlying mechanisms for the first time., Methods: Mice were treated with Rk1 (10 mg/kg or 20 mg/kg) by oral gavage once per d for 7 d. On the 7th d, all mice treated with 250 mg/kg APAP exhibited severe liver injury after 24 h, and hepatotoxicity was assessed., Results: Our results showed that pretreatment with Rk1 significantly decreased the levels of serum alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor, and interleukin-1β compared with the APAP group. Meanwhile, hepatic antioxidants, including superoxide dismutase and glutathione, were elevated compared with the APAP group. In contrast, a significant decrease in levels of the lipid peroxidation product malondialdehyde was observed in the ginsenoside Rk1-treated group compared with the APAP group. These effects were associated with a significant increase of cytochrome P450 E1 and 4-hydroxynonenal levels in liver tissues. Moreover, ginsenoside Rk1 supplementation suppressed activation of apoptotic pathways by increasing Bcl-2 and decreasing Bax protein expression levels, which was shown using western blotting analysis. Histopathological observation also revealed that ginsenoside Rk1 pretreatment significantly reversed APAP-induced necrosis and inflammatory infiltration in liver tissues. Biological indicators of nitrative stress, such as 3-nitrotyrosine, were also inhibited after pretreatment with Rk1 compared with the APAP group., Conclusion: The results clearly suggest that the underlying molecular mechanisms in the hepatoprotection of ginsenoside Rk1 in APAP-induced hepatotoxicity may be due to its antioxidation, antiapoptosis, anti-inflammation, and antinitrative effects.

Background: Similar to the leaves of P. Quinquefolius, American ginseng berry (AGB) is another important part of P. Quinquefolius with alternative therapeutic potential. The liver protection capabilities of the former have been demonstrated previously, however, the later has not yet been evaluated., Purpose: Based on our previous observation, the present work was designed to evaluate the hepatic protective effects for novel mechanisms of AGB in acetaminophen (APAP)-induced liver injury in vivo., Study Design/methods: All mice were divided into four groups as follows: normal group, APAP group and APAP + AGB (150 mg/kg and 300 mg/kg) groups. AGB were orally administered for one week before exposure to APAP (250 mg/kg). Severe liver injury was observed and hepatotoxicity was evaluated after 24 h through evaluating the biochemical markers, protein expressions levels and liver histopathology., Results: Our study results clearly demonstrated that AGB pretreatment ameliorated APAP-induced hepatic injury as evidenced by decreasing plasma alanine aminotransferase (ALT), aspartate transaminase (AST), tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) compared to the APAP group. Western blotting analysis showed that pretreatment with AGB decreased the expressions levels of TNF-α and nuclear transcription factor-κB (NF-κB p65) in liver tissues. Meanwhile, the protein expression levels of caspases, cytochrome c, and Bax were elevated by AGB treatment for seven days, while the protein expression level of Bcl-2 was inhibited comparison with that in APAP group. Furthermore, supplement of AGB resulted in increase of superoxide dismutase (SOD) and glutathione (GSH), while decrease of malondialdehyde (MDA) content and the expression levels of 4-hydroxynonenal (4-HNE) and cytochrome P450 E1 (CYP2E1). The results of histopathological staining demonstrated that AGB pretreatment inhibited APAP-induced hepatocyte infiltration, congestion, and necrosis., Conclusion: The present study demonstrated that AGB pretreatment protected liver cells against APAP-induced hepatotoxicity through inhibition of oxidative stress, inflammation responses via TNF-α-mediated caspase-3/-8/-9 signaling pathways., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Cisplatin, a potent anticancer drug, is usually causing nephrotoxicity; limiting its therapeutic application and efficiency. Maltol may be used to prevent such toxic effect. The aim of this study was to investigate the underlying protective mechanisms of maltol on nephrotoxicity by cisplatin using a cisplatin-treated mouse model and a cellular toxicity model of HEK293 cells. The blood urea nitrogen (BUN), creatinine (CRE) and neutrophil gelatinase-associated lipocalin (NGAL) levels in mice were increased by cisplatin but decreased to normal ranges by maltol pretreatment (50 and 100 mg/kg) for ten days. Besides, maltol pretreatment decreased oxidative stress, lipid peroxidation and apoptosis in cisplatin-treated mice. The inhibitory action of maltol on inflammatory responses was achieved by reducing the expressions in NF-κB, IL-1β, iNOS, and TNF-α in the mice in vivo. Additionally, maltol restored the reduction of PI3K/Akt and mTOR levels by cisplatin through increasing AMPK expression in cisplatin-treated HEK293 cells. Maltol also suppressed the expression of Bax and caspase 3 by inhibiting the p53 activity in HEK293 cells. Overall, maltol may serve as a valuable potential drug to prevent cisplatin-induced nephrotoxicity, and the underlying molecular mechanisms of maltol action may involve intracellular AMPK/PI3K/Akt and p53 signaling pathways.

Chemo-resistance is a serious obstacle for successful treatment of cancer. Apigenin, a dietary flavonoid, has been reported as an anticancer drug in various malignant cancers. This study aimed to investigate the potential chemo-sensitization effect of apigenin in doxorubicin-resistant hepatocellular carcinoma cell line BEL-7402/ADM. We observed that apigenin significantly enhanced doxorubicin sensitivity, induced miR-520b expression and inhibited ATG7-dependent autophagy in BEL-7402/ADM cells. In addition, we also showed that miR-520b mimics increased doxorubicin sensitivity and inhibited ATG7-dependent autophagy. Meanwhile, we indicated that ATG7 was a potential target of miR-520b. Furthermore, APG inhibited the growth of hepatocellar carcinoma xenografts in nude mice by up-regulating miR-520b and inhibiting ATG7. Our finding provides evidence that apigenin sensitizes BEL-7402/ADM cells to doxorubicin through miR-520b/ATG7 pathway, which furtherly supports apigenin as a potential chemo-sensitizer for hepatocellular carcinoma., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background : Frequent overdosing of acetaminophen (APAP) has become the major cause of acute liver injury (ALI). The present study aimed to evaluate the potential hepatoprotective effects of black ginseng (BG) on APAP-induced mice liver injuries and the underlying mechanisms of action were further investigated for the first time. Methods : Mice were treated with BG (300, 600 mg/kg) by oral gavage once a day for seven days. On the 7th day, all mice were treated with 250 mg/kg APAP which caused severe liver injury after 24 h and hepatotoxicity was assessed. Results : Our results showed that pretreatment with BG significantly decreased the levels of serum alanine aminotransferase (ALT) and aspartate transaminase (AST) compared with the APAP group. Meanwhile, hepatic antioxidant including glutathione (GSH) was elevated compared with the APAP group. In contrast, a significant decrease of the levels of the lipid peroxidation product malondialdehyde (MDA) was observed in the BG-treated groups compared with the APAP group. These effects were associated with significant increases of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) levels in liver tissues. Moreover, BG supplementation suppressed activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax protein expression levels according to western blotting analysis. Histopathological examination revealed that BG pretreatment significantly inhibited APAP-induced necrosis and inflammatory infiltration in liver tissues. Biological indicators of nitrative stress like 3-nitrotyrosine (3-NT) were also inhibited after pretreatment with BG, compared with the APAP group. Conclusions : The results clearly suggest that the underlying molecular mechanisms of action of BG-mediated alleviation of APAP-induced hepatotoxicity may involve its anti-oxidant, anti-apoptotic, anti-inflammatory and anti-nitrative effects.

The aim of this study was to investigate the effects of 5-hydroxymethyl-2-furfural (5-HMF) on liver fibrosis induced by carbon tetrachloride (CCl 4 ) and alcohol. Male ICR mice were treated with CCl 4 dissolved in olive oil (10% v/v, 2.5 μg/L) intraperitoneally (i.p.), and given at a dose of 2.5×10 -5 mg/kg B.W. twice a week for 7 wk. Concurrently, mice received drinking water with or without alcohol. The mice in treatment groups and positive control group were gavaged with 5-HMF (7.5, 15, and 30 mg/kg B.W.) or Huganpian (350 mg/kg B.W.) daily starting in the fourth week and lasting for 4 wk. The blood samples were analyzed for biochemical markers of hepatic injury and tissue samples were subjected for estimation of liver antioxidants and histopathological studies. The concentrations of HA (hyaluronic acid), LN (laminin), CIV (collagen type IV), and MDA (malondialdehyde), as well as the serum levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase) were markedly reduced by 5-HMF. On the other hand, enzymatic antioxidants SOD (superoxide dismutase), CAT (catalase) and GSH-Px (glutathione peroxidase) were markedly elevated in liver tissue treated with 5-HMF. Histopathological examination revealed that 5-HMF treatment noticeably prevented hepatocyte apoptosis, fatty degeneration and inflammatory cell infiltration on liver fibrosis induced by CCl 4 and alcohol. Hoechst 33258 staining also revealed hepatocyte apoptosis. 5-HMF could exert protective effects against liver injury and reduce liver fibrosis induced by CCl 4 and alcohol in mice.

Proanthocyanidins have been shown to effectively protect ischemic neurons, but its mechanism remains poorly understood. Ginkgo proanthocyanidins (20, 40, 80 mg/kg) were intraperitoneally administered 1, 24, 48 and 72 hours before reperfusion. Results showed that ginkgo proanthocyanidins could effectively mitigate neurological disorders, shorten infarct volume, increase superoxide dismutase activity, and decrease malondialdehyde and nitric oxide contents. Simultaneously, the study on grape seed proanthocyanidins (40 mg/kg) confirmed that different sources of proanthocyanidins have a similar effect. The neurological outcomes of ginkgo proanthocyanidins were similar to that of nimodipine in the treatment of cerebral ischemia/reperfusion injury. Our results suggest that ginkgo proanthocyanidins can effectively lessen cerebral ischemia/reperfusion injury and protect ischemic brain tissue and these effects are associated with antioxidant properties., Competing Interests: Zhejiang Conba Pharmaceutical Co., Ltd. provided financial support.

Aim: To investigate the anticancer effect of a recombinant adenovirus-mediated p53 (rAd-p53) combined with 5-fluorouracil (5-FU) in human colon cancer resistant to 5-FU in vivo and the mechanism of rAd-p53 in reversal of 5-FU resistance., Methods: Nude mice bearing human colon cancer SW480/5-FU (5-FU resistant) were randomly assigned to four groups (n = 25 each): control group, 5-FU group, rAd-p53 group, and rAd-p53 + 5-FU group. At 24 h, 48 h, 72 h, 120 h and 168 h after treatment, 5 mice were randomly selected from each group and sacrificed using an overdose of anesthetics. The tumors were removed and the protein expressions of p53, protein kinase C (PKC), permeability-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) (Western blot) and apoptosis (TUNEL) were determined., Results: The area ratios of tumor cell apoptosis were larger in the rAd/p53 + 5-FU group than that in the control, 5-FU and rAd/p53 groups (P < 0.05), and were larger in the rAd/p53 group than that of the control group (P < 0.05) and the 5-FU group at more than 48 h (P < 0.05). The p53 expression was higher in the rAd/p53 and the rAd/p53 + 5-FU groups than that of the control and 5-FU groups (P < 0.05), and were higher in the rAd/p53 + 5-FU group than that of the rAd/p53 group (P < 0.05). Overexpression of PKC, P-gp and MRP1 was observed in the 5-FU and control groups. In the rAd/p53 + 5-FU group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups (P < 0.05), and the expression of PKC was lower than that of the control, 5-FU and rAd/p53 groups at more than 48 h (P < 0.05). In the rAd/p53 group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups at more than 48 h (P < 0.05), and the expression of PKC was lower than that of the control and 5-FU groups at more than 120 h (P < 0.05)., Conclusion: 5-FU combined with rAd-p53 has a synergistic anticancer effect in SW480/5-FU (5-FU resistance), which contributes to reversal of 5-FU resistance.

Ginsenoside Rh2 is a potential pharmacologically active metabolite of ginseng. Previously, we have reported that an octyl ester derivative of ginsenoside Rh2 (Rh2-O), has been confirmed to possess higher bioavailability and anticancer effect than Rh2 in vitro. In order to better assess the possibility that Rh2-O could be used as an anticancer compound, the underlying mechanism was investigated in this study. The present results revealed that lysosomal destabilization was involved in the early stage of cell apoptosis in HepG2 cells induced by Rh2-O. Rh2-O could induce an early lysosomal membrane permeabilization with the release of lysosomal protease cathepsins to the cytosol in HepG2 cells. The Cat B inhibitor (leu) and Cat D inhibitor (pepA) inhibited Rh2-O-induced HepG2 apoptosis as well as tBid production and Δφm depolarization, indicating that lysosomal permeabilization occurred upstream of mitochondrial dysfunction. In addition, Rh2-O induced a significant increase in the protein levels of DRAM1 and Bax (p < 0.05) in lysosomes of HepG2 cells. Knockdown of Bax partially inhibited Rh2-O-induced Cat D release from lysosomes. Thus it was concluded that Rh2-O induced apoptosis of HepG2 cells through activation of the lysosomal-mitochondrial apoptotic pathway involving the translocation of Bax to the lysosome.

The majority of previous studies on hereditary neuropathy with liability to pressure palsies (HNPP) were focused on peripheral nerves, whereas cerebral alterations in HNPP have been less attended to. In this work, Diffusion tensor imaging (DTI) was used to detect the changes in WM, especially in the normal-appearing white matter (NAWM) in HNPP patients for its sensitivity in probing the microstructure of WM, the sensitive metric was searched for probing cerebral alterations and the regional distribution of cerebral abnormalities was identified. Twelve HNPP patients and 12 age- and gender-matched healthy controls underwent the conventional MRI, DTI scan, and electrophysiological examination. The conventional MRI images were first analyzed to identify abnormal intense regions and the NAWM regions. NAWM refers to the white matter regions that do not include the lesions on conventional MRI. The apparent diffusion coefficient and fractional anisotropy (FA) values of the NAWM were then measured and compared between patient and control groups. The sensitivity and specificity of 3 methods and the cerebral regional distribution of MR signal abnormalities were further analyzed. Hyperintense foci were observed on T2 weighted image and fluid attenuated inversion recovery images in 6 patients. Compared to the controls, FA values of the patients were significantly lower in bilateral frontal, orbitofrontal, and temporal NAWMs; whereas the electrophysiological examination results of patients and controls exhibited no statistically significant difference. The sensitivity of FA value was higher than that of electrophysiological examination and conventional MRI. The majority of abnormal signals on conventional MRI images and abnormal FA values were located in the frontal and temporal lobes. The results of our study show cerebral WM changes in HNPP patients. FA value in DTI has been shown to be sensitive to the cerebral microstructural changes in HNPP. The frontal lobe is the predilection site that is most involved in HNPP.

Aim: To determine whether the combination of platelet count (PLT) with spleen volume parameters and right liver volume (RV) measured by magnetic resonance imaging (MRI) could predict the Child-Pugh class of liver cirrhosis and esophageal varices (EV)., Methods: Two hundred and five cirrhotic patients with hepatitis B and 40 healthy volunteers underwent abdominal triphasic-enhancement MRI and laboratory examination of PLT in 10(9)/L. Cirrhotic patients underwent endoscopy for detecting EV. Spleen maximal width (W), thickness (T) and length (L) in mm together with spleen volume (SV) and RV in mm(3) were measured by MRI, and spleen volume index (SI) in mm(3) was obtained by W × T × L. SV/PLT, SI/PLT and RV × PLT/SV (RVPS) were calculated and statistically analyzed to assess cirrhosis and EV., Results: SV/PLT (r = 0.676) and SI/PLT (r = 0.707) increased, and PLT (r = -0.626) and RVPS (r = -0.802) decreased with the progress of Child-Pugh class (P < 0.001 for all). All parameters could determine the presence of cirrhosis, distinguish between each class of Child-Pugh class, and identify the presence of EV [the areas under the curve (AUCs) = 0.661-0.973]. Among parameters, RVPS could best determine presence and each class of cirrhosis with AUCs of 0.973 and 0.740-0.853, respectively; and SV/PLT could best identify EV with an AUC of 0.782., Conclusion: The combination of PLT with SV and RV could predict Child-Pugh class of liver cirrhosis and identify the presence of esophageal varices.

Aim: To investigate whether liver lobe volume and albumin (ALB) could predict the presence and severity of liver cirrhosis, and esophageal varices., Methods: Seventy-one cirrhotic patients with hepatitis B and 21 healthy individuals were enrolled in this study. All the participants underwent abdominal enhanced magnetic resonance imaging to measure each liver lobe volume, and biochemical workup for testing ALB and Child-Pugh class. All cirrhotic patients underwent upper gastrointestinal endoscopy to show the presence of cirrhotic esophageal varices. Right liver lobe volume (RV), left medial liver lobe volume (LMV), left lateral liver lobe volume (LLV), and caudate lobe volume (CV) were measured using enhanced magnetic resonance imaging. The ratios of RV to ALB (RV/ALB), LMV to ALB (LMV/ALB), LLV to ALB (LLV/ALB) and CV to ALB (CV/ALB) were calculated. Statistical analyses were performed to determine whether and how the combination of liver lobe volume measured using magnetic resonance imaging and albumin could predict the presence and severity of liver cirrhosis, and the presence of esophageal varices., Results: RV, LMV, LLV and CV decreased (r = -0.51-0.373; all P < 0.05), while RV/ALB increased (r = 0.424; P < 0.05), with the progress of Child-Pugh class of liver cirrhosis. RV, LMV, CV, LLV/ALB and CV/ALB could identify presence of liver cirrhosis; LLV and LMV could distinguish Child-Pugh class A from B; RV, LMV, LLV, CV, RV/ALB and LLV/ALB could distinguish class A from C; RV and LLV/ALB could differentiate B from C; and RV, RV/ALB and CV/ALB could identify presence of esophageal varices (all P < 0.05). Among these parameters, CV/ALB could best identify the presence of liver cirrhosis, with an area under receiver operating characteristic curve (AUC) of 0.860, a sensitivity of 82.0% and a specificity of 83.0%. LLV could best distinguish class A from B, with an AUC of 0.761, a sensitivity of 74.4% and a specificity of 73.1%. RV could best distinguish class A from C, with an AUC of 0.900, a sensitivity of 90.3% and a specificity of 84.5%. LLV/ALB could best distinguish class B from C, with an AUC of 0.900, a sensitivity of 93.8% and a specificity of 81.5%. RV/ALB could best identify esophageal varices, with an AUC of 0.890, a sensitivity of 80.0% and a specificity of 83.5%., Conclusion: The combination of liver lobe volume and ALB has potential to identify presence and severity of cirrhosis, and presence of esophageal varices.

The purpose of this study was to evaluate the hepatoprotective effect of maltol, a food-flavoring agent, on alcohol-induced acute oxidative damage in mice. Maltol used in this study was isolated from red ginseng (Panax ginseng C.A Meyer) and analyzed by high performance liquid chromatography (HPLC) and mass spectrometry. For hepatoprotective activity in vivo, pretreatment with maltol (12.5, 25 and 50 mg/kg; 15 days) drastically prevented the elevated activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and triglyceride (TG) in serum and the levels of malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) in liver tissue (p < 0.05). Meanwhile, the levels of hepatic antioxidant, such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) were elevated by maltol pretreatment, compared to the alcohol group (p < 0.05). Histopathological examination revealed that maltol pretreatment significantly inhibited alcohol-induced hepatocyte apoptosis and fatty degeneration. Interestingly, pretreatment of maltol effectively relieved alcohol-induced oxidative damage in a dose-dependent manner. Maltol appeared to possess promising anti-oxidative and anti-inflammatory capacities. It was suggested that the hepatoprotective effect exhibited by maltol on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties.

Industry-generated trans-fatty acids (TFA) are detrimental to risk of CHD, but ruminant-originated TFA have been reported as neutral or equivocal. Therefore, the total TFA amount should not be the only factor considered when measuring the effects of TFA. In the present study, we addressed whether a version of the TFA index that unifies the effects of different TFA isomers into one equation could be used to reflect CHD risk probability (RP). The present cross-sectional study involved 2713 individuals divided into four groups that represented different pathological severities and potential risks of CHD: acute coronary syndrome (ACS, n 581); chronic coronary artery disease (CCAD, n 631); high-risk population (HRP, n 659); healthy volunteers (HV, n 842). A 10-year CHD RP was calculated. Meanwhile, the equation of the TFA index was derived using five TFA isomers (trans-16 : 1n-7, trans-16 : 1n-9, trans-18 : 1n-7, trans-18 : 1n-9 and trans-18 : 2n-6n-9), which were detected in the whole blood, serum and erythrocyte membranes of each subject. The TFA index and the 10-year CHD RP were compared by linear models. It was shown that only in the erythrocyte membrane, the TFA isomers were significantly different between the groups. In the ACS group, industry-generated TFA (trans-16 : 1n-9, trans-18 : 1n-9 and trans-18 : 2n-6n-9) were the highest, whereas ruminant-originated TFA (trans-16 : 1n-7 and trans-18 : 1n-7), which manifested an inverse relationship with CHD, were the lowest, and vice versa in the HV group. The TFA index decreased progressively from 7·12 to 5·06, 3·11 and 1·92 in the ACS, CCAD, HRP and HV groups, respectively. The erythrocyte membrane TFA index was positively associated with the 10-year CHD RP (R 2 0·9981) and manifested a strong linear correlation, which might reflect the true pathological severity of CHD.

To optimize ginsenosides hydrolyzing beta-glucosidase production from Aspergillus niger, response surface methodology was carried out in two stages. The Plackett-Burman design was achieved to screen the important variables that influence beta-glucosidase production. Among 10 variables (wheat bran, soybean powder, CaCl(2), ginsenosides, KH(2)PO(4), MgSO(4), polyethylene glycol (PEG), medium volume, inoculum size, and stirring speed), it was found that wheat bran, KH(2)PO(4), and stirring speed had significant effect on beta-glucosidase activity due to very low p-values (p<0.05). Subsequently, wheat bran, KH(2)PO(4), and stirring speed were further optimized using central composite design. The optimal beta-glucosidase production was predicted to be 4650.14 U/ml with the combination of factors (wheat bran, 34.51 g/l; KH(2)PO(4), 1.78 g/l; stirring speed, 161.60 rpm/min). Finally, under optimal fermentation conditions, ginsenoside Rb(1) was converted to Rd and F(2) by A. niger within 10 min. Little compound K was detected at 30 min, and finally F(2) was completely transformed to compound K within 8 h. The putative conversion pathway of Rb(1) by A. niger was Rb(1), Rd, F(2), and compound K.

To investigate the anti-obesity effects of escins extracted from the seeds of Aesculus turbinata BLUME, anti-obesity models in vitro and in vivo were employed. In a preliminary experiment, different solvent fractions of Aesculus turbinata BlUME as well as two isolated compounds were tested for their effects on pancreatic lipase (PL) in vitro. Subsequently, female ICR mice were fed a high fat diet with or without different concentrations of total escins for 11 weeks to examine body weight, parametrial adipose tissue weight, and hepatic triacylglycerol (TG) and total cholesterol (TC) contents. Plasma triacylglycerol levels (TG) after oral administration of lipid emulsions to rats were also investigated. The results showed that total escins (1 mg/ml) as well as two compounds isolated from total escins, namely escin Ib and IIa, showed inhibitory effects on PL activity. In vivo, total escins suppressed the increase in body weight, parametrial adipose tissue weight, TG content, and TC content in mice's liver; TG content in rat plasma was also reduced at 1, 2 and 3 h after oral administration of the lipid emulsion plus different concentrations of escins compared to those in the lipid emulsion groups. Meanwhile, mice fed a high fat diet plus 2% total escins for 3 d had an increased TG level in the feces compared to the HF group. The reason for this may be due to a delay in the intestinal absorption of dietary fat by inhibiting PL activity.