Baicalin Ameliorates Radiation-Induced Lung Injury by Inhibiting the CysLTs/CysLT1 Signaling Pathway.

Objective: Radiation-induced lung injury (RILI) is a common complication of radiotherapy for thoracic tumors. This study investigated the alleviating effect of baicalin (BA) on RILI and its possible mechanism. Methods: RILI model was established by chest irradiation (IR) of C57BL/6 mice for 16 weeks. Different concentrations of BA were administered, and dexamethasone (DXM) was used as a positive control. Then, the lung pathological changes were observed by HE and Masson staining. The levels of TGF-ß, TNF-α, IL-1ß, IL-6, CysLT, LTC4, and LTE4 were measured by ELISA. The CysLT1 expression was detected by qPCR, immunohistochemistry, and western blot. Type II AEC cells were pretreated with LTD-4 to establish the RILI cell model and intervened with different concentrations of BA. Then, the collagen I protein level was measured by ELISA. The CysLT1 and α-SMA expression were detected by qPCR, immunofluorescence, and western blot. Results: BA could effectively improve lung histopathological changes and pulmonary fibrosis. In vivo, BA could inhibit the levels of TGF-ß, TNF-α, IL-1ß, and IL-6 and reduce the levels of CysLT, LTC4, and LTE4. In vitro, different concentrations of LTD4 could reduce the viability of type II AEC cells, which could be reversed by the administration of different concentrations of BA. In addition, BA could reduce CysLT1 mRNA, as well as CysLT1 and α-SMA protein levels in vitro and in vivo. Conclusion: BA attenuated lung inflammation and pulmonary fibrosis by inhibiting the CysLTs/CysLT1 pathway, thereby protecting against RILI.

Antioxidant Peptides From Protein Hydrolysate of Marine Red Algae Eucheuma cottonii: Preparation, Identification, and Cytoprotective Mechanisms on H2O2 Oxidative Damaged HUVECs.

To screen, prepare, identify, and evaluate the activities of natural antioxidants for treating chronic diseases caused by oxidative stress. Two algal proteins, namely ZD10 and ZD60, precipitated with 10 and 60% (NH4)2SO4 were extracted from red algae Eucheuma cottonii (E. cottonii) and hydrolyzed using five proteolytic enzymes. The results showed that ZD60 played the most significant role in the enhancement of 2,2-diphenyl-1-picrylhydrazyl radical (DPPH⋅) scavenging activity (25.91 ± 0.24%) among all protein hydrolysates. Subsequently, six antioxidant peptides (EP1-EP6) were isolated from the papain hydrolysate of ZD60 by ultrafiltration and chromatography methods. Their amino acid sequences were identified as Thr-Ala (EP1), Met-Asn (EP2), Tyr-Ser-Lys-Thr (EP3), Tyr-Ala-Val-Thr (EP4), Tyr-Leu-Leu (EP5), and Phe-Tyr-Lys-Ala (EP6) with molecular weights of 190.21, 263.33, 497.55, 452.51, 407.51, and 527.62 Da, respectively. Of which, EP3, EP4, EP5, and EP6 showed strong scavenging activities on DPPH⋅, hydroxyl radical (HO⋅), and superoxide anion radical (O- 2⋅). Moreover, EP4 and EP5 could significantly protect human umbilical vein endothelial cells (HUVECs) from H2O2-induced oxidative damage by increasing the levels of antioxidant enzyme systems including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) to reduce the levels of reactive oxygen species (ROS) (60.51 and 51.74% of model group) and malondialdehyde (MDA) (75.36 and 64.45% of model group). In addition, EP4 and EP5 could effectively inhibit H2O2-induced apoptosis by preventing HUVECs from early apoptosis to late apoptosis. These results indicated that the antioxidant peptides derived from E. cottonii, especially EP4 and EP5, could serve as the natural antioxidants applied in pharmaceutical products to treat chronic cardiovascular diseases caused by oxidative damage, such as coronary heart disease, atherosclerosis, etc.

3,3'-Diindolylmethane attenuates inflammation and fibrosis in radiation-induced lung injury by regulating NF-κB/TGF-ß/Smad signaling pathways.

OBJECTIVE: This study aims to investigate the protective effect of 3,3'-diindolylmethane (DIM) on the radiation-induced lung injury (RILI) model and to explore its possible mechanism. Methods: A mouse model of RILI was established by thoracic irradiation, and dexamethasone was used as a positive drug to investigate the effect of DIM on RILI mice. Lung histopathology was analyzed by HE staining and Masson staining. Then the levels of inflammatory cytokines (TGF-ß, TNF-α, IL-1ß, and IL-6), inflammatory cell counts, and activity of MPO were detected. The expression of TGFß1/Smad signaling pathway-related proteins was determined by immunohistochemistry. qPCR was used to analyze the mRNA expression levels of inflammatory factors, α­SMA and COL1A1. The expression of COX-2, NF-κB, IκBα, PI3K, and Akt proteins was assessed by Western blot. Results: Histopathological staining of lung tissues showed that DIM administration alleviated the pulmonary inflammation and fibrosis caused by RILI. Moreover, the content of inflammatory factors such as IL-1ß and IL-6, the expression of NF-κB pathway-related proteins, and the counts of inflammatory cells were inhibited in lung tissue, indicating that DIM can inhibit the NF-κB pathway to reduce inflammation. In addition, DIM could down-regulate the mRNA levels of α-SMA, COL1A1, and downregulate TGFß1, Smad3, and p-Smad2/3 in lung tissues. Conclusion: Our study confirms that DIM has the potential to treat RILI in vivo by inhibiting fibrotic and inflammatory responses in lung tissue through the TGFß/Smad and NF-κB dual pathways, respectively.

Molecular hydrogen alleviates lung injury after traumatic brain injury: Pyroptosis and apoptosis.

BACKGROUND: Traumatic brain injury (TBI)-induced acute lung injury (ALI) is a critical condition, and inflammation and apoptosis play essential roles. Molecular hydrogen (H2) exerts anti-inflammatory and anti-apoptotic effects. Our previous work has shown that 42% H2 can improve TBI. In the current study, we tested the hypothesis that inhalation of hydrogen (42% H2, 21% O2, balanced nitrogen) for 1 h per day can improve TBI-induced ALI. METHODS: Sprague-Dawley male rats were randomly divided into 3 groups. Except for the sham group (group S), rats were subjected to a fluid percussion injury (FPI) and the H2 treatment group were given inhaled hydrogen for 1 h per day. We evaluated the lung function, pyroptosis and apoptosis at 24 h, 48 h and 72 h. RESULTS: Compared with group S, the rats in the TBI group (group T) showed obvious pulmonary edema after a TBI. Inhalation of high-concentration hydrogen significantly improved the rats. During this process, rats had some tendency to heal on their own, and H2 also accelerated the self-healing process. Lung injury scores, oxygenation index and pulmonary edema were consistent. Compared with group S, the pyroptosis-related proteins Caspase-1, apoptosis-associated speck-like protein containing CARD (ASC) and Gasdermin-D (GSDM-D) in the lung tissues of the rats in group T were significantly increased after a TBI. In the H2 treatment group (group H), these proteins were significantly decreased. The levels of IL-1ß and IL-18 were significantly increased after TBI while in group H were significantly decreased. At the same time, cleaved caspase-3 and BCL-2/Bax were also changed after H2 treatment. These demonstrates the powerful ameliorating effect of H2 on pyroptosis, apoptosis and systemic inflammation. However, rats also had tendency to heal on their own, and H2 also accelerated the self-healing process at the same time. CONCLUSIONS: H2 improves TBI-ALI, and the mechanism may be due to the decrease of both pyroptosis and apoptosis and the alleviation of inflammation. These findings provide a reference and evidence for the use of H2 in TBI-ALI patients in the intensive care unit (ICU).

Antioxidant Mechanisms of the Oligopeptides (FWKVV and FMPLH) from Muscle Hydrolysate of Miiuy Croaker against Oxidative Damage of HUVECs.

In this work, the antioxidant mechanisms of bioactive oligopeptides (FWKVV and FMPLH) from protein hydrolysate of miiuy croaker muscle against H2O2-damaged human umbilical vein endothelial cells (HUVECs) were researched systemically. The finding demonstrated that the HUVEC viability treated with ten antioxidant peptides (M1 to M10) at 100.0 µM for 24 h was not significantly affected compared with that of the normal group (P < 0.05). Furthermore, FWKVV and FMPLH at 100.0 µM could very significantly enhance the viabilities (75.89 ± 1.79% and 70.03 ± 4.37%) of oxidative-damaged HUVECs by H2O2 compared with those of the model group (51.66 ± 2.48%) (P < 0.001). The results indicated that FWKVV and FMPLH played their protective functions through increasing the levels of antioxidant enzymes including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreasing the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO) in oxidative-damaged HUVECs in a dose-dependent manner. In addition, the comet assay revealed that FWKVV and FMPLH could dose-dependently protect deoxyribonucleic acid (DNA) from oxidative damage in the HUVEC model. These results suggested that antioxidant pentapeptides (FWKVV and FMPLH) could serve as potential antioxidant additives applied in the food products, pharmaceuticals, and health supplements.

Inhibition of nitric oxide synthase aggravates brain injury in diabetic rats with traumatic brain injury.

Studies have shown that hyperglycemia aggravates brain damage by affecting vascular endothelial function. However, the precise mechanism remains unclear. Male Sprague-Dawley rat models of diabetes were established by a high-fat diet combined with an intraperitoneal injection of streptozotocin. Rat models of traumatic brain injury were established using the fluid percussion method. Compared with traumatic brain injury rats without diabetic, diabetic rats with traumatic brain injury exhibited more severe brain injury, manifested as increased brain water content and blood-brain barrier permeability, the upregulation of heme oxygenase-1, myeloperoxidase, and Bax, the downregulation of occludin, zona-occludens 1, and Bcl-2 in the penumbra, and reduced modified neurological severity scores. The intraperitoneal injection of a nitric oxide synthase inhibitor N(5)-(1-iminoethyl)-L-ornithine (10 mg/kg) 15 minutes before brain injury aggravated the injury. These findings suggested that nitric oxide synthase plays an important role in the maintenance of cerebral microcirculation, including anti-inflammatory, anti-oxidative stress, and anti-apoptotic activities in diabetic rats with traumatic brain injury. The experimental protocols were approved by the Institutional Animal Care Committee of Harbin Medical University, China (approval No. ky2017-126) on March 6, 2017.

Effects of a high concentration of hydrogen on neurological function after traumatic brain injury in diabetic rats.

Reactive oxygen species, inflammation, and apoptosis are major contributors to secondary injuries that follow traumatic brain injury (TBI) in diabetic patients. Hydrogen (H2) can selectively neutralize reactive oxygen species and downregulate inflammatory and apoptotic factors. Therefore, we investigated the effects of inhaled high and low concentrations of hydrogen on neurological function after TBI in diabetic rats and the potential mechanism. We found that the inhalation of high concentrations of H2 significantly improved outcomes following TBI in diabetic rats. The inhalation of 42% H2 for one hour per day for 48 h significantly reduced brain edema, decreased the extravasation of sodium fluorescein, and reduced oxidative stress markers (p < 0.05). In addition, the inhalation of a high concentration of H2 (42% for one hour per day for 7 days) improved neurological deficits (p < 0.05) and reduced the expression of apoptotic protein markers (p < 0.05). However, the inhalation of 3% H2 did not yield significant effects. These results showed that the inhalation of 42% H2 can alleviate nerve damage and improve neurological function after TBI in diabetic rats. Therefore, the inhalation of a high concentration of H2 may be associated with the treatment of traumatic brain injuries.

Recent advances in the neuroprotective effects of medical gases.

Central nervous system injuries are a leading cause of death and disability worldwide. Although the exact pathophysiological mechanisms of various brain injuries vary, central nervous system injuries often result in an inflammatory response, and subsequently lead to brain damage. This suggests that neuroprotection may be necessany in the treatment of multiple disease models. The use of medical gases as neuroprotective agents has gained great attention in the medical field. Medical gases include common gases, such as oxygen, hydrogen and carbon dioxide; hydrogen sulphide and nitric oxide that have been considered toxic; volatile anesthetic gases, such as isoflurane and sevoflurane; and inert gases like helium, argon, and xenon. The neuroprotection from these medical gases has been investigated in experimental animal models of various types of brain injuries, such as traumatic brain injury, stroke, subarachnoid hemorrhage, cerebral ischemic/reperfusion injury, and neurodegenerative diseases. Nevertheless, the transition into the clinical practice is still lagging. This delay could be attributed to the contradictory paradigms and the conflicting results that have been obtained from experimental models, as well as the presence of inconsistent reports regarding their safety. In this review, we summarize the potential mechanisms underlying the neuroprotective effects of medical gases and discuss possible candidates that could improve the outcomes of brain injury.

Therapeutic hypercapnia reduces blood-brain barrier damage possibly via protein kinase Cε in rats with lateral fluid percussion injury.

BACKGROUND: This study investigated whether therapeutic hypercapnia (TH) ameliorated blood-brain barrier (BBB) damage and improved the neurologic outcome in a rat model of lateral fluid percussion injury (FPI), and explored the possible underlying mechanism. METHODS: Rats underwent lateral FPI and received inhalation of 30%O2-70%N2 or 30%O2-N2 plus CO2 to maintain arterial blood CO2 tension (PaCO2) between 80 and 100 mmHg for 3 h. To further explore the possible mechanisms for the protective effects of TH, a PKC inhibitor staurosporine or PKCαß inhibitor GÖ6976 was administered via intracerebral ventricular injection. RESULTS: TH significantly improved neurological function 24 h, 48 h, 7 d, and 14 d after FPI. The wet/dry ratio, computed tomography values, Evans blue content, and histological lesion volume were significantly reduced by TH. Moreover, numbers of survived neurons and the expression of tight junction proteins (ZO-1, occludin, and claudin-5) were significantly elevated after TH treatment at 48-h post-FPI. TH significantly increased the expression of protein kinase Cε (PKCε) at 48-h post-FPI, but did not significantly change the expression of PKCα and PKCßII. PKC inhibitor staurosporine (but not the selective PKCαß inhibitor-GÖ6976) inhibited the protective effect of TH. CONCLUSIONS: Therapeutic hypercapnia is a promising candidate that should be further evaluated for clinical treatment. It not only protects the traumatic penumbra from secondary injury and improves histological structure but also maintains the integrity of BBB and reduces neurologic deficits after trauma in a rat model of FPI.

Adrenomedullin Reduces Secondary Injury and Improves Outcome in Rats with Fluid Percussion Brain Injury.

OBJECTIVE: Traumatic brain injury (TBI) is a devastating neurologic injury and remains a major cause of death in the world. Secondary injury after TBI is associated with long-term disability in patients with TBI. This study evaluated adrenomedullin (AM) on secondary injury and neurologic functional outcome in rats after TBI. METHODS: Forty-eight Sprague Dawley rats were randomly assigned into 3 groups: sham, TBI, and TBI with AM groups. TBI was induced by fluid percussion injury, and AM was intravenously injected. Neurologic function was examined at 2, 3, and 7 days after TBI. Enzyme-linked immunosorbent assay was used to test tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-8 levels in the brain. Brain edema and blood-brain barrier (BBB) permeability in brain tissue were tested. Western blot was used to examine the expression of aquaporin-4, phosphorylated myosin light-chain, and cleaved caspase-3. Terminal deoxynucleotidyl transferase dUTP nick end labeling was used to test the apoptosis. RESULTS: Compared with the sham group, TNF-α, IL-1ß, and IL-6 levels, brain edema, BBB permeability, neurologic examination scores, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells, and expression of aquaporin-4, phosphorylated myosin light-chain, and cleaved caspase-3 significantly increased in the TBI group. AM treatment significantly inhibited TBI-induced effects. CONCLUSIONS: AM can improve neurologic function and ameliorate brain injury in rats with TBI. AM exerts its neuroprotective effect via its anti-inflammatory and antiapoptotic effect.

DCE-MRI-Derived Volume Transfer Constant (Ktrans) and DWI Apparent Diffusion Coefficient as Predictive Markers of Short- and Long-Term Efficacy of Chemoradiotherapy in Patients With Esophageal Cancer.

This study aimed to evaluate both the short- and long-term efficacies of chemoradiotherapy in relation to the treatment of esophageal cancer . This was achieved through the use of dynamic contrast-enhanced magnetic resonance imaging-derived volume transfer constant and diffusion weighted imaging-derived apparent diffusion coefficient . Patients with esophageal cancer were assigned into the sensitive and resistant groups based on respective efficacies in chemoradiotherapy. Dynamic contrast-enhanced magnetic resonance imaging and diffusion weighted imaging were used to measure volume transfer constant and apparent diffusion coefficient, while computed tomography was used to calculate tumor size reduction rate. Pearson correlation analyses were conducted to analyze correlation between volume transfer constant, apparent diffusion coefficient, and the tumor size reduction rate. Receiver operating characteristic curve was constructed to analyze the short-term efficacy of volume transfer constant and apparent diffusion coefficient, while Kaplan-Meier curve was employed for survival rate analysis. Cox proportional hazard model was used for the risk factors for prognosis of patients with esophageal cancer. Our results indicated reduced levels of volume transfer constant, while increased levels were observed in ADCmin, ADCmean, and ADCmax following chemoradiotherapy. A negative correlation was determined between ADCmin, ADCmean, and ADCmax, as well as in the tumor size reduction rate prior to chemoradiotherapy, whereas a positive correlation was uncovered postchemoradiotherapy. Volume transfer constant was positively correlated with tumor size reduction rate both before and after chemoradiotherapy. The 5-year survival rate of patients with esophageal cancer having high ADCmin, ADCmean, and ADCmax and volume transfer constant before chemoradiotherapy was greater than those with respectively lower values. According to the Cox proportional hazard model, ADCmean, clinical stage, degree of differentiation, and tumor stage were all confirmed as being independent risk factors in regard to the prognosis of patients with EC. The findings of this study provide evidence suggesting that volume transfer constant and apparent diffusion coefficient as being tools allowing for the evaluation of both the short- and long-term efficacies of chemoradiotherapy esophageal cancer treatment.

Clinical significance of gefitinib antitumor activity in patients with lung adenocarcinoma.

Non-small cell lung cancer is a subtype of adenocarcinoma, which has previously shown positive responses to gefitinib. The aim of the current study was to determine a clinical profile of gefitinib-induced disease controls for patients with lung adenocarcinoma. Retrospective evaluation of the clinical characteristics of 52 lung adenocarcinoma patients, enrolled at the Zhejiang Cancer Hospital (Hangzhou, China) between October 2004 and August 2008, was undertaken. All patients received gefitinib (250 mg/day orally) until disease progression or until an unacceptable toxicity was observed. Of the 52 patients, complete response (CR) and partial response (PR) rates were 23.1% (12/52) and 57.7% (30/52), respectively. An additional 19.2% (10/52) of patients demonstrated stable disease (SD) after three months of treatment with gefitinib. Disease control was observed in the primary lesion, and tumor metastasis to the lungs, brain, adrenal glands, pleura, peritoneum, pericardium, bone and lymph nodes was identified. The one-year progression-free survival (PFS) and overall survival (OS) rates were 74.8 and 78.0%, respectively. Multivariate analysis revealed that female patients were associated with significantly longer survival times when compared with males (hazard ratio, 0.077; 95% confidence interval [CI], 0.007-0.083; P=0.035). One-year PFS and OS rates in CR, PR and SD patients were 77.8, 73.9 and 33.3%, and 89.2, 79.8 and 33.7%, respectively, although neither difference was identified to be statistically significant. In addition, the median OS of SD patients was 12 months (95% CI, 7.2-16.8 months). Brain metastasis was the major site of disease progression (23.1%). Gefitinib treatment for patients with lung adenocarcinoma showed a marked long-term survival benefit, even in SD patients. However, further studies are required to analyze the efficacy of gefitinib in penetrating the blood-brain barrier in order to prolong PFS in patients with lung adenocarcinoma.

Cerebellar, brainstem and spinal cord metastases from esophageal cancer following radiotherapy: A case report and literature review.

Cerebellar, brainstem and spinal cord metastases from esophageal cancer following radiotherapy are extremely rare. The current study presents the case of a 74-year-old male who was admitted to the Zhejiang Cancer Hospital (Hangzhou, China) with a poorly-differentiated neuroendocrine carcinoma of the esophagus. Following radiotherapy, multiple abnormal signals in the brainstem and spinal cord were found on magnetic resonance imaging (MRI). Following palliative radiochemotherapy, the clinical symptoms and abnormal MRI signals in the brainstem and spinal cord were found to improve. This case revealed that brain metastasis from esophageal carcinoma may occur simultaneously with brainstem and spinal cord metastases.

[The impact of an asthmatic patient education program on asthma control and quality of life].

OBJECTIVE: To evaluate the impact of an asthmatic patient education program on asthma control and quality of life. METHODS: The program, which consisted of a special clinic for asthma, an asthma education center and the Asthmatic Patients Association, was carried out in Peking University People's Hospital. Interview-administered questionnaire of two groups of adult outpatients between Apr. and Jun. in 2005, the educated group (56 cases), including those having taken part in the asthma education program, and the control group (30 cases), including those of another hospital in Beijing without systematic asthma education program. The level of control of asthma and the quality of life in the past 8 weeks were evaluated and compared. RESULTS: The rate of well-controlled asthma for the two groups was 61% (34 cases) and 10% (3 cases), respectively (chi2 = 20.50, P < 0.01); and the total score of quality of life for the two groups was 155 +/- 12 and 132 +/- 24, respectively (t = 5.17, P < 0.01). The results in the educated group were all better than those in the control group, the differences between the two groups being statistically significant. CONCLUSION: Our asthmatic patient education program can significantly improve asthma control and quality of life.