The role of Foxo3a in neuron-mediated cognitive impairment.

Cognitive impairment (COI) is a prevalent complication across a spectrum of brain disorders, underpinned by intricate mechanisms yet to be fully elucidated. Neurons, the principal cell population of the nervous system, orchestrate cognitive processes and govern cognitive balance. Extensive inquiry has spotlighted the involvement of Foxo3a in COI. The regulatory cascade of Foxo3a transactivation implicates multiple downstream signaling pathways encompassing mitochondrial function, oxidative stress, autophagy, and apoptosis, collectively affecting neuronal activity. Notably, the expression and activity profile of neuronal Foxo3a are subject to modulation via various modalities, including methylation of promoter, phosphorylation and acetylation of protein. Furthermore, upstream pathways such as PI3K/AKT, the SIRT family, and diverse micro-RNAs intricately interface with Foxo3a, engendering alterations in neuronal function. Through several downstream routes, Foxo3a regulates neuronal dynamics, thereby modulating the onset or amelioration of COI in Alzheimer's disease, stroke, ischemic brain injury, Parkinson's disease, and traumatic brain injury. Foxo3a is a potential therapeutic cognitive target, and clinical drugs or multiple small molecules have been preliminarily shown to have cognitive-enhancing effects that indirectly affect Foxo3a. Particularly noteworthy are multiple randomized, controlled, placebo clinical trials illustrating the significant cognitive enhancement achievable through autophagy modulation. Here, we discussed the role of Foxo3a in neuron-mediated COI and common cognitively impaired diseases.

Complete response of recurrent perihilar cholangiocarcinoma following sintilimab combined with lenvatinib plus S-1: a case report and review of literature.

Perihilar cholangiocarcinoma is a refractory malignancy with an unfavorable prognosis and a high probability of recurrence. Systemic chemotherapy is critical for palliative treatment, but effective therapeutic strategies for perihilar cholangiocarcinoma after first-line chemotherapy failure are scarce. Here, we introduced a sustained benefit following sintilimab combined with lenvatinib plus S-1 in a patient with recurrent perihilar cholangiocarcinoma. A 52-year-old female patient was admitted to our hospital due to yellow skin and sclera, and further radiological examination revealed perihilar cholangiocarcinoma. The patient underwent surgery and histopathological results confirmed moderately differentiated adenocarcinoma with metastatic lymph nodes. Postoperative adjuvant chemotherapy with gemcitabine and S-1 was given. One year after surgery, the patient experienced hepatic recurrence. Then, she received radiofrequency ablation combined with gemcitabine and cisplatin. Unfortunately, radiological assessment revealed progressive disease with multiple liver metastases after treatment. Subsequently, she received sintilimab combined with lenvatinib plus S-1 and the lesions were completely regressed following 14 cycles of combination therapy. The patient recovered well without disease recurrence at the last follow-up. Sintilimab combined with lenvatinib plus S-1 may be an alternative therapeutic option for chemotherapy-refractory perihilar cholangiocarcinoma, and further evaluation in a larger number of patients is needed.

Real-world experience of postoperative adjuvant chemoimmunotherapy in patients with perihilar cholangiocarcinoma at high risk of recurrence.

BACKGROUND: This study aimed to assess whether postoperative adjuvant chemoimmunotherapy could lead to better clinical outcomes for high-risk patients with perihilar cholangiocarcinoma (pCCA). METHODS: In the cohort study, we retrospectively reviewed patients who received surgical resection for pCCA with curative intent from January 2018 to December 2021 at the Sun Yat-sen Memorial Hospital. The patients at high risk for relapse were further analyzed. Among them, 20 patients received adjuvant chemoimmunotherapy, 28 patients received adjuvant chemotherapy, and 33 patients received surgery alone. The oncological outcomes and drug-associated adverse events were evaluated. RESULTS: The 2-year overall survival (OS) rates in patients treated with adjuvant chemoimmunotherapy, adjuvant chemotherapy, and surgery alone were 80.0%, 49.4% and 22.6%, respectively. Univariable and multivariable Cox analyses showed that the treatment regimen and TNM stage were associated with adverse OS. Adjuvant chemoimmunotherapy led to an increase in OS compared with adjuvant chemotherapy [hazard ratio (HR) = 3.253; 95% confidence interval (CI) 1.072-9.870; P = 0.037] or surgery alone (HR = 7.560; 95% CI 2.508-22.785; P < 0.001). The median recurrence-free survival was 22.0 months for the adjuvant chemoimmunotherapy group, 17.0 months for the adjuvant chemotherapy group, and 13.2 months for the surgery alone group (P = 0.177); these differences were not significant. The chemoimmunotherapy group was associated with more frequent hematological side effects than the chemotherapy group, but the difference was not statistically significant. CONCLUSION: Postoperative adjuvant chemoimmunotherapy for resected pCCA patients showed improved OS compared with adjuvant chemotherapy or surgery alone, and further prospectively randomized controlled trials are necessary to validate these results.

Transcriptome analysis provides insights into the molecular mechanism of liver inflammation and apoptosis in juvenile largemouth bass Micropterus salmoides fed low protein high starch diets.

The present study was conducted to investigate the regulatory mechanism of liver injury in largemouth bass Micropterus salmoides (LMB) fed low protein high starch diets. Two isolipidic and isoenergetic diets were formulated with different protein and starch ratios, being named as diets P49S9 (48.8 % protein and 9.06 % starch) and P42S18 (42.4 % protein and 18.2 % starch). Each diet was fed to triplicate replicates of LMB (initial body weight, 4.65 ± 0.01 g) juveniles. Fish were fed to visual satiation for 8 weeks. The results indicated that though the P42S18 fish up-regulated the feeding ratio to meet their protein requirements, feeding efficiency ratio and growth performance were impaired in treatment P42S18 as compared to treatment P49S9. Periodic acid-Schiff (PAS) staining showed glycogen accumulated in the liver of LMB fed low protein high starch diets, and the reason should be attributed to down-regulated expression of the glycogenolytic glycogen debranching enzyme. Lower liver lipid level was associated with feeding low protein high starch diets in LMB, which should be resulted from the changes in hepatic glycerolipid metabolism regulated by lipoprotein lipase (representative of triglyceride synthesis, up-regulated) and diacylglycerol acyltransferase (representative of triglyceride breakdown, down-regulated). Though fasting plasma glucose level was comparable, treatment P42S18 performed inferior glucose tolerance to treatment P49S9. Hematoxylin-eosin (HE) and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining suggested that feeding low protein high starch diets induced disruption of structural integrity, inflammation and apoptosis in the hepatocytes of LMB. As expected, KEGG pathways analysis indicated that many of the up-regulated differentially expressed genes were enriched in AGE (advanced glycation end product)/RAGE (receptor for AGE), Toll-like receptor and apoptosis signaling pathways. Our transcriptome data revealed that feeding low protein high starch diets might promote the accumulation of AGEs in LMB, which bound to RAGE and subsequently induced PI3K/Akt signal pathway. The activation of Akt induced NF-κB translocation into the nucleus thus releasing proinflammatory factors including tumor necrosis factor-α (TNF-α) and interleukin-8. The release of these inflammatory factors concomitantly induced T cell stimulation and natural killer cells chemotactic effects through Toll-like receptor signaling pathway. Besides mediating inflammation and immune response, TNF-α signal transduction participated in mediating apoptosis through the receptor of TNF (TNF-R1) pathway by up-regulating the expression of caspase 8 and cytochrome c. In conclusion, our results demonstrated that feeding low protein and high starch diets induced hepatocytes inflammation and apoptosis in LMB through the PI3K/Akt/NF-κB signaling pathway.

Effects of WB-EMS and protein supplementation on body composition, physical function, metabolism and inflammatory biomarkers in middle-aged and elderly patients with sarcopenic obesity: A meta-analysis of randomized controlled trials.

BACKGROUND: The patients with sarcopenic obesity (SO) have the characteristics of both sarcopenia and obesity, that is, less muscle mass and increased fat mass, and their morbidity, disability and mortality are higher than patients with sarcopenia or obesity alone. OBJECTIVES: To investigate the effects of whole-body electromyostimulation (WB-EMS) training and protein supplementation intervention on body composition, physical function, metabolism and inflammatory biomarkers in middle-aged and elderly patients with SO. METHODS: We searched for randomized controlled trials in seven databases, including PubMed, Web of Science, Embase, Cochrane Library, Scopus, SinoMed, and CNKI as of July 3, 2021. The methodological quality of each included study was assessed using the Physiotherapy Evidence Database (PEDro) scale. The Cochrane Risk of Bias Tool was used to assess the risk of bias. Statistical analysis was performed using Review Manager 5.3. RESULTS: Eleven randomized controlled studies with a total of 779 participants were included in this meta-analysis. WB-EMS training improved sarcopenia Z-score (MD = -1.52, 95 % CI: -2.27, -0.77, P < 0.0001) and waist circumference (WC) (MD = -1.41, 95 % CI: -2.62, -0.20, P = 0.02), and increased skeletal muscle mass index (SMI) (MD = 1.27, 95 % CI: 0.66,1.88, P < 0.0001) and appendicular skeletal muscle mass (ASMM) (MD = 0.68, 95 % CI: 0.08, 1.27, P = 0.03). Protein supplementation intervention reduced body fat rate (BF%) (MD = -1.28, 95 % CI: -1.88, -0.68, P < 0.0001, I2 = 0 %), total body fat (TBF) (MD = -0.98, 95 % CI: -1.65, -0.31, P = 0.004, I2 = 0 %) and trunk body fat mass (TBFM) (MD = -0.50, 95 % CI: -0.94, -0.06, P = 0.03, I2 = 0 %), and increased grip strength (GS) (MD = 1.13, 95 % CI: 0.06, 2.21, P = 0.04, I2 = 0 %). The combination of WB-EMS and protein supplements is beneficial to most body components and physical functions, such as SMI (MD = 1.21, 95 % CI: 0.73, 1.51, P < 0.00001, I2 = 0 %), GS (MD = 1.60, 95 % CI: 0.80, 2.40, P < 0.0001, I2 = 45 %) and walking speed (WS) (MD = 0.04, 95 % CI: 0.02, 0.06, P < 0.0001, I2 = 49 %). Compared with protein supplementation alone, WB-EMS could have an additional beneficial effect on BF% (MD = -0.92, 95 % CI: -1.80, -0.04, P = 0.04) and WC (MD = -1.03, 95 % CI: -1.70, -0.36, P = 0.003). Nevertheless, the addition of protein supplements did not provide any additional benefit compared with WB-EMS alone. In addition, there was almost no positive effect of WB-EMS and protein supplements on metabolic and inflammatory biomarkers. CONCLUSIONS: As things stand, protein supplementation intervention can effectively reduce body fat percentage, fat mass, and increase grip strength in SO patients. Both WB-EMS and protein supplementation intervention had no significant effects on metabolic and inflammatory biomarkers. WB-EMS combined with protein supplementation intervention was beneficial for SO patients in many ways. Due to the small number of studies, further studies are needed to confirm the efficacy of WB-EMS alone or in combination with protein supplementation intervention in SO patients. REGISTRATION NUMBER: INPLASY202190096 DOI:10.37766/inplasy2021.9.0096.

Effects of resistance training on body composition and physical function in elderly patients with osteosarcopenic obesity: a systematic review and meta-analysis.

Osteosarcopenic obesity (OSO) is a complex disease commonly seen in the elderly. We found that resistance training may improve bone mineral density, skeletal muscle mass, and body fat percentage in patients with OSO. Therefore, resistance training is beneficial for elderly OSO patients and is worth being promoted. PURPOSE: Investigate effects of resistance training on body composition and physical function in elderly osteosarcopenic obesity (OSO) patients. METHODS: PubMed, Web of Science, Embase, Cochrane Library, Medline, SinoMed, CNKI, and Wanfang Database were searched from inception until October 13, 2021.Two independent researchers extracted the key information from each eligible study. The methodological quality of included studies was assessed using the Physiotherapy Evidence Database (PEDro) scale. The Cochrane Risk of Bias Tool was used to assess the risk of bias. Grading of Recommendations Assessment Development and Evaluation (GRADE) was used to evaluate the quality of the outcomes. Sensitivity analysis indicated the stability of the results. Statistical analysis was performed using Review Manager 5.3. RESULTS: Four randomized controlled studies meeting the inclusion criteria were included, with 182 participants. Twelve weeks of resistance training improved bone mineral density (BMD, mean difference (MD) = 0.01 g/cm2, 95% confidence interval (CI): 0.001, 0.02, P = 0.03, I2 = 0%), skeletal muscle mass (SMM, MD = 1.19 kg, 95% CI: 0.50, 1.89, P = 0.0007, I2 = 0%), Z score, timed chair rise test (TCR), and body fat percentage (BFP, MD = - 1.61%, 95% CI: - 2.94, - 0.28, P = 0.02, I2 = 50%) but did not significantly affect skeletal muscle mass index (SMI, MD = 0.20 kg/m2, 95% CI: - 0.25, 0.64, P = 0.38, I2 = 0%) or gait speed (GS). CONCLUSIONS: Resistance training is a safe and effective intervention that can improve many parameters, including BFP, SMM, and Z score, among OSO patients and is a good option for elderly individuals to improve their physical fitness.

Complete Response to Combined Chemotherapy and Anti-PD-1 Therapy for Recurrent Gallbladder Carcinosarcoma: A Case Report and Literature Review.

Background: Gallbladder carcinosarcoma (GBCS) is a rare and aggressive malignancy with extremely poor prognosis. Although surgery is regarded as the primary therapy for GBCS, the effective therapeutic strategies for unresected lesions have been poorly defined. Case Presentation: We presented a case of a 74-year-old male who underwent radical resection of gallbladder carcinoma at a local hospital. Seven months later, he was admitted to our hospital due to right upper abdominal discomfort. Postoperative radiological examinations showed multiple hepatic lesions, hilar lymph node metastasis, and main portal vein tumor thrombus. The pathological consultation results confirmed GBCS and immunohistochemical examinations revealed PD-L1 expression in 20% of tumor cells. Then, the patient received chemotherapy (Gemcitabine plus Oxaliplatin, GEMOX) in combination with anti-PD-1 therapy. After nine courses of the combination therapy, complete regression of the tumors was achieved with no evidence of relapse till now. Conclusions: We, for the first time, reported a patient with recurrent GBCS who benefited from the combined chemotherapy and immunotherapy, providing a potential effective management strategy for the refractory malignant tumor.

XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX).

BACKGROUND: There is no consensus on whether triplet regimen is better than doublet regimen in the first-line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of oxaliplatin plus capecitabine (XELOX) and epirubicin, oxaliplatin, plus capecitabine (EOX) regimens in treating AGC. METHODS: This phase III trial enrolled previously untreated patients with AGC who were randomly assigned to receive the XELOX or EOX regimen. The primary endpoint was non-inferiority in progression-free survival (PFS) for XELOX as compared with EOX on an intention-to-treat basis. RESULTS: Between April 10, 2015 and August 20, 2020, 448 AGC patients were randomized to receive XELOX (n = 222) or EOX (n = 226). The median PFS (mPFS) was 5.0 months (95% confidence interval [CI] = 4.5-6.0 months) in the XELOX arm and 5.5 months (95% CI = 5.0-6.0 months) in the EOX arm (hazard ratio [HR] = 0.989, 95% CI = 0.812-1.203; Pnon-inferiority = 0.003). There was no significant difference in median overall survival (mOS) (12.0 vs. 12.0 months, P = 0.384) or objective response rate (37.4% vs. 45.1%, P = 0.291) between the two groups. In patients with poorly differentiated adenocarcinoma and liver metastasis, the EOX arm had a significantly longer mOS (P = 0.021) and a trend of longer mPFS (P = 0.073) than the XELOX arm. The rate of grade 3/4 adverse events (AEs) was 42.2% (90/213) in the XELOX arm and 72.5% (156/215) in the EOX arm (P = 0.001). The global health-related quality of life (QoL) score was significantly higher in the XELOX arm than in the EOX arm during chemotherapy. CONCLUSIONS: This non-inferiority trial demonstrated that the doublet regimen was as effective as the triplet regimen and had a better safety profile and QoL as a first-line treatment for AGC patients. However, the triplet regimen might have a survival advantage in patients with poorly differentiated adenocarcinoma and liver metastasis.

Laparoscopic pancreaticoduodenectomy: a retrospective study of 200 cases and the optimization of the single-center learning curve.

BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) is widely used in several centers. This study analyzed the postoperative complications rate curve, possible cause, and solution of LPD and open pancreaticoduodenectomy (OPD). METHODS: Between January 2015 and December 2019, the study included 213 and 204 patients undergoing OPD and LPD, respectively. Postoperative outcomes, complications, and complication risk, along with operation time were analyzed, and the learning curve was determined. RESULTS: The OPD group (378.7±8.98 min) had shorter operation time than the LPD group (402.5±7.12 min) (P=0.037). Blood loss was significantly lower in the LPD group (389.9±19.05 mL) than in the OPD group (530.1±33.55 mL) (P<0.001). The incidence of biliary-enteric anastomosis leakage was higher in the LPD group (2.9%) than in the OPD group (0.5%) (P=0.0495). The LPD group showed lower lung infection (7.4% vs. 17.4%, P=0.037), incision infection (1% vs. 8.5%, P<0.001), and anal exhaust time (3.35±0.07 vs. 4.05±0.07 days, P<0.001) than the OPD group. The biliary-enteric anastomosis leakage was strongly correlated with the pancreatic fistula (B/C) (R=0.6410), intraperitoneal infection (R=0.6126) and Clavien-Dindo Classification ≥3 (R=0.7403). According to the cumulative sum (CUSUM) curve, pancreatic fistula had a negative K value in 44 cases, biliary-enteric anastomosis leakage had a negative K value in 46 cases, and Clavien-Dindo Classification ≥3 had a negative K value in 40 cases. The learning curve for LPD has an inflection point in 86 cases. CONCLUSIONS: LPD is safe and effective for patients with pancreatic cancer, and has a long learning curve and improved postoperative complications in 50 cases. This study's results will help in reducing the complication rates of the first 50 consecutive cases of LPD.

Secreted Wnt6 mediates diabetes-associated centrosome amplification via its receptor FZD4.

We recently published that type 2 diabetes promotes cell centrosome amplification via upregulation of Rho-associated protein kinase 1 (ROCK1) and 14-3-3 protein-σ (14-3-3σ). This study further investigates the molecular mechanisms underlying diabetes-associated centrosome amplification. We found that treatment of cells with high glucose, insulin, and palmitic acid levels increased the intracellular and extracellular protein levels of Wingless-type MMTV integration site family member 6 (Wnt6) as well as the cellular level of ß-catenin. The treatment also activated ß-catenin and promoted its nuclear translocation. Treatment of cells with siRNA species for Wnt6, Frizzled-4 (FZD4), or ß-catenin as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture medium could all attenuate the treatment-triggered centrosome amplification. Moreover, we showed that secreted Wnt6-FZD4-ß-catenin was the signaling pathway that was upstream of ROCK1 and 14-3-3σ. We found that advanced glycation end products (AGEs) were also able to increase the cellular and extracellular levels of Wnt6, the cellular protein level of ß-catenin, and centrosome amplification. Treatment of the cells with siRNA species for Wnt6 or FZD4 as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture could all inhibit the AGEs-elicited centrosome amplification. In colon tissues from a diabetic mouse model, the protein levels of Wnt6 and 14-3-3σ were increased. In conclusion, our results showed that the pathophysiological factors in type 2 diabetes, including AGEs, were able to induce centrosome amplification. It is suggested that secreted Wnt6 binds to FZD4 to activate the canonical Wnt6 signaling pathway, which is upstream of ROCK1 and 14-3-3σ, and that this is the cell signaling pathway underlying diabetes-associated centrosome amplification.

Insights into the Effect of Reactive Oxygen Species Regulation on Photocatalytic Performance via Construction of a Metal-Semiconductor Heterojunction.

Reactive oxygen species (ROS), as primary intermediates formed during photocatalytic reactions, are critical for a photocatalyst to realize high activity. The major objective of this study was to investigate the regulation of ROS involved in the photocatalytic degradation process via constructing a typical metal-semiconductor hybrid heterojunction using Ag nanoparticles/anatase TiO2 as an example. Based on radical capturing, electron paramagnetic resonance, and electron spin resonance experiments, an increase in the available ROS can be achieved in the Ag/TiO2 heterojunction due to the fast separation of photogenerated carriers. In addition, due to the change in the electron transfer pathway, superoxide radicals (·O-2) are the dominant reactive species responsible for dye degradation using Ag/TiO2 rather than hydroxyl radicals (·OH) as the main free radicals in pristine TiO2. This study offers fresh insight into the regulation of ROS in photodegradation via the construction of a Ag/TiO2 heterojunction.

PPARγ promotes diabetes-associated centrosome amplification via increasing the expression of SKA1 directly at the transcriptional level.

We have recently published that type 2 diabetes can induce cell centrosome amplification due to the action of high glucose, palmitic acid, and insulin, and ROCK1 and 14-3-3σ are signal mediators. In this study, we further investigated the molecular mechanisms of the centrosome amplification in colon cancer HCT116 cells. Treatment of the cells with high glucose, palmitic acid, and insulin increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) as well as the spindle and kinetochore associated protein 1 (SKA1), knockdown of each of which resulted in the inhibition of the treatment-triggered centrosome amplification. Knockdown of PPARγ inhibited the treatment-evoked increase in the SKA1 level, whereas knockdown of SKA1 did not modify the treatment-increased PPARγ level. We found a predicted binding site for PPARγ in the promoter region of the SKA1 gene from the JASPAR database. Experimental results showed that the treatment increased the messenger RNA level of SKA1, which could be inhibited by PPARγ chemical inhibitor or small interfering RNA. Moreover, we were able to show that PPARγ could bind to the binding site in the SKA1 gene promoter, which was increased by the experimental treatment. In conclusion, it is suggested that the pathophysiological factors in type 2 diabetes, high glucose, palmitic acid, and insulin, induce the cell centrosome amplification through the PPARγ-SKA1 pathway, in which PPARγ increases the expression of SKA1 via directly enhancing the SKA1 gene transcription.

Epithelial HO-1/STAT3 affords the protection of subanesthetic isoflurane against zymosan-induced lung injury in mice.

Epithelial dysfunction is a key characteristic of acute lung injury (ALI). Isoflurane (ISO) confers lung protection via anti-inflammatory and anti-apoptotic properties. However, the specific role and potential mechanisms of subanesthetic ISO in lung epithelium protection during zymosan-induced ALI remain unclear. In this study, zymosan increased the expression and activity of beneficial heme oxygenase-1 (HO-1) and signal transducers and activators of transcription 3 (STAT3) in the lung and isolated type II alveolar epithelial cells (AECs-II) from wild-type (WT) mice, which was further enhanced by ISO treatment. ISO reduced the mortality, lung edema, histological changes and pulmonary cell apoptosis, and simultaneously decreased total cells, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) levels in bronchoalveolar lavage fluid in the zymosan-stimulated WT mice but not in HO-1-deficient mice. Moreover, ISO abated zymosan-augmented lactate dehydrogenase activity, TNF-α and IL-1ß production, and apoptosis in WT AECs-II but not in HO-1- or STAT3-silenced cells. Mechanisticly, the epithelial protective effects of ISO on zymosan insult in vivo and in vitro were mediated by a positive feedback loop comprising STAT3 and HO-1. Pro-survival and anti-apoptosis by ISO was highly reliant on activated STAT3, involving in downstream Akt activation and reduced ratio of pro-apoptotic/anti-apoptotic molecules. Overall, HO-1/STAT3 signaling is in favor of lung epithelial protection of ISO in zymosan-challenged mice, suggesting ISO as a valuable therapeutic agent for ALI.

Swimming attenuates inflammation, oxidative stress, and apoptosis in a rat model of dextran sulfate sodium-induced chronic colitis.

Increasing evidence suggests that regular physical exercise suppresses chronic inflammation. However, the potential inhibitory effects of swimming on dextran sulfate sodium (DSS)-induced chronic colitis, and its underlying mechanisms, remain unclear. In this study, rats were orally administered DSS to induce chronic colitis, and subsequently treated with or without swimming exercise. A 7-week swimming program (1 or 1.5 hours per day, 5 days per week) ameliorated DSS-caused colon shortening, colon barrier disruption, spleen enlargement, serum LDH release, and reduction of body weight gain. Swimming for 1.5 hours per day afforded greater protection than 1 hour per day. Swimming ameliorated DSS-induced decrease in crypt depth, and increases in myeloperoxidase activity, infiltration of Ly6G+ neutrophils and TNF-α- and IFN-γ-expressing CD3+ T cells, as well as fecal calprotectin and lactoferrin. Swimming inhibited pro-inflammatory cytokine and chemokine production and decreased the protein expression of phosphorylated nuclear factor-κB p65 and cyclooxygenase 2, whereas it elevated interleukin-10 levels. Swimming impeded the generation of reactive oxygen species, malondialdehyde, and nitric oxide; however, it boosted glutathione levels, total antioxidant capacity, and superoxide dismutase and glutathione peroxidase activities. Additionally, swimming decreased caspase-3 activity and expression of apoptosis-inducing factor, cytochrome c, Bax, and cleaved-caspase-3, but increased Bcl-2 levels. Overall, these results suggest that swimming exerts beneficial effects on DSS-induced chronic colitis by modulating inflammation, oxidative stress, and apoptosis.

Subanesthetic isoflurane relieves zymosan-induced neutrophil inflammatory response by targeting NMDA glutamate receptor and Toll-like receptor 2 signaling.

Neutrophil release of NO/ONOO- induces endothelial cell barrier dysfunction in inflammatory acute lung injury (ALI). Previous studies using zymosan-triggered inflammation and ALI model revealed that zymosan promotes inducible NO synthase (iNOS) expression in neutrophils, and that isoflurane inhibits zymosan-induced oxidative stress and iNOS biosynthesis. However, the underlying mechanisms remain largely unknown. We found here that in zymosan-primed neutrophils, iNOS is transcriptionally activated by NF-κB, whose nuclear translocation is triggered by excessive reactive oxygen species (ROS) and consequently activated p38 MAPK. ROS production is attributed to zymosan-initiated Toll-like receptor 2 (TLR2) signaling, in which the adaptor MyD88 recruits and activates c-Src, and c-Src activates NADPH oxidase to generate ROS. Subanesthetic isoflurane counteracts the aforementioned zymosan-induced signaling by targeting N-methyl-D-aspartic acid (NMDA) glutamate receptor and thereby suppressing calcium influx and c-Src activation. Whereas iNOS accelerates NO/ONOO- production in neutrophils which eventually promote protein leak from pulmonary microvascular endothelial cells (PMVEC), isoflurane reduced NO/ONOO- release from zymosan-treated neutrophils, and thus relieves trans-PMVEC protein leak. This study provides novel insights into the roles of neutrophils and the underlying mechanisms in zymosan-induced ALI, and has implications for the therapeutic potential of subanesthetic isoflurane in attenuating inflammatory responses causing lung endothelial cell damage.

Targeting ubiquitin-specific protease 22 suppresses growth and metastasis of anaplastic thyroid carcinoma.

Ubiquitin-specific protease 22 (USP22) aberrance has been implicated in several malignancies; however, whether USP22 plays a role in anaplastic thyroid carcinoma (ATC) remains unclear. Here, we report that USP22 expression is highly elevated in ATC tissues, which positively correlated with tumor size, extracapsular invasion, clinical stages, and poor prognosis of ATC patients. In vitro assays showed that USP22 depletion suppressed ATC cell survival and proliferation by decreasing Rb phosphorylation and cyclin D2, inactivating Akt, and simultaneously upregulating Rb; USP22 silencing restrained cell migration and invasion by inhibiting epithelial-mesenchymal transition; USP22 knockdown promoted mitochondrion- mediated and caspase-dependent apoptosis by upregulating Bax and Bid and promoting caspase-3 activation. Consistent with in vitro findings, downregulation of USP22 in ATC cells impeded tumor growth and lung metastasis in vivo. These results raise the applicability for USP22 as a useful predictor of ATC prognosis and a potential therapeutic target for ATC.

MiRNA-101 inhibits breast cancer growth and metastasis by targeting CX chemokine receptor 7.

Whereas miR-101 is involved in the development and progression of breast cancer, the underlying molecular mechanisms remain to be elucidated. Here, we report that miR-101 expression is inversely correlated with the clinical stage, lymph node metastasis and prognosis in breast cancers. Introduction of miR-101 inhibited breast cancer cell proliferation and invasion in vitro and suppressed tumor growth and lung metastasis of in vivo. CX chemokine receptor 7 (CXCR7) is a direct target of miR-101, positively correlating with the histological grade and the incidence of lymph node metastasis in breast cancer patients. The effects of miR-101 were mimicked and counteracted by CXCR7 depletion and overexpression, respectively. STAT3 signaling downstream of CXCR7 is involved in miR-101 regulation of breast cancer cell behaviors. These findings have implications for the potential application of miR-101 in breast cancer treatment.

[Inhibitory effects of gamma secretase inhibitor on human multiple myeloma xenograft mouse model].

OBJECTIVE: To explore the tumor growth inhibition of gamma secretase inhibitor MRK003 on human multiple myeloma xenograft mice by inhibition of AKT and Notch1 expression. METHODS: NOD/SCID mice were injected with human multiple myeloma cell lines RPMI8226 to establish a xenograft mouse model. Mice were randomized into two groups：the experimental group were injected with MRK003 at a dose of 5 mg× kg⁻¹×d⁻¹ for 14 days; the inhibitor was replaced by an equal saline in the control group. Mice were sacrificed by cervical dislocation on the next day after the last injection and tumor tissue was removed to detect the expression of Notch1 and AKT by immunohistochemistry. RESULTS: After subcutaneous injection with RPMI8226, mice had tumor formation in 5-7 days and the largest tumor block in 10-12 days. Before RPMI8226 injection, the mean sizes of tumor block in the experimental and the control groups were 509.2 mm³, 511.2 mm³(P>0.05). 9 days after injection, the mean sizes of tumor tissue in the experimental and the control groups were 636.6 mm³, 691.2 mm³(P<0.01). On the next day after the last injection, the tumor sizes of the experimental and the control groups were 683.5 mm³ and 1798.7 mm³(P<0.01). The size of tumor block in the experimental group was significantly smaller than that of the control group(P<0.01). Immunohistochemistry staining showed that the positive expression rates of Notch1(11.1%, P<0.01) and AKT(13.3%, P<0.01) in experimental group were significantly decreased compared with the control group(Notch1: 95.6%; AKT: 93.3%). Western blot results showed that Notch1 and AKT protein in experimental group were significantly lower than those in the control group. CONCLUSION: MRK003 could inhibit the tumor growth of human multiple myeloma xenograft mice by downregulated expression of Notch1 signaling pathway.