Adipose tissue remodeling is a dynamic process during nutritional fluctuation that plays critical roles in metabolic homeostasis and insulin sensitivity. The process is highly regulated by many factors, including adipokines and cytokines that are locally released within fat pads. In a recent study published in Nature, Jonker and colleagues identified FGF1 as an important mediator that is selectively induced in fat cells by high-fat diet feeding and established the PPARγ-FGF1 axis as a critical pathway that regulates adipose tissue remodeling and ultimately systemic metabolic homeostasis.
We examined rodent models with altered levels of mitoNEET, a protein residing in the mitochondrial outer membrane. Adipocyte-specific overexpression of mitoNEET enhances lipid-uptake and storage, leading to an expansion of adipose tissue mass. Despite the resulting massive obesity, benign aspects of adipose tissue expansion prevail and insulin sensitivity is preserved. MitoNEET inhibits mitochondrial iron transport into the matrix. Since iron is a rate-limiting component for electron transport, mitoNEET reduces β-oxidation rates. This is associated with reduced mitochondrial membrane potential and reduced reactive oxygen species damage, along with higher levels of adiponectin production. Conversely, the reduction of mitoNEET enhances mitochondrial respiratory capacity through enhanced iron content in the matrix, with reduced weight gain on a high fat diet. However, a reduction of mitoNEET also causes heightened oxidative-stress and glucose-intolerance. MitoNEET is therefore a potent regulator of mitochondrial function that profoundly impacts the dynamics of cellular and whole-body lipid homeostasis.
Tumor microenviroment is characteristic of inflammation, ischemia and starvation of nutrient. TNF-α, which is an extraordinarily pleiotropic cytokine, could be an endogenous tumor promoter in some tumor types. The basic objective of this study was to investigate the effects of TNF-α on the cell viability and apoptosis of hepatocellular carcinoma cells under serum starvation, and to identify the molecular mechanisms involved.
For this purpose, five different concentrations of TNF-α and two different serum settings (serum-cultured and serum-deprived) were used to investigate the effects of TNF-α on the cell viability and apoptosis of Hep3B and SMMC-7721 cells.
TNF-α (10 ng/ml) attenuated serum starvation-induced apoptosis of hepatocellular carcinoma cells, and autophagy conferred this process. BAY11-7082, a specific inhibitor of NF-κB, reversed the suppression of serum starvation-induced apoptosis by TNF-α. Moreover, TNF-α-induced NF-κB transactivation was suppressed by autophagy inhibitor 3-MA. In addition, TNF-α up-regulated Ferritin heavy chain (FHC) transiently by NF-κB activation and FHC levels were correlated with the TNF-α-induced protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells. Furthermore, FHC-mediated inhibition of apoptosis depended on suppressing ROS accumulation.
Our findings suggested that autophagy conferred the TNF-α protection against serum starvation-mediated apoptosis of hepatocellular carcinoma cells, the mechanism involved with the activation of the TNF-α/ NF-κB /FHC signaling pathway.
TNF-α; Starvation; NF-κB; Ferritin heavy chain; Autophagy; Hepatocellular carcinoma
Resuscitation with bag and mask is a high-impact intervention that can reduce neonatal deaths in resource-poor countries. This study assessed the capacity to perform newborn resuscitation at facilities offering comprehensive emergency obstetric and newborn care (EmONC) in Afghanistan, as well as individual and facility characteristics associated with providers’ knowledge and clinical skills.
Assessors interviewed 82 doctors and 142 midwives at 78 facilities on their knowledge of newborn resuscitation and observed them perform the procedure on an anatomical model. Supplies, equipment, and infrastructure were assessed at each facility. Descriptive statistics and simple and multivariate regression analyses were performed using STATA 11.2 and SAS 9.1.3.
Over 90% of facilities had essential equipment for newborn resuscitation, including a mucus extractor, bag, and mask. More than 80% of providers had been trained on newborn resuscitation, but midwives were more likely than doctors to receive such training as part of pre-service education (59% and 35%, respectively, p < 0.001). No significant differences were found between doctors and midwives on knowledge, clinical skills, or confidence in performing newborn resuscitation. Doctors and midwives scored 71% and 66%, respectively, on knowledge questions and 66% and 71% on the skills assessment; 75% of doctors and 83% of midwives felt very confident in their ability to perform newborn resuscitation. Training was associated with greater knowledge (p < 0.001) and clinical skills (p < 0.05) in a multivariable model that adjusted for facility type, provider type, and years of experience offering EmONC services.
Lack of equipment and training do not pose major barriers to newborn resuscitation in Afghanistan, but providers’ knowledge and skills need strengthening in some areas. Midwives proved to be as capable as doctors of performing newborn resuscitation, which validates the major investment made in midwifery education. Competency-based pre-service and in-service training, complemented by supportive supervision, is an effective way to build providers’ capacity to perform newborn resuscitation. This kind of training could also help skilled birth attendants based in the community, at private clinics, or at primary care facilities save the lives of newborns.
Intrapartum hypoxia; Birth asphyxia; Emergency obstetric care; Neonatal mortality; Newborn resuscitation; Afghanistan; Lower income countries
Autophagy serves as a dynamic degradation and recycling system that provides biological materials and energy in response to stress. The role of autophagy in tumor development is complex. Various studies suggest that autophagy mainly contributes to tumor suppression during the early stage of tumorigenesis and tumor promotion during the late stage of tumorigenesis. During the tumorization of normal cells, autophagy protects genomic stability by retarding stem cells-involved damage/repair cycle, and inhibits the formation of chronic inflammatory microenvironment, thus protecting normal cell homeostasis and preventing tumor generation. On the other hand, autophagy also protects tumor cells survival during malignant progression by supporting cellular metabolic demands, decreasing metabolic damage and supporting anoikis resistance and dormancy. Taken together, autophagy appears to play a role as a protector for either normal or tumor cells during the early or late stage of tumorigenesis, respectively. The process of tumorigenesis perhaps needs to undergo twice autophagy-associated screening. The normal cells that have lower autophagy capacity are prone to tumorization, and the incipient tumor cells that have higher autophagy capacity possibly are easier to survival in the hash microenvironment and accumulate more mutations to promote malignant progression.
Autophagy; Protector; Early tumorigenesis; Tumor progression; Metastasis
Hypoxia-inducible factor 1α (HIF1α) induction in adipocytes is a critical component of the “fibrotic response,” directly linked to metabolic dysfunction in adipose tissues under hypoxic conditions. We reasoned that inhibition of HIF1α may ameliorate the negative aspects of the obesity-associated fat pad expansion. We used the selective HIF1α inhibitor PX-478, whose effectiveness has previously been established in tumor models. We demonstrate that PX-478 treatment effectively suppresses the high-fat-diet (HFD)-induced HIF1α activation in adipose tissue. HIF1α inhibition causes a reduction of weight gain in mice on an HFD but not on a chow diet. Treatment increases energy expenditure and prompts resistance to HFD-mediated deterioration of metabolic parameters. Moreover, PX-478-treated mice have reduced fibrosis and fewer inflammatory infiltrates in their adipose tissues. We confirm the metabolic effects obtained with PX-478 treatment using an adipose tissue-specific, doxycycline-inducible dominant negative HIF1α mutant (dn-HIF1α). Consistent with the pharmacological results, genetic inhibition of endogenous HIF1α activity prompts similar metabolic improvements in HFD-fed mice. Collectively, our results demonstrate that HIF1α inhibition in the adipocyte leads to significant metabolic improvements, suggesting that selective HIF1α inhibition in adipose tissue may be an effective therapeutic avenue in the context of metabolic dysfunction.
Acute type A aortic dissection (AAAD) remains one of the most lethal conditions requiring surgical repair, and is associated with a high rate of postoperative mortality and morbidity. Despite the satisfactory clinical outcomes achieved with the frozen elephant trunk technique so far, controversies still exist regarding the use of this aggressive approach in patients with AAAD. In this study, we seek to analyze the early outcomes of the Sun’s procedure, which is an approach integrating total arch replacement using a 4-branched graft with implantation of a special stented graft in the descending aorta, and identify the risk factors for postoperative mortality and morbidity of the Sun’s procedure in patients with AAAD.
Clinical data of 398 consecutive AAAD patients undergoing the Sun’s procedure were analyzed. The associations between 20 preoperative and intraoperative variables and early mortality were assessed by univariate and multivariate analysis.
Early mortality occurred in 31 patients (7.8%, 31/398), with leading causes including multi-organ failure in 16 patients (51.6%), permanent neurologic deficit in 6 (19.4%), and low cardiac output syndrome in 4 (12.9%). Permanent neurologic deficit and spinal cord injury occurred, each in 10 patients (2.5%, 10/398). Five significant risk factors for early mortality were identified with multivariate analysis: preexisting cerebrovascular disease [relative risk (RR) 14.76; P<0.001], acute heart failure (RR 18.18; P=0.001), spinal cord malperfusion (RR 60.13; P<0.002), visceral malperfusion (RR 30.25; P<0.001) and cardiopulmonary bypass time >190 minutes (RR 3.62; P=0.007).
The Sun’s procedure has generated a relatively lower mortality rate in 398 patients with AAAD. Patients with preexisting cerebrovascular disease, acute heart failure, spinal cord malperfusion, visceral malperfusion and long cardiopulmonary bypass time are at a higher risk of early mortality.
Aortic dissection; stented graft; surgery; outcome; mortality; complication
Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT). It has been previously reported that lung GVHD severity directly correlates with the expansion of donor Th17 cells in the absence of IFN-γ. However, the consequence of Th17-associated lung GVHD in the presence of IFN-γ has not been well-characterized. In the current study, T cells from IFN-γ receptor knockout (IFN-γR-/-) mice, capable of producing IFN-γ but unable to signal in response to IFN-γ, have been used to further elucidate the role of IFN-γ in GVHD. We found the transfer of donor T cells from either IFN-γR-/- or IFN-γ knockout (IFN-γ-/-) mice resulted in significant increases in donor Th17 cells in the lung. Marked increases in IL4-producing Th2 cells infiltrating the lungs were also observed in the mice of donor IFN-γR-/- T cells. Interestingly, despite the presence of these cells, these mice did not show the severe immune mediated histopathological lung injury observed in mice receiving donor IFN-γ-/- T cells. Increases in lung GVHD did occur in mice with donor IFN-γR-/- T cells when treated in vivo with anti-IFN-γ demonstrating that the cytokine has a protective role on host tissues in GVHD. A survival benefit from acute GVHD was also observed using donor cells from IFN-γR-/-T cells compared with control donors. Importantly, tumor-bearing mice receiving IFN-γR-/- T cells, versus wild-type donor T cells, displayed similar graft-versus tumor (GVT) effects. These results demonstrate the critical role of the IFN-γ on host tissues and cell effector functions in GVHD/GVT.
Glioblastomas are the most aggressive forms of primary brain tumors due to their tendency to invade surrounding healthy brain tissues, rendering them largely incurable. The water channel protein, Aquaporin-4 (AQP4) is a key molecule for maintaining water and ion homeostasis in the central nervous system and has recently been reported with cell survival except for its well-known function in brain edema. An increased AQP4 expression has been demonstrated in glioblastoma multiforme (GBM), suggesting it is also involved in malignant brain tumors. In this study, we show that siRNA-mediated down regulation of AQP4 induced glioblastoma cell apoptosis in vitro and in vivo. We further show that several apoptotic key proteins, Cytochrome C, Bcl-2 and Bad are involved in AQP4 signaling pathways. Our results indicate that AQP4 may serve as an anti-apoptosis target for therapy of glioblastoma.
To assess whether selenium and carboxymethyl-lysine (CML), two biomarkers of oxidative stress, are independent predictors of anemia in older, community-dwelling adults.
Plasma selenium, CML, folate, vitamin B12, testosterone, and markers of iron status and inflammation were measured at baseline in 1,036 adults, ≥65 years, in the InCHIANTI Study, a population-based cohort study of aging in Tuscany, Italy, and examined in relationship to prevalent anemia and incident anemia over 6 years of follow-up.
At enrollment, 11.6% of participants were anemic. Of 472 participants who were non-anemic at enrollment 72 (15.3%) developed anemia within 6 years of follow-up. At enrollment, plasma CML in the highest quartile (>425 ng/mL) and plasma selenium in the lowest quartile (<66.6 μg/L) predicted incident anemia (Hazards Ratio [H.R.] 1.67, 95% Confidence Interval [C.I.] 1.07–2.59, P = 0.02; H.R. 1.55, 95% C.I.1.01–2.38, P = 0.05, respectively) in a multivariate Cox proportional hazards model that adjusted for age, education, body mass index, cognition, inflammation, red cell distribution width, ferritin, vitamin B12, testosterone, and chronic diseases.
Elevated plasma carboxymethyl-lysine and low plasma selenium are long-term independent predictors of anemia among older community-dwelling adults. These findings support the idea that oxidative stress contributes to the development of anemia.
advanced glycation end products; aging; anemia; carboxymethyl-lysine; oxidative stress; selenium
Hepatic ischemia/reperfusion is a multi-factorial process which causes liver injury. It is reported that ischemia alone is sufficient to induce liver injury. Nutrient deprivation is a crucial factor impacting ischemic injury of the liver. Therefore, we explored the role of autophagy in ischemia through using hepatic ischemia rat model in vivo and nutrient-free model in vitro.
We found that both ischemia in vivo and nutrient deprivation in vitro activated autophagy, inhibition of which aggravated ischemia- or nutrient deficiency-induced injury. In the nutrient-free condition, autophagy inhibition enhanced liver cell necrosis but not apoptosis by promoting reactive oxygen species (ROS) accumulation, and antioxidant NAC could reverse this trend. Inhibition of autophagy also resulted in the increase of the percentage of necrotic cell but not apoptotic cell in the ischemia-treated rat livers. Further studies showed that under nutrient deprivation, autophagy inhibition promoted mitochondrial ROS generation, which further aggravated mitochondria damage. These changes formed a “vicious cycle” that accelerated the process of cell necrosis. Autophagy inhibition also increased mitochondrial oxidative stress during hepatic ischemia, and antioxidant could suppress the aggravation of ischemia-induced liver damage in the co-treatment of autophagy inhibitor.
Taken together, our results suggested that autophagy suppressed ischemic liver injury by reducing ROS-induced necrosis. This finding will contribute to the development of the therapeutic strategy about the pre-treatment of liver surgery.
Liver ischemia; Nutrient deprivation; Autophagy; Reactive oxygen species; Necrosis
Cardiotonic pill (CP) is a compound Chinese medicine currently used in China for treatment of ischemic angina pectoris. Our previous results indicated that a single dosing of CP pretreatment at 0.8 g/kg attenuates ischemia/reperfusion- (I/R-) induced myocardial injury and cardiac microcirculatory disturbance. The present study aimed to investigate the effect of CP at low dosage in a multiple dosing manner and to uncover the mechanism of antioxidative activity of CP. Male Sprague-Dawley rats were subjected to left anterior descending artery occlusion for 30 min followed by 60 min reperfusion. CP was administrated daily by gavage for six days at 0.1, 0.4, and 0.8 g/kg/day before I/R. Results showed that multiple dosing of CP at three doses significantly reduced I/R-induced myocardial injury, microcirculatory disturbance, and oxidative stress. CP dramatically inhibited I/R-induced nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase subunit gp91phox expression and p67phox and p47phox translocation from cytosol to cell membrane. Translocation of cytosolic subunits to membrane is required for the activation of NADPH oxidase. These data suggested that multiple dosing of CP at doses ranging from 0.1 to 0.8 g/kg/day reduced I/R-induced rat myocardial injury and microcirculatory disturbance, which was mediated by inhibition of NADPH oxidase activation.
Huang Qi Jian Zhong Pellet (HQJZ) is a famous Chinese medicine formula for treatment of various gastrointestinal tract diseases. This study investigated the role of HQJZ in 2,4,6-trinitrobenzene sulfonic acid- (TNBS-) induced colitis and its underlying mechanism. Colonic mucosal injury was induced by TNBS in the Sprague-Dawley rats. In the HQJZ treatment group, HQJZ was administered (2 g/kg) for 14 days starting from day 1 after TNBS infusion. Colonic mucosal injury occurred obviously 1 day after TNBS challenge and did not recover distinctively until day 15, including an increase in macro- and microscopic scores, a colonic weight index, a decrease in colonic length, a number of functional capillaries, and blood flow. Inverted intravital microscopy and ELISA showed colonic microcirculatory disturbances and inflammatory responses after TNBS stimulation, respectively. TNBS decreased occludin, RhoA, and ROCK-I, while increasing Rac-1, PAK-1, and phosphorylated myosin light chain. In addition, ATP content and ATP5D expression in colonic mucosa decreased after TNBS challenge. Impressively, treatment with HQJZ significantly attenuated all of the alterations evoked by TNBS, promoting the recovery of colonic injury. The present study demonstrated HQJZ as a multitargeting management for colonic mucosal injury, which set in motion mechanisms involving improvement of energy metabolism.
Our data demonstrate that estrogens, estrogen receptor-α (ERα), and estrogen receptor-β (ERβ) regulate adipose tissue distribution, inflammation, fibrosis, and glucose homeostasis, by determining that αERKO mice have increased adipose tissue inflammation and fibrosis prior to obesity onset. Selective deletion of adipose tissue ERα in adult mice using a novel viral vector technology recapitulated the findings in the total body ERα null mice. Generation of a novel mouse model, lacking ERα specifically from adipocytes (AdipoERα), demonstrated increased markers of fibrosis and inflammation, especially in the males. Additionally, we found that the beneficial effects of estrogens on adipose tissue require adipocyte ERα. Lastly, we determined the role of ERβ in regulating inflammation and fibrosis, by breeding the AdipoERα into the βERKO background and found that in the absence of adipocyte ERα, ERβ has a protective role. These data suggest that adipose tissue and adipocyte ERα protects against adiposity, inflammation, and fibrosis in both males and females.
ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; WAT, white adipose tissue; BAT, brown adipose tissue; Estrogen receptor alpha (ERα); White adipose tissue (WAT); Fibrosis; Inflammation
The aging suppressor gene klotho encodes a single-pass transmembrane protein klotho that in mice is known to extend life span when overexpressed and to resemble accelerated aging, with skeletal muscle atrophy and decreased bone mineral density, when expression is disrupted. We sought to examine the relationship between plasma klotho and disability in activities of daily living (ADL) in older community-dwelling adults. In a cross-sectional study, plasma klotho was measured in a population-based sample of 802 adults, ≥65 years, who participated in the “Invecchiare in Chianti” (Aging in the Chianti Area) (InCHIANTI) study in Tuscany, Italy. The overall proportion of adults with ADL disability was 11.9%. Mean (standard deviation) klotho concentrations were 689 (238) pg/mL. From the lowest to the highest tertile of plasma klotho, 16.1%, 9.7%, and 5.6% of participants, respectively, had ADL disability (p=0.0004). Plasma klotho, per 1 standard deviation increase, was associated with ADL disability (odds ratio=0.57, 95% confidence interval 0.35–0.93, p=0.02) in a multivariate logistic regression model adjusting for age, education, cognition, physical activity, physical performance, total cholesterol, alcohol and tobacco use, and chronic diseases. Low plasma klotho concentrations were independently associated with ADL disability among older community-dwelling men and women.
Recent studies have expanded the functions of vitamin D to a possible role in pulmonary function. Our objective was to examine the relationship between serum 25-hydroxyvitamin D (25[OH]D), serum parathyroid hormone, and pulmonary function in older women.
We examined the relationship of serum 25(OH)D and parathyroid hormone with pulmonary function (forced expiratory volume in one second [FEV1], forced vital capacity [FVC], and FEV1/FVC ratio) in a cross-sectional study of 646 moderately to severely disabled women, 65 years or more, living in the community in Baltimore, Maryland, who participated in the Women’s Health and Aging Study I.
Overall, median (25th, 75th percentile) serum 25-hydroxyvitamin D concentrations were 19.9 (14.7, 26.7) ng/mL. Serum 25(OH)D was positively associated with FEV1 (p = .03), FVC (p = .18), and FEV1/FVC (p = .04) in multivariable linear regression models adjusting for age, race, education, smoking, height, physical activity, cognition, interleukin-6, chronic diseases, and other potential confounders. In the same models, serum parathyroid hormone was not significantly associated with FEV1, FVC, or FEV1/FVC.
These findings support the idea that vitamin D deficiency is independently associated with poor pulmonary function in older disabled women.
Aging; Lung function; Parathyroid hormone; Vitamin D; Women
AIM: To investigate the regulative effect of miRNA-338-3p (miR-338-3p) on cell growth in colorectal carcinoma (CRC).
METHODS: The lentiviral vector pLV-THM-miR-338-3p and pLV-THM-miR-338-3p-inhibitor were constructed. The recombinant viral vector encoding the pre-miR-338-3p or miR-338-3p-inhibitor and the two packaging plasmids psPAX2 and pMD2.G were cotransfected into human embryonic kidney 293T cells to package lentivirus. The supernatant containing the lentivirus particles was harvested to determine the viral titer, and this supernatant was then used to transduce CRC-derived cell line, SW-620. Flow cytometry was utilized for sorting the green fluorescent protein (GFP)+ cells to establish the SW-620 cell line stably expressing pre-miR-338-3p or miR-338-3p-inhibitor. Moreover, the expression of miR-338-3p was determined by real-time reverse transcriptase polymerase chain reaction, and Western blotting was used to detect the expression of the smoothened (SMO, the possible target of miR-338-3p) protein in SW-620 cells. Furthermore, the status of CRC cell proliferation and apoptosis were detected by 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay and flow cytometry, respectively.
RESULTS: Restriction enzyme digestion and DNA sequencing demonstrated that the lentiviral vector pLV-THM-miR-338-3p and pLV-THM-miR-338-3p-inhibitor were constructed successfully. GFP was expressed after the SW-620 cells were transduced by the lentivirus. Expression of miR-338-3p in SW-620 cells transduced with the lentivirus pLV-THM-miR-338-3p was significantly increased (relative expression 3.91 ± 0.51 vs 2.36 ± 0.44, P < 0.01). Furthermore, overexpression of miR-338-3p inhibited the expression of SMO protein in SW-620 cells, which showed obviously suppressed proliferation ability [cellular proliferation inhibition rate (CPIR) 61.9% ± 5.2% vs 41.6% ± 4.8%, P < 0.01]. Expression of miR-338-3p in SW-620 cells transduced with the lentivirus pLV-THM-miR-338-3p-inhibitor was significantly decreased (relative expression 0.92 ± 0.29 vs 2.36 ± 0.44, P < 0.01). Moreover, the downregulated expression of miR-338-3p caused upregulated expression of the SMO protein in SW-620 cells, which showed significantly enhanced proliferation ability (CPIR 19.2% ± 3.8% vs 41.6% ± 4.8%, P < 0.01). However, anti-SMO-siRNA largely, but not completely, reversed the effects induced by blockage of miR-338-3p, suggesting that the regulative effect of miR-338-3p on CRC cell growth was indeed mediated by SMO.
CONCLUSION: miR-338-3p could suppress CRC growth by inhibiting SMO protein expression.
Colorectal carcinoma; Hsa-miRNA-338-3p; Smoothened; Lentivirus
In this paper we report the enzymatic properties of Ti-doped CeO2 nanoparticles. The superoxide dismutase activity of Ti-doped nanoparticles is reduced in comparison to undoped nanoceria. In contrast, the oxidase activity of these nanoparticles was unchanged. The change in enzymatic activity was accompanied by a dramatic change in shape to a spherical nanostructure. In addition to reporting a new type of enzymatically-active nanoparticle, Ti-doped cerium oxide nanoparticles are well suited for biological applications.
nanoparticles; nanoceria; enzymatic activity; metal oxides
Background: To investigate the efficacy of TACE combined with CQ, an autophagic inhibitor, in a rabbit VX2 liver tumor model.
Methods: Tumor size was measured. And tumor growth rate was calculated to examine the effect of the combined treatment. Apoptosis was detected by TUNEL assay. Meanwhile, autophagic activity was detected by immunohistochemistry and Western blotting to investigate the mechanism underlying. Liver function was also examined to assess feasibility and safety of the combined therapy.
Results: Tumors in the control grew more than 4 times bigger after 14 days, while that in the group of TACE alone just showed mild growth. But a slight shrinkage was shown after the treatment of CQ+TACE. Growth ratio of TACE alone was 96.45% ± 28.958% while that of CQ+TACE was -28.73% ± 12.265%. Compared with TACE alone, necrosis in CQ+TACE showed no significant difference, however, the apoptosis was much higher. There were only 14.8±3.11% apoptotic cells in TACE, but 33±4.18% in CQ+TACE, which suggests the increased apoptosis in CQ+TACE contributed to the decrease of tumor volume. In terms of autophagic activity, the result is negative when we immunostained sections of the control with LC3 antibody, but positive in TACE alone and CQ+TACE. And the result of Western blot showed that there was just a low level of LC3Ⅱexpressed in the control and CQ alone, but higher in TACE, and much higher in CQ+TACE because CQ inhibited its degradation in autophagy. Compared with control, p62 decreased in TACE, but the decrease was partially reversed in CQ+TACE. In addition, toxicity of CQ+TACE was assessed not higher than TACE alone, which supports the safety of CQ+TACE.
Conclusion: CQ+TACE works better than TACE alone in rabbit VX2 liver tumor model because CQ inhibits autophagy induced by TACE. The inhibited autophagy loses its resistance to apoptosis that apoptosis increased, which contributes to the inhibition of tumor growth. This study indicates CQ may be a promising adjuvant to promote the effect of TACE.
Hepatocellular carcinoma; transcatheter arterial chemoembolization; chloroquine; apoptosis; autophagy.
The effect of Cuscuta chinensis extract on the rabbit penile corpus cavernosum (PCC) was evaluated in the present study. Penises obtained from healthy male New Zealand white rabbits (2.5–3.0 kg) were precontracted with phenylephrine (Phe, 10 µmol l−1) and then treated with various concentrations of Cuscuta chinensis extract (1, 2, 3, 4 and 5 mg ml−1). The change in penile tension was recorded, and cyclic nucleotides in the PCC were measured by radioimmunoassay (RIA). The interaction between Cuscuta chinensis and sildenafil was also evaluated. The result indicated that the PCC relaxation induced by Cuscuta chinensis extract was concentration-dependent. Pre-treatment with an nitric oxide synthase (NOS) inhibitor (Nω nitro-L-arginine-methyl ester, L-NAME), a guanylyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ), or a protein kinase A inhibitor (KT 5720) did not completely inhibit the relaxation. Incubation of penile cavernous tissue with the Cuscuta chinensis extract significantly increased cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) in the PCC. Moreover, the Cuscuta chinensis extract significantly enhanced sildenafil-induced PCC relaxation. In conclusion, the Cuscuta chinensis extract exerts a relaxing effect on penile cavernous tissue in part by activating the NO-cGMP pathway, and it may improve erectile dysfunction (ED), which does not completely respond to sildenafil citrate.
Cuscuta chinensis; erectile dysfunction (ED); NO-cGMP pathway; penile corpus cavernosum (PCC); sildenafil
In a community-based study, the relationship between age and human prostate size was investigated in a population of men between the ages of 40 and 70 years to determine the normal prostate increase curve equation. One thousand male volunteers were randomly recruited from the Shanghai community, and the length, width, height, volume of the transition zone (TZ) and the whole prostates were measured by transrectal ultrasound (TRUS). Each volunteer was evaluated by the International Prostate Symptom Score (IPSS). Among those who completed the examination, the mean prostate parameters were all positively associated with increased age. There were statistically significant differences between each age group (P<0.05). The mean transition zone volume (TZV) had a higher increase rate with age than the mean total prostate volume (TPV), indicating that the enlargement of the TZ contributed the most to the increase in TPV. While all prostate parameters were positively correlated with the IPSS, the strongest correlation was associated with the TZ length (TZL) and TZV. The growth curve equations for prostate width, height and length were also positively associated with increasing age.
benign prostate hyperplasia (BPH); growth equation; International Prostate Symptom Score (IPSS); prostate; transrectal ultrasound (TRUS)
An effective cancer therapeutic should target tumours specifically with limited systemic toxicity. Here, we transformed an attenuated Salmonella typhimurium (S. typhimurium) with an Apoptin expressing plasmid into a human laryngeal carcinoma cell line. The expression of the inserted gene was measured using fluorescence and immunoblotting assays. The attenuated S. typhimurium-mediated Apoptin significantly decreased cytotoxicity and strongly increased cell apoptosis through the activation of caspase-3. The process was mediated by Bax, cytochrome c and caspase-9. A syngeneic nude murine tumour model was used to determine the anti-tumour effects of the recombinant bacteria in vivo. Systemic injection of the recombinant bacteria with and without re-dosing caused significant tumour growth delay and reduced tumour microvessel density, thereby extending host survival. Our findings indicated that the use of recombinant Salmonella typhimurium as an Apoptin expression vector has potential cancer therapeutic benefits.
tumours specifically therapy; attenuated Salmonella typhimurium; laryngeal cancer; Apoptin; apoptosis
Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes1. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control2. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism3. Moreover, in animal models, autophagy protects against diseases such as cancer, neuro-degenerative disorders, infections, inflammatory diseases, ageing and insulin resistance4-6. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)- induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.
Aggregation of amyloid-β peptides (Aβ) into fibrils is the key pathological feature of many neurodegenerative disorders. Typical drugs inhibit Aβ fibrillation by binding to monomers in 1:1 ratio and display low efficacy. Here, we report that model CdTe nanoparticles (NPs) can efficiently prevent fibrillation of Aβ associating with 100–330 monomers at once. The inhibition is based on the binding multiple Aβ oligomers rather than individual monomers. The oligomer route of inhibition is associated with strong van der Waals interactions characteristic for NPs and presents substantial advantages in the mitigation of toxicity of the misfolded peptides. Molar efficiency and the inhibition mechanism revealed by NPs are analogous to those found for proteins responsible for prevention of amyloid fibrillation in human body. Besides providing a stimulus for finding biocompatible NPs with similar capabilities, these data suggest that inorganic NPs can mimic some sophisticated biological functionalities of proteins.
amyloid beta-peptides; fibril; nanoparticles; inhibition; nanoscale assemblies