OBJECTIVE: To evaluate the protective effects of resveratrol against acute lung injury (ALI) and investigate the potential mechanisms underlying the reactive oxygen species (ROS)-triggered thioredoxin-interacting protein (TXNIP)/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) pathway. METHODS: C57BL/6 mice and J774A.1 cells were selected as the research subjects. Thirty Mice were randomly divided into 5 groups of 6 in each group: control with 0.9% saline, 5 mg/kg lipopolysaccharide (LPS) 24 h, 25 mg/kg resveratrol + 5 mg/kg LPS, 100 mg/kg resveratrol + 5 mg/kg LPS, and 4 mg/kg NLRP3 inhibitor CY-09 + 5 mg/kg LPS. For cell stimulation, cells were pretreated with 5 and 20 µmol/L resveratrol for 2 h, and stimulated with or without 1 µg/mL LPS and 3 mmol/L ATP for 2 h. The antioxidant N-acetyl-L-cysteine (NAC, 2 µmol/L) was used as the positive control group. Hematoxylin and eosin staining was used to evaluate the degree of lung LPS-induced tissue damage, and enzyme-linked immunosorbent assay was used to evaluate the contents of interleukin-1 β (IL-1 β) and IL-18 in the serum and cell supernatant. ROS and malondialdehyde (MDA) levels in the lung tissue were detected using the corresponding kits. Western blotting was used to detect the expressions of TXNIP, high-mobility group box 1 (HMGB1), NLRP3, as well as cysteine-aspartic acid protease 1 (caspase-1) and gasdermin D (GSDMD) along with their cleaved forms in lung tissue. Additionally, reverse transcription quantitative polymerase chain reaction was performed to analyze the expression of related inflammatory cytokines. ROS content was detected using flow cytometry and confocal laser microscopy. Mitochondrial morphological changes were observed using transmission electron microscopy, and HMGB1 expression was detected using immunofluorescence. RESULTS: Resveratrol significantly alleviated LPS-induced lung damage with reduced inflammation, interstitial edema, and leukocyte infiltration (P<0.01). It also decreased serum levels of IL-1 β and IL-18 (P<0.05), while downregulating the expressions of NLRP3, IL-6, and other inflammatory markers at both the protein and mRNA levels (P<0.05). Notably, the higher dose (100 mg/kg) demonstrated a better effect than the lower dose (25 mg/kg). In macrophages, resveratrol reduced IL-1 β and IL-18 following LPS and ATP stimulation, suppressed HMGB1 translocation, and inhibited formation and activation of the NLRP3 inflammasome (P<0.05 or P<0.01). These anti-inflammatory effects were mediated through the suppression ROS accumulation (P<0.01) and mitochondrial dysfunction. Transmission electron microscopy revealed that resveratrol preserved mitochondrial structure, preventing the mitochondrial damage seen in LPS-treated groups (P<0.01). The expressions of cleaved caspase-1, cleaved GSDMD, and cytoplasmic HMGB1 were all reduced following resveratrol treatment (P<0.01). Moreover, resveratrol inhibited dissociation of TXNIP from thioredoxin, blocking subsequent activation of NLRP3 and downstream inflammatory cytokines (P<0.01). Similarly, the higher concentration of resveratrol (20 µ mol/L) exhibited superior efficacy in vitro. CONCLUSION Resveratrol can reduce the inflammatory response following ALI and inhibit the activation of NLRP3 inflammasome and the level of HMGB1 in the cytoplasm by inhibiting ROS overproduction.
Acute Lung Injury/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Animals ; Resveratrol/pharmacology* ; Reactive Oxygen Species/metabolism* ; Inflammation/complications* ; Mice, Inbred C57BL ; Carrier Proteins/metabolism* ; Signal Transduction/drug effects* ; Lipopolysaccharides ; Thioredoxins/metabolism* ; Mice ; Lung/drug effects* ; Male ; Cell Line ; Interleukin-1beta/metabolism* ; Cell Cycle Proteins ; Stilbenes/therapeutic use*

OBJECTIVES: Pain sensitization, as a core feature of neuropathic pain (NP), is closely associated with inflammatory imbalance within the central nervous system. To investigate the effects of intrathecal injection of noggin (NOG) on mechanical hypersensitivity, microglial (MG) activation and polarization, and iron metabolism in a spinal nerve ligation (SNL)-induced rat model of NP, and to explore the role of signal transducer and activator of transcription 3 (STAT3) in MG phenotypic transformation. METHODS: Sixty-six Sprague-Dawley (SD) rats were randomly divided into 3 groups: Sham, SNL, and SNL+NOG. Paw withdrawal threshold (PWT) was assessed using von Frey filaments. Western blotting and real-time polymerase chain reaction (RT-PCR) were used to detect spinal cord expression of MG activation marker CD11b, STAT3, phosphorylated STAT3 (p-STAT3), M1 polarization markers [CD86, CD32, interleukin (IL)-1β], tumor necrosis factor-alpha (TNF-α), and CC chemokine receptor 2 (CCR2), M2 markers [CD204, CD163, CX3C chemokine receptor 1 (CX3CR1), IL-10, and arginase-1 (ARG-1)], and iron metabolism-related proteins including ferroportin (FPN, gene: SLC40A1), hepcidin (gene: HAMP), transferrin receptor (gene: TFRC), and divalent metal transporter 1 (DMT-1, gene: SLC11A2). p-STAT3 localization in MGs was visualized via immunofluorescence. In vitro, primary MGs were divided into Control, bone morphogenetic protein-4 (BMP4), and BMP4+Stattic (STAT3 inhibitor) groups to examine the effects of STAT3 inhibition on MG activation, polarization, and iron regulation. RESULTS: In vivo, compared with the Sham group, the SNL and SNL+NOG groups exhibited significantly decreased PWT (P<0.05), elevated spinal CD11b and p-STAT3 protein levels (all P<0.05), increased M1 markers (CD86, CD32, IL-1β, TNF-α, and CCR2) (all P<0.05), and decreased M2 markers (CD204 protein; mRNA of CD204, ARG-1) (all P<0.05). Hepcidin protein and mRNA levels of HAMP, SLC11A2, and TFRC were significantly elevated, while FPN protein and SLC40A1 mRNA were reduced (all P<0.05). Compared to SNL alone, the SNL+NOG group showed increased PWT, decreased CD11b, p-STAT3, and M1 marker expression (except TNF-α), increased M2 marker expression, reduced hepcidin and HAMP levels, and increased FPN and SLC40A1 expression (all P<0.05). In vitro, BMP4 treatment increased CD11b, STAT3, p-STAT3, CD86, and hepcidin levels, while reducing CD204 and FPN (all P<0.05). Inhibition STAT3 with Stattic reversed these changes (all P<0.05). CONCLUSIONS NOG alleviates SNL-induced NP by antagonizing the STAT3 signaling pathway, thereby rebalancing microglial polarization and restoring iron metabolism.
Animals ; Neuralgia/drug therapy* ; Rats, Sprague-Dawley ; Microglia/cytology* ; STAT3 Transcription Factor/metabolism* ; Rats ; Iron/metabolism* ; Male ; Signal Transduction/drug effects* ; Carrier Proteins/therapeutic use* ; Homeostasis/drug effects* ; Spinal Cord/metabolism*

OBJECTIVETo observe the clinical efficacy of combination therapy with peg-IFNalpha and adefovir (CPIA) in women who were hepatfis B virus (HBV) carriers and had just given birth and received telbivudine (LdT) during pregnancy for prevention of mother-to-child transmission.

METHODSOne-hundred-and-fifty third trimester-pregnant women who were HBV carriers with highly-viremic were treated with LdT until time of birth. After delivery, those women with alanine aminotransferase (ALT) level exceeding two times the upper limit of normal and HBV DNA level that had decreased more than 31 gIU/mL or hepatitis B e antigen (HBeAg) titer that had decreased more than 50% were switched to CPIA for 96 weeks.

RESULTSFollowing delivery, 45 of the women were switched to the CPIA treatment, of which 91.1% (41/45) achieved virological response, 55.6% (25/45) achieved HBeAg clearance or seroconversion, and 26.7% (12/45) achieved hepatitis B surface antigen (HBsAg) clearance or seroconversion.The immediate post-delivery (and pre-CPIA) levels of HBeAg and HBV DNA were negatively associated with HBeAg clearance. Ninety-eight of the total study participants stopped the LdT treatment and there were no cases of significant deterioration of liver function.

CONCLUSIONPregnant women who are HBV carriers and receive LdT for protection against mother-to-child transmission, and who show significant ALT elevation and decreased HBeAg titer and/or reduced HBV DNA after delivery, may be good candidates for the CPIA therapy following delivery.

Adenine ; analogs & derivatives ; therapeutic use ; Alanine Transaminase ; blood ; Antiviral Agents ; therapeutic use ; Carrier State ; virology ; DNA, Viral ; blood ; Drug Therapy, Combination ; Female ; Hepatitis B Surface Antigens ; blood ; Hepatitis B e Antigens ; blood ; Hepatitis B, Chronic ; drug therapy ; Humans ; Infectious Disease Transmission, Vertical ; prevention & control ; Interferon-alpha ; therapeutic use ; Organophosphonates ; therapeutic use ; Polyethylene Glycols ; therapeutic use ; Pregnancy ; Pregnancy Complications, Infectious ; drug therapy ; virology ; Pregnancy Trimester, Third ; Recombinant Proteins ; therapeutic use ; Thymidine ; analogs & derivatives ; therapeutic use

With the development of the quality of life, the morbidity of hyperuricemia is increasing year by year. At the same time, it appears that this disease attacks the young people currently. As the study of pathogenesis of hyperuricemia advanced, a series of uric acid transporters were found during this process. Meanwhile, the definition of transporterome was proposed. They were divided into three groups according to the functions: reabsorption proteins, excretion proteins and skeleton proteins. At moment, the drugs for hyperuricmia mainly include uric acid composition inhibitors and uric acid excretion promoters. Since the excretion of uric acid plays a leading role during the process of attack of hyperurecimia, it makes sense to explore Chinese medicines with clear mechanism targeting the transporterome. Therefore, this paper would focus on transporterome and summarize the mechanisms of Chinese medicines in treating hyperuricemia.
Animals ; Biological Transport ; Carrier Proteins ; antagonists & inhibitors ; genetics ; metabolism ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Hyperuricemia ; drug therapy ; metabolism ; Uric Acid ; metabolism

OBJECTIVETo study the expression and prognostic significance of ERG and SPINK1 expression in endocrine-treated prostatic cancer.

METHODSProstatic needle biopsies from 118 prostatic cancer patients primarily treated with endocrine therapy were reviewed. Immunohistochemical study for ERG and SPINK1 protein was carried out.

RESULTSCo-expression of ERG and SPINK1 was not observed. The frequency of ERG protein expression in the 118 biopsies studied was 9.3% (11/118). The positive expression correlated with T stage (P=0.04) but not with patient age at diagnosis, prostatic specific antigen level, Gleason's score, M stage, tumor area and progression-free survival. Positive expression of SPINK1 was demonstrated in 11.0% (13/118) of the biopsies. SPINK1-positive cases carried a significantly shorter progression-free survival, as compared with SPINK1-negative cases (P=0.022). The expression was not associated with any other clinicopathologic variables. The following expression pattern showed statistically significant correlation with the clinical progress (P=0.029): ERG+/SPINK1- (11/118, 9.3%), ERG-/SPINK1+ (13/118, 11.0%) and ERG-/SPINK1- (94/118, 79.7%).

CONCLUSIONSERG and SPINK1 proteins are mutually exclusive.SPINK1 expression is associated with more aggressive clinical behavior and can serve as a prognostic biomarker in prostatic cancer.

Aged ; Aged, 80 and over ; Antineoplastic Agents, Hormonal ; therapeutic use ; Carrier Proteins ; metabolism ; Disease-Free Survival ; Follow-Up Studies ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Prognosis ; Prostatic Neoplasms ; drug therapy ; metabolism ; pathology ; Trans-Activators ; metabolism ; Transcriptional Regulator ERG ; Trypsin Inhibitor, Kazal Pancreatic

BACKGROUND/AIMS: A polymorphism in the microsomal triglyceride transfer protein (MTP) is associated with hepatic fibrosis, and carriers showed higher levels of steatosis, higher levels of hepatitis C virus (HCV) RNA and advanced fibrosis. The aim of this study was to study MTP expression pattern in HCV patients and impact of the MTP polymorphism on the response to antiviral therapy. METHODS: One hundred consecutive naive HCV genotype 4 patients were recruited to receive antiviral therapy, and 40 control subjects were also recruited. Demographic, laboratory, and histopathology data were collected. DNA was isolated, and the samples were subjected to polymerase chain reaction analysis and genotyping for MTP by restriction fragment length polymorphism analysis. RESULTS: Patients and controls were age- and sex-matched (male/female, 56/44, age, 39.2+/-7.8 years for patients with HCV; male/female, 18/22, age, 38.1+/-8.1 years for controls). MTP single nucleotide polymorphisms (SNPs) (GG, GT, TT) and alleles (G, T) in the patients versus the controls were 70%, 21%, 9% & 80.5%, 19.5% versus 10%, 87.5%, 2.5% & 53.8%, 46.3%, respectively (p=0.0001). The sustained viral response (SVR) of the patients was 60%. SNPs in MTP genotypes (GG, GT, and TT) and alleles (G and T) in the responders and nonresponders were 71.7%, 25%, 3.3% & 84.2%, 15.8% versus 67.5%, 15%, 17.5% & 75%, 25% (p=0.038 and p=0.109, respectively). A multivariate analysis showed that the GT genotype was an independent predictor of SVR (area under the curve 90% and p=0.0001). CONCLUSIONS: MTP could be a new predictor for SVR to antiviral therapy in patients with HCV genotype 4 infection.
Adult ; Antiviral Agents/*therapeutic use ; Carrier Proteins/*genetics ; Case-Control Studies ; Egypt ; Female ; Genotype ; Hepacivirus/genetics ; Hepatitis C, Chronic/*drug therapy/genetics ; Humans ; Male ; Middle Aged ; Polymorphism, Restriction Fragment Length ; Polymorphism, Single Nucleotide ; RNA, Viral/blood ; Treatment Outcome ; Viral Load

Adult ; Age of Onset ; Amino Acid Metabolism, Inborn Errors ; complications ; diagnosis ; genetics ; therapy ; Betaine ; administration & dosage ; therapeutic use ; Carrier Proteins ; genetics ; metabolism ; Child ; China ; epidemiology ; DNA Mutational Analysis ; Gas Chromatography-Mass Spectrometry ; Genotype ; Homocysteine ; urine ; Humans ; Hydroxocobalamin ; administration & dosage ; therapeutic use ; Hyperhomocysteinemia ; complications ; diagnosis ; genetics ; therapy ; Infant ; Methylmalonic Acid ; blood ; urine ; Mutation ; Vitamin B 12 ; metabolism

No abstract available.
Adenocarcinoma/*diagnosis/radiography/secondary ; Adult ; Antineoplastic Agents/therapeutic use ; Breast Neoplasms/*diagnosis/drug therapy/pathology ; Carrier Proteins/metabolism ; Doxorubicin/therapeutic use ; Drug Therapy, Combination ; Endoscopy, Digestive System ; Female ; Glycoproteins/metabolism ; Humans ; Mastectomy, Modified Radical ; Positron-Emission Tomography and Computed Tomography ; Stomach Neoplasms/*diagnosis/radiography/secondary ; Taxoids/therapeutic use ; Tomography, X-Ray Computed

BACKGROUNDEverolimus, a derivative of sirolimus, is a potent immunosuppressant that has important anti-proliferative properties. In the present study, we demonstrated the inhibiting neointimal hyperplasia in injured carotid arteries in rats by using two different doses of everolimus administrated via the oral route for a long time.

METHODSA rat model of carotid artery injury was established by balloon inflation. Eighty rats were randomly divided into the sham-operated group (n = 20), injury group (n = 20), low dosage of everolimus group (n = 20), and high dosage of everolimus group (n = 20). The low dose of everolimus (1.5 mg/kg) was given one day before injuring the carotid artery by balloon, followed by 0.75 mg/kg per day for 28 days via intragastric gavage. High dose everolimus (2.5 mg/kg) was given one day before injuring the carotid artery by balloon, followed by 1 mg/kg per day for 28 days. Expression of eukaryotic translation initiation factor 4E (eIF-4E) and phosphorylation of ribosomal protein S6 kinase 1 (P70S6K) were determined by reverse transcription-polymerase chain reaction and Western blotting analysis.

RESULTSIn the injured carotid artery, neointimal hyperplasia was normally observed four weeks after injury. Everolimus inhibited neointimal hyperplasia after balloon injury in a dose dependent manner. At the same time, the study demonstrated that everolimus reduced the expression of P-P70S6K, eIF-4E, transforming growth factor (TGF)-β1 and of proliferating cell nuclear antigen (PCNA).

CONCLUSIONSEverolimus significantly inhibited neointimal hyperplasia of the injured carotid artery. The effect depended on dosage and was associated with the reduction of phosphorylation of P70S6K and the eIF-4E expression level.

Animals ; Carotid Arteries ; drug effects ; Carotid Artery Injuries ; drug therapy ; Carrier Proteins ; metabolism ; Everolimus ; Male ; Neointima ; drug therapy ; Phosphoproteins ; metabolism ; Phosphorylation ; drug effects ; Rats ; Rats, Sprague-Dawley ; Ribosomal Protein S6 Kinases, 70-kDa ; metabolism ; Sirolimus ; analogs & derivatives ; therapeutic use

OBJECTIVETo investigate the effects of pegylated interferon a-2a (Peg-INFa-2a) treatment on expression of CD8 and CD38 surface molecules on lymphocytes from peripheral blood of inactive hepatitis B surface antigen (HBsAg) carriers.

METHODSForty-four patients with hepatitis B virus (HBV) chronic infection (CHB) received a 48-week course of Peg-INFa-2a treatment, with 30 administered 135 mug/week and 14 administered 180 mug/week. Every 12 weeks of treatment, the subjects were assessed for HBsAg titer, presence of anti-hepatitis B e (HBe) antibody, serum alanine amino transaminase (ALT) levels, and lymphocyte surface expression of CD8 and CD38 molecules. Patients were classified as responders and non-responders according to standard parameters. Dynamic differences between the two groups over time were assessed by multivariate repeated measures ANOVA with Greenhouse-Geisser correction and differences at single time points were assessed by univariate ANOVA. Linear regression analysis was performed to evaluate the relationship of two variables.

RESULTSThe responders showed a significantly higher increase in ALT at week 12 (60.75+/-24.95 U/L vs. non-responders: 37.03+/-18.45 U/L; t = 2.905, P less than 0.01) and significantly higher proportion of CD8+CD38+ cells at week 24 (71.20+/-11.70% vs. non-responders: 56.79+/-7.72%; F = 23.941, P less than 0.01). The decline in level of HBsAg at week 24 was positively correlated with the increase in ALT level at week 12 (r = 0.386, P less than 0.01) and with expression levels of CD8 and CD38 molecules on lymphocytes at week 24 (r = 0.397, P less than 0.01).

CONCLUSIONLower baseline levels of HBsAg correlated to better Peg-INFa-2a-related HBsAg clearance. Increased expression of CD8 and CD38 on lymphocytes is suggestive of intensive cellular immunity in CHB patients and may be related to HBV-induced hepatocyte damage and may promote the HBsAg clearance.

ADP-ribosyl Cyclase 1 ; metabolism ; Adult ; Aged ; Antiviral Agents ; administration & dosage ; therapeutic use ; CD8-Positive T-Lymphocytes ; Carrier State ; Hepatitis B Surface Antigens ; blood ; Hepatitis B, Chronic ; blood ; drug therapy ; Humans ; Interferon-alpha ; administration & dosage ; therapeutic use ; Middle Aged ; Polyethylene Glycols ; administration & dosage ; therapeutic use ; Recombinant Proteins ; administration & dosage ; therapeutic use ; T-Lymphocyte Subsets