ABSTRACT
Chronic kidney disease (CKD) poses a significant global health dilemma, emerging from complex causes. Although our prior research has indicated that a deficiency in Reticulon-3 (RTN3) accelerates renal disease progression, a thorough examination of RTN3 on kidney function and pathology remains underexplored. To address this critical need, we generated Rtn3-null mice to study the consequences of RTN3 protein deficiency on CKD. Single-cell transcriptomic analyses were performed on 47,885 cells from the renal cortex of both healthy and Rtn3-null mice, enabling us to compare spatial architectures and expression profiles across 14 distinct cell types. Our analysis revealed that RTN3 deficiency leads to significant alterations in the spatial organization and gene expression profiles of renal cells, reflecting CKD pathology. Specifically, RTN3 deficiency was associated with Lars2 overexpression, which in turn caused mitochondrial dysfunction and increased reactive oxygen species levels. This shift induced a transition in renal epithelial cells from a functional state to a fibrogenic state, thus promoting renal fibrosis. Additionally, RTN3 deficiency was found to drive the endothelial-to-mesenchymal transition process and disrupt cell-cell communication, further exacerbating renal fibrosis. Immunohistochemistry and Western-Blot techniques were used to validate these observations, reinforcing the critical role of RTN3 in CKD pathogenesis. The deficiency of RTN3 protein in CKD leads to profound changes in cellular architecture and molecular profiles. Our work seeks to elevate the understanding of RTN3's role in CKD's narrative and position it as a promising therapeutic contender.
Subject(s)
Disease Progression , Fibrosis , Gene Expression Profiling , Renal Insufficiency, Chronic , Single-Cell Analysis , Animals , Mice , Fibrosis/pathology , Fibrosis/metabolism , Fibrosis/genetics , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/pathology , Renal Insufficiency, Chronic/metabolism , Mice, Knockout , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Kidney/pathology , Kidney/metabolism , Transcriptome , Reactive Oxygen Species/metabolism , Epithelial-Mesenchymal Transition/genetics , Disease Models, Animal , Mitochondria/metabolism , Mitochondria/pathology , Mitochondria/geneticsABSTRACT
Alcoholic fatty liver disease (FALD) and non-alcoholic fatty liver disease (NAFLD) have similar pathological spectra, both of which are associated with a series of symptoms, including steatosis, inflammation, and fibrosis. These clinical manifestations are caused by hepatic lipid synthesis and metabolism dysregulation and affect human health. Despite having been studied extensively, targeted therapies remain elusive. The Cytochrome P450 (CYP450) family is the most important drug-metabolising enzyme in the body, primarily in the liver. It is responsible for the metabolism of endogenous and exogenous compounds, completing biological transformation. This process is relevant to the occurrence and development of AFLD and NAFLD. In this review, the correlation between CYP450 and liver lipid metabolic diseases is summarised, providing new insights for the treatment of AFLD and NAFLD.
ABSTRACT
Dermal exposure to chemicals derived from object surface contact is an important contributor to increased health risk. However, chemical transfer induced by mechanical friction between dermal and object surface has yet to be adequately addressed. To fill this knowledge gap, rubbing fabrics were used as surrogate skins to stimulate dermal mechanical friction with pad products with phthalates as target analytes. The results showed that the amounts of phthalates transferred increased linearly with contact burden (50-1000 g), contact duration (1-10 min), and sliding speed (3.0-9.0 cm s-1). The surface texture of surrogate skins dictated the accumulation of phthalates. Net/pocket micro-surface structures of rubbing fabrics induced a higher accumulation of phthalates than U-shape structures of fabrics with a similar surface roughness. Covering of the pad surface by a layer of textile was effective in minimizing the transfer of phthalates induced by mechanical motion. The estimated transfer efficiency of bis(2-ethylhexyl) ester (DEHP) derived from rubbing friction (0.005-0.05%) upon the pad surface over 8 h was greater than those for gas-phase emission (0.00002-0.0005% over 24 h) and sweat transfer (0.008-0.012% over 24 h). These results indicated that dermal frictional contact with the surface of pad products was an important exposure pathway.
Subject(s)
Diethylhexyl Phthalate , Phthalic Acids , Environmental Exposure , Esters , FrictionABSTRACT
OBJECTIVE: To investigate the effect of acute graft-versus-host disease (aGVHD) mouse models established respectively by total body irradiation (TBI) and busulfan combined with cyclophosphamide (BU/CY) conditioning regimens after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Bone marrow cells and splenic mononuclear cells were isolated respectively from femur, tibia, and spleen of C57BL/6 male mice (H-2Kb) which were selected as donors. After TBI pretreatment, BALB/c female mice (H-2Kd) were injected with donor bone marrow cells 1×107/50 µl and splenic mononuclear cells 2×107/100 µl through caudal vein, while CB6F1 female mice (H-2Kd/b) with donor bone marrow cells 2×107/100 µl and splenic mononuclear cells 1×108/500 µl after BU/CY pretreatment. The successful establishment of the aGVHD models were determined by post-transplant manifestations, rate of chimerism, target organ damage, etc. Results: After transplantation, mice of both groups showed listlessness, low activity, continued weight loss, and typical manifestations of aGVHD such as alopecia, hunched posture, diarrhea, and anal swelling. and died within 4 weeks. Flow cytometry detection showed complete chimerism in all the mice. Pathological examination of skin, intestines, liver, lung, and spleen tissues showed obvious aGVHD pathological changes. However, the weight loss, ruffled fur, and alopecia combined with severe scurf on those hair-free areas were significantly apparent in TBI group than BU/CY group, as well as higher aGVHD score, and the differences were statistically significant (P<0.05). CONCLUSION: Both TBI and BU/CY as conditioning regimens can successfully establish stable mouse models of aGVHD after fully allo-HSCT and haploidentical HSCT for further research about mechanism of aGVHD. BU/CY conditioning regimen can more truly simulate physiological status in vivo of patients with chemotherapy based conditioning regimen, while TBI conditioning regimen shows significantly more typical aGVHD symptoms and easier to operate.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Alopecia/drug therapy , Animals , Busulfan/therapeutic use , Cyclophosphamide , Female , Graft vs Host Disease/drug therapy , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Transplantation Conditioning , Transplantation, Homologous , Weight Loss , Whole-Body IrradiationABSTRACT
BACKGROUNDS AND AIMS: Leucine, isoleucine, and valine are diet derived and essential amino acids that are termed branched-chain amino acids (BCAA). BCAA are widely used as dietary supplements to boost muscle growth and enhance exercise performance. However, the effects of BCAA on myocardial function are largely unknown. This study was designed to investigate whether BCAA affect heart function and, if so, to further explore the underlying molecular basis for the observed effects. METHODS AND RESULTS: C57BL/6J mice were randomly divided into two groups, the control group received solvent (water) and the BCAA group received 2% BCAA dissolved in water, for a successive period of 12 weeks. Compared with control, BCAA treatment significantly increased water consumption without changing body weight or diet consumption; heart tissue BCAA levels were increased, markers representative of myocardial injury in heart tissue including c-reactive protein and cardiac muscle troponin were increased ; and creatine kinase, creatine kinase-MB, and lactate dehydrogenase were increased in serum; severe myocardial fibrosis was observed by Masson staining, which was accompanied by increased reactive oxygen species (ROS) production and decreased superoxide dismutase activity in heart tissue; both p-AMPK and p-ULK1 were significantly increased as was autophagy, judged by the presence of LC3 by western blotting and immunofluorescence, increased numbers of autophagosomes were found by transmission electron microscopy in the BCAA group. In vitro, 20 mmol/L BCAA significantly decreased cell viability and increased the production of ROS, as well as the expression of p-AMPK/AMPK and p-ULK1/ULK1 in cultured H9C2 cells. Treatment with the ROS scavenger N-acetyl-L-cysteine (NAC) improved cell viability and reversed ROS changes. Decreased H9C2 cell viability induced with 20 mmol/L BCAA was reversed by either blocking AMPK or inhibition of ULK1. Furthermore, blocking AMPK significantly decreased p-ULK1/ULK1, while inhibition of ULK1 reversed the enhanced expression of LC3-II/LC3-I induced by BCAA. Excessive ROS production and decreased cell viability induced by BCAA were further confirmed in primary cultured murine cardiomyocytes. Pharmacological activation of α7nAChR with PNU-282987 attenuated BCAA-induced injury in primary murine cardiomyocytes. However, this compound failed to suppress BCAA activation of AMPK and autophagy (LC3-II/I ratio). CONCLUSION: These results provide the first evidence that treatment of mice with BCAA induced myocardial injury by triggering excessive ROS production and by enhancing AMPK-ULK1 pathway-dependent autophagy. These findings suggested that inhibition of either ROS production or autophagy may alleviate myocardial injury induced by BCAA.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Amino Acids, Branched-Chain/adverse effects , Autophagy-Related Protein-1 Homolog/metabolism , Autophagy , Heart Injuries/metabolism , Myocardium/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Amino Acids, Branched-Chain/pharmacology , Animals , Cell Line , Heart Injuries/chemically induced , Heart Injuries/pathology , Male , Mice , Myocardium/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathologyABSTRACT
BACKGROUND: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy is widely used in peripheral T cell lymphoma (PTCL). Here we conducted a phase 2, multicenter, randomized, controlled trial, comparing the efficacy and safety of CEOP/IVE/GDP alternating regimen with CEOP in newly diagnosed PTCL. METHODS: PTCL patients, except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, were 1:1 randomly assigned to receive CEOP/IVE/GDP (CEOP, cyclophosphamide 750 mg/m2, epirubicin 70 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1, and prednisone 60 mg/m2 [maximum 100 mg] on days 1-5 every 21 days, at the first and fourth cycle; IVE, ifosfamide 2000 mg/m2 on days 1-3, epirubicin 70 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1-3 every 21 days, at the second and fifth cycle; and GDP, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1-3, and dexamethasone 40 mg on days 1-4 every 21 days, at the third and sixth cycle) and CEOP (every 21 days for 6 cycles). Analysis of efficacy and safety was of the intent-to-treatment population. The primary endpoint was a complete response rate at the end of treatment. Meanwhile, whole exome sequencing and targeted sequencing were performed in 62 patients with available tumor samples to explore prognostic biomarkers in this cohort as an exploratory post hoc analysis. RESULTS: Among 106 patients, 53 each were enrolled to CEOP/IVE/GDP and CEOP. With 51 evaluable patients each in two groups, a complete response rate of the CEOP/IVE/GDP group was similar to that of the CEOP group (37.3% vs. 31.4%, p = 0.532). There was no difference in median progression-free survival (PFS; 15.4 months vs. 9.2 months, p = 0.122) or overall survival (OS; 24.3 months vs. 21.9 months, p = 0.178). Grade 3-4 hematological and non-hematological adverse events were comparable. Histone modification genes were most frequently mutated (25/62, 40.3%), namely KMT2D, KMT2A, SETD2, EP300, and CREBBP. Multivariate analysis indicated that CREBBP and IDH2 mutations were independent factors predicting poor PFS and OS (all p < 0.001), while KMT2D predicting poor PFS (p = 0.002). CONCLUSIONS: CEOP/IVE/GDP alternating regimen showed no remission or survival advantage to standard chemotherapy. Future clinical trials should aim to develop alternative regimen targeting disease biology as demonstrated by recurrent mutations in epigenetic factors. TRIAL REGISTRATION: The study was registered on ClinicalTrial.gov (NCT02533700) on August 27, 2015.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Deoxycytidine/analogs & derivatives , Lymphoma, T-Cell, Peripheral/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Cisplatin/adverse effects , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Drug Administration Schedule , Epirubicin/administration & dosage , Epirubicin/adverse effects , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Humans , Ifosfamide/administration & dosage , Ifosfamide/adverse effects , Lymphoma, T-Cell, Peripheral/genetics , Male , Middle Aged , Prednisone/administration & dosage , Prednisone/adverse effects , Prognosis , Vincristine/administration & dosage , Vincristine/adverse effects , Exome SequencingABSTRACT
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Prognosis is often unfavorable. In this study, the effects of microRNA-802 (miR-802) on HCC progression were assessed in vivo and in vitro. miR-802 was found to be significantly upregulated in HCC tumor tissue compared to paired adjacent nontumor tissue. In vitro, transfection with a miR-802 mimic accelerated SMMC-7721 cellular proliferation, increased accumulation of the cell-cycle S-phase cell populations, as well as cell migration. In vivo injection of a miR-802 agomir promoted HCC proliferation in nude mice. Targets of miR-802 were predicted by miRWalk, miRanda, RNA22, and Targetscan. By luciferase reporter assay RUNX3 was identified as a direct target of miR-802. As judged by western blot analysis, RUNX3 was upregulated when miR-802 was inhibited. These data demonstrate increased miR-802 expression in patients with HCC and that miR-802 overexpression promotes tumor cell growth, in a RUNX3-dependent manner.
Subject(s)
Carcinoma, Hepatocellular/genetics , Core Binding Factor Alpha 3 Subunit/genetics , Liver Neoplasms/genetics , MicroRNAs/genetics , Adult , Animals , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Core Binding Factor Alpha 3 Subunit/metabolism , Disease Progression , Female , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Mice , Mice, Nude , MicroRNAs/antagonists & inhibitors , MicroRNAs/metabolism , Middle Aged , Up-RegulationABSTRACT
Aging is a worldwide challenge, and it is accompanied by the accumulation of senescent cells. Cellular senescence is traditionally defined as permanent cell growth arrest and currently includes the senescence-associated secretory phenotype (SASP). There are two main types of cellular senescence, including telomere-dependent replicative senescence and stress-induced premature senescence. The process of cellular senescence is mainly controlled by two effector pathways, namely, the p53-p21 and p16-retinoblastoma protein (pRB) pathways. Vascular smooth muscle cells (VSMCs) are integral parts of arteries and play an important role in vascular structure and function. VSMC senescence may be triggered by many factors, such as angiotensin II, oxidative stress, inflammation, DNA damage, and small molecule compounds. These inducers are able to genetically and epigenetically regulate VSMC senescence. The senescence of VSMCs together with the SASP contributes to chronic vascular inflammation, the loss of arterial function, and the development of age-related diseases. Current evidence suggests that the senescence of VSMCs might be harmful to individual health, whereas its influence on the lifespan is not clear. The purpose of this paper was to review the current knowledge regarding VSMC senescence and its relevance to hypertension, atherosclerosis, and diabetes, as well as the potential mechanisms responsible for VSMC senescence in these age-related diseases.
Subject(s)
Atherosclerosis/physiopathology , Cellular Senescence , Diabetes Mellitus/physiopathology , Hypertension/physiopathology , Muscle, Smooth, Vascular/physiopathology , Aging , Animals , Atherosclerosis/metabolism , Diabetes Mellitus/metabolism , Humans , Hypertension/metabolism , Inflammation/metabolism , Inflammation/physiopathology , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/metabolism , Oxidative StressABSTRACT
Backgrounds and Aims: Na+ is an important nutrient and its intake, mainly from salt (NaCl), is essential for normal physiological function. However, high salt intake may lead to vascular injury, independent of a rise in blood pressure (BP). Canonical NALP3 inflammasome activation is a caspase-1 medicated process, resulting in the secretion of IL-18 and IL-1ß which lead to endothelial dysfunction. However, some researches uncovered a direct and inflammasome-independent role of NALP3 in renal injury. Thus, this study was designed to investigate the possible mechanisms of NALP3 in high salt induced endothelial dysfunction. Methods and Results: Changes in endothelial function were measured by investigating mice (C57BL/6J, NALP3-/- and wild-type, WT) fed with normal salt diet (NSD) or high salt diet (HSD) for 12W, and thoracic aortic rings from C57BL/6J mice cultured in high-salt medium. Changes of tube formation ability, intracellular reactive oxygen species (ROS), and NALP3 inflammasome expression were detected using mouse aortic endothelial cells (MAECs) cultured in high-salt medium. Consumption of HSD for 12W did not affect BP or body weight in C57BL/6J mice. Endothelium-dependent relaxation (EDR) decreased significantly in C57BL/6J mice fed with HSD for 12W, and in isolated thoracic aortic rings cultured in high-salt medium for 24 h. Results from the aortic ring assay also revealed that the angiogenic function of thoracic aortas was impaired by either consumption of HSD or exposure to high-salt medium. NALP3-/- mice fed with HSD showed a relatively mild decrease in EDR function when compared with WT mice. Tube length of thoracic aortic rings from NALP3-/- mice was longer than those from WT mice after receiving high-salt treatment. Inhibiting NALP3 with a NALP3 antagonist, small interfering (si) RNA experiments using si-NALP3, and decomposing ROS significantly improved tube formation ability in MAECs under high salt medium. NALP3 expression was increased in MAECs cultured with high salt treatment and inhibiting NALP3 reversed the down-regulation of p-eNOS induced by high salt in MAECs. Conclusion: High salt intake impairs endothelial function, which is at least in part mediated by increasing NALP3 expression.
ABSTRACT
BACKGROUND: Cervical cancer incidence and mortality is high in Uyghur ethnics. Their life style and dietary habit were different from other ethnics living together. Study on the role of trace elements in HPV infection and cervical lesion of Uyghur minority is needed for future intervention and prevention work. METHODS: In total, 833 Uyghur women were randomly selected from the screening site and hospital. The concentrations of the trace elements As, Fe, Cd, Ni, Cu, Zn, Mn, and Se were determined by atomic absorption spectrophotometry and inductively coupled plasma atomic emission spectroscopy. Univariate analysis was performed with chi-squared test between the HPV-positive and HPV-negative groups and between the case group and the control group. Multivariate analysis was performed with logistic regression. RESULTS: An As concentration ≥ 0.02 mg/kg was a risk factor for HPV infection (OR > 1, P < 0.05), and Ni concentration ≥ 0.1232 mg/kg and Se concentration ≥ 0.02 mg/kg were protective factors (OR < 1, P < 0.05). Concentrations of Fe ≥ 6.9153 mmol/L and As ≥0.02 mg/kg were risk factors for CIN2+ (OR > 1, P < 0.05), and concentrations of Ni ≥0.0965 mg/kg and Se ≥0.02 mg/kg were protective factors (OR < 1, P < 0.05). CONCLUSIONS: Low serum concentrations of Se and Ni and a high serum concentration of As might be related to HPV infection and CIN2+ in Uyghur women in rural China.
Subject(s)
Arsenic/blood , HIV Infections/epidemiology , Nickel/blood , Selenium/blood , Uterine Cervical Neoplasms/epidemiology , Adult , China/ethnology , Female , HIV Infections/blood , Humans , Logistic Models , Middle Aged , Rural Population , Spectrophotometry, Atomic , Trace Elements/blood , Uterine Cervical Neoplasms/blood , Young AdultABSTRACT
Interleukin-6 (IL-6) is a pleiotropic cytokine produced by a variety of cell types, including fibroblasts, endothelial cells, lymphocytes, and bone marrow stromal cells (BMSCs). Levels of IL-6 are increased in serum of CLL patients and correlated with adverse clinical features and short survival. In our study, we observed that IL-6 induced the resistance of CLL cells to pan-histone deacetylase (HDAC) inhibitors vorinostat (SAHA) and panobinostat (LBH589). Furthermore, low concentrations of SAHA and LBH589 enhanced the activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway induced by IL-6 in CLL cells. All of these effects were blocked by the STAT3-selective inhibitor, WP1066. Meanwhile, WP1066 decreased the expressions of Mcl-1 and Bcl-xL protein induced by IL-6 with or without low concentrations of HDAC inhibitors. Co-culture of CLL cells with BMSCs could also facilitate the activation of STAT3 and protected CLL cells from apoptosis when treated with HDAC inhibitors, and this cytoprotection was reversed by WP1066. The present study indicated that IL-6 or co-culture with BMSCs prevented HDAC inhibitor-induced apoptosis of CLL cells. This prevention was mediated by activation of the STAT3 signaling pathway. Moreover, WP1066 reversed the resistance of CLL cells to SAHA and LBH589 induced by either IL-6 or co-culture with BMSCs. Our findings suggest that targeting the STAT3 pathway may be a novel way to improve the efficacy of the HDAC inhibitor in CLL patients by overcoming antiapoptotic signaling of the microenvironment.
Subject(s)
Antineoplastic Agents/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Interleukin-6/physiology , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Pyridines/pharmacology , STAT3 Transcription Factor/antagonists & inhibitors , Tyrphostins/pharmacology , Adult , Aged , Aged, 80 and over , Cell Survival/drug effects , Coculture Techniques , Drug Resistance, Neoplasm , Female , Humans , Hydroxamic Acids/pharmacology , Indoles/pharmacology , Male , Middle Aged , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Panobinostat , Phosphorylation , Protein Processing, Post-Translational/drug effects , Stromal Cells/drug effects , Stromal Cells/physiology , Tumor Cells, Cultured , Vorinostat , bcl-X Protein/metabolismABSTRACT
Non-Hodgkin's lymphoma (NHL) is a malignant tumor originated in lymphatic hematopoietic tissue. At present, chemotherapy is the main treatment method of NHL, but the chemoresistance is still an important reason for NHL treatment failure. The mechanism of NHL multidrug resistance (MDR) is complex, involving a variety of singnal pathways, in which mutation in the genetic level of the key genes can result in tumor cell resistance phenomenon. MicroRNA are small non-coding RNA that can be widely detected in plants,animal species and viruses. They regulate protein expression by repressing translation mRNA target at the post-transcriptional level, participating in the differentiation and development of tumor cells, as well as the occurrence and development of tumor, the change of the expression level microRNA plays an important role in the genesis and chemoresistance mechanism of NHL. Therefore, the intervening factitiously the expression level of microRNA in NHL through manufacturing antisense oligonucleotide (AMO) or using substitution of microRNA, changing the expression level of their target protein, and combining with the therapy of NHL, there will be an guiding significance in reversing the drug and radiation resistance of NHL, thus improving its poor prognosis. This article reviews the microRNAs closely related with drug and radiation resistance of NHL, and their potential targets. Furthermore, the specific role of these microRNAs in the genesis and chemoresistance mechanism of NHL are deeply elaborated.
Subject(s)
Drug Resistance, Neoplasm , Lymphoma, Non-Hodgkin/genetics , MicroRNAs/genetics , Animals , Drug Resistance, Multiple , Lymphoma, Non-Hodgkin/drug therapyABSTRACT
Post-transplant lymphoproliferative disorder (PTLD) is one of the main complications after stem cell transplantation and is often induced by EBV. The optimal treatment of PTLD includes reduction of immunosuppressant dose, transplant organ resection, radiotherapy and chemotherapy, and so on. Recently, a new therapeutic approach was developed in PTLD: the anti-CD20 monoclonal antibody or rituximab. In this review, the application of rituximab in treatment of PTLD is summarized, including risk factors and mechanism of PTLD, therapeutic strategy, application of rituximab in PTLD and so on.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/etiology , Humans , Risk Factors , RituximabABSTRACT
Non-Hodgkin's lymphoma (NHL) is a heterogeneous group of malignancies that originate in lymphatic hematopoietic tissue. Chemotherapy has been used as the main therapy for NHL all the time, and local radiotherapy is also a necessary approach to supplementary treatment. However, resistance of tumor cells to chemo- and radiotherapy often prevent a successful long-term treatment of NHL. MicroRNAs (miRNAs) are a class of approximately 22-nucleotide endogenous non-coding RNAs that play an important regulatory role in gene expression, involving in the process of cell proliferation and differentiation. Alterations of miRNAs have been reported in a variety of human cancers, such as lymphomas, and will critically influence the tumor development and progression. Recently, there is increasing evidence that miRNAs could also influence sensitivity of tumor cells to chemo- and radiotherapy, revealing a crucial role of microRNAs in resistance to anticancer treatment. Therefore, understanding the role of miRNAs in chemo- and radio-resistance of tumor and targeting specific miRNAs will open novel avenues for lymphoma treatment and improve the prognosis of NHL patients. This review outlines the role of miRNAs associated with chemo-and radiotherapy resistance in NHL.
ABSTRACT
OBJECTIVE: To observe the effects of rosiglitazone (RSG) and ceftazidime (CAZ) on peroxisome proliferator activated receptor γ (PPARγ) activity in nucleated cells and interleukin (IL-4, IL-6) levels in plasma in septic rats. METHODS: According to randomized digital table, 180 male Sprague-Dawley (SD) rats were assigned to control group, sham operation group, sepsis group, CAZ group, RSG group and combined CAZ and RSG group. Sepsis model was established by cecal ligation and puncture (CLP). Drugs were administered by intraperitoneal injection at 3-hour post-operation, once every 12-hour. The PPARγ activity in nucleated cells and IL-4, IL-6 levels in plasma were detected by enzyme linked immunosorbent assay (ELISA) at 12, 24 and 48 hours post-operation. RESULTS: There was no difference in PPARγ activity and levels of IL-4 and IL-6 at each time point post-operation between control group and sham operation group. Compared with control group and sham operation group, PPARγ activity [absorbance (A) value] in nucleated cells in sepsis group, where downward trend was seen as time went on, significantly reduced (0.263±0.017 vs. 0.292±0.005, 0.294±0.007, both P<0.05). PPARγ activity was significantly higher in CAZ group, RSG group and CAZ + RSG group than in sepsis group (0.282±0.008, 0.336±0.020, 0.347±0.007 vs. 0.263±0.017, all P<0.05), CAZ + RSG group>RSG group >CAZ group (both P<0.05). Plasma IL-6 and IL-4 levels were higher in sepsis group than in control group and sham operation group (IL-6: 436.77±62.28 ng/L vs. 45.11±10.42 ng/L, 42.28±7.54 ng/L; IL-4: 89.24±25.06 ng/L vs. 41.34±7.08 ng/L, 41.49±7.27 ng/L, all P<0.05) and reached peak at 24 hours and 48 hours post-operation, respectively. Compared with sepsis group, IL-6 and IL-4 levels in CAZ group, RSG group and CAZ + RSG group were significantly decreased (IL-6: 273.48±12.13 ng/L, 317.64±14.10 ng/L, 253.94±13.57 ng/L vs. 436.77±62.28 ng/L; IL-4: 59.12±7.03 ng/L, 68.37±8.28 ng/L, 53.81±8.34 ng/L vs. 89.24±25.06 ng/L, all P<0.05), CAZ + RSG group < CAZ group < RSG group (all P<0.05). CONCLUSION: In septic rats, PPARγ activity in nucleated cells was decreased. On the basis of effective antibiotic treatment, RSG might play a role in improving PPARγ activity in nucleated cells and reducing the levels of inflammation mediators and anti-inflammatory in plasma.
Subject(s)
Ceftazidime/therapeutic use , PPAR gamma/metabolism , Sepsis/drug therapy , Sepsis/metabolism , Thiazolidinediones/therapeutic use , Animals , Drug Therapy, Combination , Interleukin-4/blood , Interleukin-6/blood , Male , Rats , Rats, Sprague-Dawley , RosiglitazoneABSTRACT
This study was aimed to investigate the expression and clinical significance of IL-18, IL-18 binding protein (IL-18BP), IFN-γ and IL-4 secreted from splenocytes of patients with idiopathic thrombocytopenic purpura (ITP) in vitro. Spleen mononuclear cells (MNC) were prepared by using routine sterile method, and were cultured in RPMI 1640 complete medium containing 10 µg/ml PHA, 10% fetal calf serum at 37°C and 5% CO2. The levels of IFN-γ, IL-4, IL-18 and IL-18BP secreted from MNC of ITP patients and normal controls were determined after culture for 48 hours. The results showed that after culture of spleen MNC for 48 hours, the levels of IL-18 and IFN-γ were significantly higher in patients with ITP than that in controls, but the levels of IL-18BP was not significantly elevated in ITP patients. The level of IL-4 was below the detectable limit of the assay used. It is concluded that imbalance between IL-18 and IL-18BP may play an important role in pathogenesis of ITP, and regulation of balance between IL-18 and IL-18BP may be a therapeutic approach against ITP.
Subject(s)
Intercellular Signaling Peptides and Proteins/metabolism , Interleukin-18/metabolism , Purpura, Thrombocytopenic, Idiopathic/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Cells, Cultured , Female , Humans , Interferon-gamma/metabolism , Interleukin-4/metabolism , Lymphocytes/cytology , Lymphocytes/metabolism , Male , Middle Aged , Spleen/cytology , Spleen/metabolism , Young AdultABSTRACT
OBJECTIVE: To investigate the role of IL-18 and IL-18BP balance in aplastic anemia (AA). METHODS: A total of 29 AA patients and 22 controls were recruited in present research. The expressions of IL-18 and IL-18BP were measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expressions of IL-18 and IL-18BP were measured in all subjects using real-time quantitative polymerase chain reaction (RT-PCR). RESULTS: The levels of the IL-18 in plasma of AA and normals were (365.5 ± 160.6) pg/ml and (175.9 ± 92.8) pg/ml (P < 0.01); and the expression of IL-18 in severe AA patients (441.3 ± 116.9) pg/ml were higher than that in non-severe AA patients (326.4 ± 167.0) pg/ml (P < 0.05). The level of IL-18BP was increased in plasma of AA (1788.6 ± 523.8) pg/ml than in normals (1083.6 ± 489.6) pg/ml (P < 0.05). But the ratio of IL-18/IL-18BP in AA patients was much higher than that in controls (P < 0.05). RT-PCR revealed the levels of IL-18 and IL-18BP mRNA were up-regulated in AA patients when compared to controls, but the ratio of IL-18/IL-18BP was significantly elevated in AA patients. CONCLUSION: IL-18/IL-18BP imbalance may play an important role in pathogenesis of AA and regulating the balance of IL-18 and IL-18BP may be a therapeutic approach to AA.
Subject(s)
Anemia, Aplastic/blood , Intercellular Signaling Peptides and Proteins/blood , Interleukin-18/blood , Adolescent , Adult , Case-Control Studies , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
The antitumor mechanisms of adriamycin (ADR) have been thought to contribute to induction of apoptosis and inefficiency of DNA repair, processes that are to a large extent mediated by mitochondria. This study aimed to investigate characteristics of ADR, including its antineoplastic activity, drug resistance, and unexpected toxicity in non-Hodgkin lymphoma (NHL) Raji cells at the mitochondrial proteomic level. The alterations of the mitochondrial proteome of Raji cells treated with ADR were analyzed by two-dimensional differential in-gel electrophoresis (2D-DIGE) coupled with linear ion trap quadrupole-electrospray ionization tandem mass spectrometry (LTQ-ESI-MS/MS).The altered patterns of three identified proteins were validated by Western blot and analyzed by pathway studio software. The results showed that 34 proteins were downregulated and 3 proteins upregulated in the study group compared with the control group. The differentially expressed proteins distributed their functions in reduction-oxidation reactions, DNA repair, cell cycle regulation, transporters and channels, and oxidative phosphorylation. Furthermore, heat shock protein 70 (HSP70), ATP-binding cassette transporter isoform B6 (ABCB6), and prohibitin (PHB) identified in this study may be closely related to chemoresistance and could serve as potential chemotherapeutic targets for NHL. Collectively, these results suggest that specific mitochondrial proteins are uniquely susceptible to alterations in abundance following exposure to ADR and carry implications for the investigation of therapeutic and prognostic markers. Further studies focusing on these identified proteins will be used to predict treatment response and reverse apoptosis resistance,and to explore drug-combination strategies associated with ADR for NHL therapy.