Gut microbiota-induced microRNA-206-3p increases anxiety-like behaviors by inhibiting expression of Cited2 and STK39.

BACKGROUND: Anxiety disorder is highly prevalent worldwide and represents a chronic and functionally disabling condition, with high levels of psychological stress characterized by cognitive and physiological symptoms. The purpose of this study is to evaluate the clinical significance of gut microbiota regulating microRNA (miR)-206-3p as a biomarker in the anxiety-like behaviors. METHODS: Initially, bioinformatics analysis was performed to predict the related factors for gut microbiota affecting anxiety-like behaviors. Next, the anxiety-like behaviors in mice were measured by multiple experiments. Western blot analysis, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were utilized to measure the levels of 5-hydroxytryptamine (5-HT), brain derived neurotrophic factor (BDNF), and neutrophil expressed (NE) in brain tissues and serum and cAMP responsive element binding protein 1 (CREB) phosphorylation in brain tissues of germ-free (GF) mice. Dual-luciferase reporter gene assay was employed to verify the relationship between miR-206-3p and Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 (Cited2)/serine/threonine kinase 39 (STK39). Ectopic expression and depletion experiments of miR-206-3p were conducted to determine the expression of miR-206-3p and mRNA and protein levels of Cited2, and STK39 in HT22 cells and brain tissues. Finally, transmission electron microscope (TEM) was used to observe the effects of miR-206-3p on hippocampal mitochondria and synapses. RESULTS: Gut microbiota could elevate miR-206-3p expression in brain tissues to increase the anxiety-like behaviors. GF mice displayed the increased levels of 5-HT, BDNF, and NE in brain tissues and serum and CREB phosphorylation in brain tissues. Cited2/STK39 was identified as the target genes of miR-206-3p. Upregulated miR-206-3p increased anxiety-like behaviors by promoting degeneration of mitochondria and synapses in hippocampus via downregulation of Cited2 and STK39. CONCLUSIONS: In conclusion, the key findings of the current study demonstrate that gut microbiota aggravated anxiety-like behaviors via the miR-206-3p/Cited2/STK39 axis.

Positive associations between sex hormones, bone metabolism and cognitive impairment in Chinese oldest-old females.

PURPOSE: With a rapid increase in older adults, progressive impairment in cognitive function has become an increasing concern owing to high social and economic burdens. The current study was designed to investigate the associations of sex hormones and bone metabolism with cognitive impairment (CI) in Chinese oldest-old females. METHODS: There were 396 oldest-old females from the China Hainan Oldest-old Cohort Study (CHOCS). Following standardized procedures, Mini Mental State Examination was effectively completed, and sex hormones and bone metabolism were assessed in these females. RESULTS: The median age of all females was 101 years (range: from 80 to 116). There were 340 females (86%) with CI. Participants with CI had significantly higher levels of age, progesterone, prolactin and estradiol than those without CI (P < 0.05 for all). Total type I collagen N-terminal elongation peptide [hazard ratio (HR): 1.018, 95%CI: 1.001-1.035] and prolactin (HR: 1.065, 95%CI: 1.005-1.129) levels were positively and significantly associated with CI (P < 0.05 for all). CONCLUSIONS: Prolactin and total type I collagen N-terminal elongation peptide had positive associations with CI in Chinese oldest-old females. Thus, a balance in sex hormones and bone metabolism may have significant effects on cognitive function during the aging process.

Fabrication of blended nanofibrous cardiac patch transplanted with TGF-ß3 and human umbilical cord MSCs-derived exosomes for potential cardiac regeneration after acute myocardial infarction.

Acute myocardial infarction (AMI) is a common cardiovascular condition that progressively results in heart failure. In the present study, we have designed to load transforming growth factor beta 3 (TGF-ß3) and cardio potential exosomes into the blended polycaprolactone/type I collagen (PCL/COL-1) nanofibrous patch (Exo@TGF-ß3@NFs) and examined its feasibility for cardiac repair. The bioactivity of the developed NFs towards the migration and proliferation of human umbilical vein endothelial cells was determined using in vitro cell compatibility assays. Additionally, Exo@TGF-ß3/NFs showed up-regulation of genes involved in angiogenesis and mesenchymal differentiations in vitro. The in vivo experiments performed 4 weeks after transplantation showed that the Exo@TGF-ß3@NFs had a higher LV ejection fraction and fraction shortening functions. Subsequently, it has been determined that Exo@TGF-ß3@NFs significantly reduced AMI size and fibrosis and increased scar thickness. The developed NFs approach will become a useful therapeutic approach for the treatment of AMI.

S100A4 promotes liver fibrosis via activation of hepatic stellate cells.

BACKGROUND & AIMS: S100A4 has been linked to the fibrosis of several organs due to its role as a fibroblast-specific marker. However, the role of S100A4 itself in the development of fibrosis has not been much investigated. Here, we determined whether S100A4 regulates liver fibrogenesis and examined its mechanism by focusing on the activation of hepatic stellate cells (HSCs). METHODS: S100A4 deficient mice were used to determine the role of S100A4 in liver fibrogenesis. The effect of S100A4 on HSC activation was estimated by using primary mouse HSCs and the human HSC cell line LX-2. Serum levels of S100A4 in cirrhotic patients were determined by ELISA. RESULTS: S100A4 was found to be secreted by a subpopulation of macrophages and to promote the development of liver fibrosis. It accumulated in the liver during the progression of liver fibrosis and activated HSCs in mice. In vitro studies demonstrated that S100A4 induced the overexpression of alpha-smooth muscle actin through c-Myb in HSCs. Both, the selective depletion of S100A4-expressing cells and knockdown of S100A4 in the liver by RNA interference, resulted in a reduction of liver fibrosis following injury. Importantly, increased S100A4 levels in both the liver tissue and serum correlated positively with liver fibrosis in humans. CONCLUSIONS: S100A4 promotes liver fibrosis by activating HSCs, which may represent a potential target for anti-fibrotic therapies.

Chlorogenic acid attenuates cardiac hypertrophy via up-regulating Sphingosine-1-phosphate receptor1 to inhibit endoplasmic reticulum stress.

AIMS: Cardiac hypertrophy, an adaptive response of the heart to stress overload, is closely associated with heart failure and sudden cardiac death. This study aimed to investigate the therapeutic effects of chlorogenic acid (CGA) on cardiac hypertrophy and elucidate the underlying mechanisms. METHODS AND RESULTS: To simulate cardiac hypertrophy, myocardial cells were exposed to isoproterenol (ISO, 10 µM). A rat model of ISO-induced cardiac hypertrophy was also established. The expression levels of cardiac hypertrophy markers, endoplasmic reticulum stress (ERS) markers, and apoptosis markers were measured using quantitative reverse transcription PCR and western blotting. The apoptosis level, size of myocardial cells, and heart tissue pathological changes were determined by terminal deoxynucleotidyl transferase dUTP nick-end labelling staining, immunofluorescence staining, haematoxylin and eosin staining, and Masson's staining. We found that CGA treatment decreased the size of ISO-treated H9c2 cells. Moreover, CGA inhibited ISO-induced up-regulation of cardiac hypertrophy markers (atrial natriuretic peptide, brain natriuretic peptide, and ß-myosin heavy chain), ERS markers (C/EBP homologous protein, glucose regulatory protein 78, and protein kinase R-like endoplasmic reticulum kinase), and apoptosis markers (bax and cleaved caspase-12/9/3) but increased the expression of anti-apoptosis marker bcl-2 in a dose-dependent way (0, 10, 50, and 100 µM). Knockdown of sphingosine-1-phosphate receptor 1 (S1pr1) reversed the protective effect of CGA on cardiac hypertrophy, ERS, and apoptosis in vitro (P < 0.05). CGA also restored ISO-induced inhibition on the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signalling in H9c2 cells, while S1pr1 knockdown abolished these CGA-induced effects (P < 0.05). CGA (90 mg/kg/day, for six consecutive days) protected rats against cardiac hypertrophy in vivo (P < 0.05). CONCLUSIONS: CGA treatment attenuated ISO-induced ERS and cardiac hypertrophy by activating the AMPK/SIRT1 pathway via modulation of S1pr1.

Hepatoprotection of berberine against hydrogen peroxide-induced apoptosis by upregulation of Sirtuin 1.

Berberine (BBR) has been suggested to be a hepatoprotective agent for oxidative-stress-related liver diseases because of its antioxidant activity. However, the antioxidant mechanisms of BBR are still not fully understood. In the present study, the protective effect of BBR was evaluated, and the underlying molecular mechanisms were investigated in hepatic cell line L02. Results from cell viability and apoptosis assay showed that in cells exposed to hydrogen peroxide (H2 O2 ), the pretreatment of 12 µM BBR could increase cell viability by 19.10 ± 7.40% and reduce apoptotic cells by 7.91 ± 0.78%. A significant change in the expression levels of sirtuin 1 (SIRT1) and apoptosis-related proteins was also observed in the BBR-pretreated hepatocytes under exposure to H2 O2 . Furthermore, BBR exhibited a time-dependent effect on upregulation of SIRT1 in L02 cells. This study demonstrated that the protective effect of BBR against H2 O2 -induced apoptosis was associated with regulation of SIRT1 in hepatic cell line L02, which provided a possible explanation for its antioxidant activity, and implied an application of BBR for the therapeutic relevance in oxidative-stress-related liver diseases.

A high-sensitivity rotatable 3D displacement sensor.

Aiming at the problems of low sensitivity and low accuracy caused by the displacement transfer mechanism of three displacement sensors used simultaneously in the 3D displacement monitoring of seismic isolation bearings, the paper has proposed a high-sensitivity rotatable 3D displacement sensor. The sensor adds through holes on the surface of the equal-strength cantilever beam to form a cross beam, which increases the bending strain on the beam surface to improve the sensitivity. By adding a gyroscope and a mechanical rotation structure, a single sensor can measure the 3D displacement at the same time, reducing the adverse effects displacement transmission mechanism on the accuracy of the measurement. ANSYS software was used to simulate and optimize the parameters of the size of through-hole of the sensor beam to determine the appropriate size and location of the through-hole. Finally, the sensor was developed and its static characteristics and displacement measurement performance in static and dynamic 3D space were tested based on the simulation results. The test results have shown that the sensor has a sensitivity of 16.29 mV/mm and an accuracy of 0.9% in the range of 0-160 mm. Its static and dynamic 3D spatial displacement measurement errors are less than 2 mm, which can meet the accuracy requirements of 3D displacement measurement and sensitivity for structural health monitoring of seismic isolation bearings.

Amorphous selenium inhibits oxidative stress injury of neurons in vascular dementia rats by activating NMDAR pathway.

Vascular dementia (VD) is one of the most common causes of dementia, taking account for about 20% of all cases. Although studies have found that selenium supplementation can improve the cognitive ability of Alzheimer's patients, there is currently no research on the cognitive impairment caused by VD. This study aimed to investigate the role and mechanism of Amorphous selenium nanodots (A SeNDs) in the prevention of VD. The bilateral common carotid artery occlusion (BCCAO) method was used to establish a VD model. The neuroprotective effect of A SeNDs was evaluated by Morris water maze, Transcranial Doppler TCD, hematoxylin-eosin (HE) staining, Neuron-specific nuclear protein (Neu N) staining and Golgi staining. Detect the expression levels of oxidative stress and Calcium-calmodulin dependent protein kinase II (CaMK II), N-methyl-D-aspartate receptor subunit NR2A, and postsynaptic dense protein 95 (PSD95). Finally, measure the concentration of calcium ions in neuronal cells. The results showed that A SeNDs could significantly improve the learning and memory ability of VD rats, restore the posterior arterial blood flow of the brain, improve the neuronal morphology and dendritic remodeling of pyramidal cells in hippocampal CA1 area, reduce the level of oxidative stress in VD rats, increase the expression of NR2A, PSD95, CaMK II proteins and reduce intracellular calcium ion concentration, but the addition of selective NR2A antagonist NVP-AAMO77 eliminated these benefits. It suggests that A SeNDs may improve cognitive dysfunction in vascular dementia rats by regulating the NMDAR pathway.

Hinge-type FBG acceleration sensor based on double elastic plate.

It is critical for the health monitoring of large-scale structures such as bridge, railway and tunnel to acquire the medium-frequency and high-frequency vibration signals. To solve the problems of low sensitivity and poor transverse anti-interference of the medium-frequency and high-frequency fiber acceleration sensor, a hinge-type Fiber Bragg Grating(FBG) acceleration sensor based on double elastic plate has been proposed, and the hinge and elastic plate are used as elastomer to realize the miniaturization and transverse interference suppression of the sensor. The MATLAB and the ANSYS are used for theoretical analysis and optimization of sensor sensitivity and resonance frequency, structural static stress analysis and modal simulation analysis, while the test system is built to test the sensor performance. The results show that the resonance frequency of the sensor is 1300 Hz; the sensor has a flat sensitivity response in the middle-high frequency band of 200-800 Hz; the sensitivity is about 20 pm/g, and the fiber central wavelength drift and acceleration have good linearity and stability, while the transverse anti-interference is about 3.16%, which provides a new idea for monitoring of medium-frequency and high-frequency vibration signals in large-scale structures.

Amorphous Selenium Nanoparticles Improve Vascular Function in Rats With Chronic Isocarbophos Poisoning via Inhibiting the Apoptosis of Vascular Endothelial Cells.

AIM: This study aimed to investigate the preventive effect and possible mechanism of amorphous selenium nanoparticles (A-SeQDs) on isocarbophos induced vascular dysfunction. METHODS: A-SeQDs was made by auto redox decomposition of selenosulfate precursor. Male rats were given isocarbophos (0.5 mg/kg/2 days) by intragastric administration for 16 weeks to induce vascular dysfunction. During the course, A-SeQDs (50 mg/kg/day) was added to the water from week 5. Then, the rats were killed to observe and test the influence of A-SeQDs on the vascular dysfunction induced by isocarbophos. Finally, human umbilical vein endothelial cells (HUVECs) were treated with 10% DMEM of isocarbophos (100 µM) for 5 days to detect the related indexes. Before the use of isocarbophos treatment, different drugs were given. RESULTS: A-SeQDs could reduce total carbon dioxide, MDA, VCAM-1, ICAM-1, IL-1, and IL-6 while increasing oxygen saturation, NO content, and SOD activity in rats. A-SeQDs also resulted in relatively normal vascular morphology, and the expression of sodium hydrogen exchanger 1 (NHE1) and caspase-3 decreased in rats. Furthermore, in HUVECs treated with isocarbophos, A-SeQDs maintained mitochondrial membrane potential, inhibited the cleaved caspase-3 expression, and released cytochrome c from mitochondria to cytosol. CONCLUSION: A-SeQDs can inhibit the apoptosis of HUVECs through the mitochondrial pathway, and effectively treat the impairment of vascular endothelial function caused by isocarbophos, which is NHE1-dependent.

Amorphous nano-selenium quantum dots prevent pulmonary arterial hypertension through recoupling endothelial nitric oxide synthase.

AIMS: We have previously reported that nano-selenium quantum dots (SeQDs) prevented endothelial dysfunction in atherosclerosis. This study is to investigate whether amorphous SeQDs (A-SeQDs) increase endogenous tetrahydrobiopterin biosynthesis to alleviate pulmonary arterial hypertension. RESULTS: Both A-SeQDs and C-SeQDs were stable under physiological conditions, while the size of A-SeQDs was smaller than C-SeQDs by high resolution-transmission electron microscopy scanning. In monocrotaline-injected mice, oral administration of A-SeQDs was more effective to decrease pulmonary arterial pressure, compared to C-SeQDs and organic selenium. Further, A-SeQDs increased both nitric oxide productions and intracellular BH4 levels, upregulated dihydrofolate reductase activity in lungs, and improved pulmonary arterial remodeling. Gene deletion of dihydrofolate reductase abolished these effects produced by A-SeQDs in mice. Finally, the blood levels of tetrahydrobiopterin and selenium were decreased in patients with pulmonary arterial hypertension. CONCLUSION: A-SeQDs increase intracellular tetrahydrobiopterin to prevent pulmonary arterial hypertension through recoupling endothelial nitric oxide synthase. METHODS: Two polymorphs of SeQDs and A-SeQDs, and a crystalline form of SeQDs (C-SeQDs) were prepared through self-redox decomposition of selenosulfate precursor. Mice were injected with monocrotaline to induce pulmonary arterial hypertension in vivo. Pulmonary arterial pressure was measured.

Regulation of Hippo signaling and triple negative breast cancer progression by an ubiquitin ligase RNF187.

Breast cancer is the most common malignancy for women worldwide, while Triple Negative Breast Cancer (TNBC) accounts for 20% in all patients. Compared with estrogen receptor positive breast cancer, which could be effectively controlled via endocrine therapy, TNBC is more aggressive and worse in prognosis. It is therefore urgent and necessary to develop a novel therapeutic strategy for TNBC treatment. Recent studies identified Hippo signaling is highly activated in TNBC, which could be a driving pathway for TNBC progression. In our study, we determine RNF187 as a negative regulator for Hippo signaling activation. RNF187 depletion significantly decreases cell migration and invasion capacity in TNBC. These effects could be rescued by further YAP depletion. Depletion of RNF187 increases the YAP protein level and Hippo signaling target genes, such as CTGF and CYR61 in TNBC. Immuno-precipitation assay shows that RNF187 associates with YAP, promoting its degradation possibly via inducing YAP K48-dependent poly-ubiquitination. Interestingly, Our clinical data reveals that RNF187 reversely correlates with YAP protein level and Hippo target genes. RNF187 tends to correlate with good prognosis in TNBC patients. Our study provides evidence to establish a proteolytic mechanism in regulation Hippo signaling activation in TNBC.

Blocking CD38-driven fratricide among T cells enables effective antitumor activity by CD38-specific chimeric antigen receptor T cells.

Chimeric antigen receptor T-cell (CAR T) therapy is a kind of effective cancer immunotherapy. However, designing CARs remains a challenge because many targetable antigens are shared by T cells and tumor cells. This shared expression of antigens can cause CAR T cell fratricide. CD38-targeting approaches (e.g., daratumumab) have been used in clinical therapy and have shown promising results. CD38 is a kind of surface glycoprotein present in a variety of cells, such as T lymphocytes and tumor cells. It was previously reported that CD38-based CAR T cells may undergo apoptosis or T cell-mediated killing (fratricide) during cell manufacturing. In this study, a CAR containing a sequence targeting human CD38 was designed to be functional. To avoid fratricide driven by CD38 and ensure the production of CAR T cells, two distinct strategies based on antibodies (clone MM12T or clone MM27) or proteins (H02H or H08H) were used to block CD38 or the CAR single-chain variable fragment (scFv) domain, respectively, on the T cell surface. The results indicated that the antibodies or proteins, especially the antibody MM27, could affect CAR T cells by inhibiting fratricide while promoting expansion and enrichment. Anti-CD38 CAR T cells exhibited robust and specific cytotoxicity to CD38+ cell lines and tumor cells. Furthermore, the levels of the proinflammatory factors TNF-α, IFN-γ and IL-2 were significantly upregulated in the supernatants of A549CD38+ cells. Finally, significant control of disease progression was demonstrated in xenograft mouse models. In conclusion, these findings will help to further enhance the expansion, persistence and function of anti-CD38 CAR T cells in subsequent clinical trials.

[Influencing factors of medial patellofemoral ligament reconstruction for patellar dislocation].

Objective: To review the influencing factors of medial patellofemoral ligament (MPFL) reconstruction for patellar dislocation. Methods: The literature of MPFL reconstruction for patellar dislocation at home and abroad in recent years were summarized and analyzed. Results: The influencing factors such as the location of the femoral insertion point, the tension and the fixed angle of the grafts, the dysplasia of the femoral trochlear before operation, the abnormal tuberositas tibiae-trochlear groove value, the high position of the patellar, and the tilting angle of the patellar, are all the factors affecting the effectiveness of MPLF reconstruction. Conclusion: During MPFL reconstruction, the surgical techniques and elimination of other factors that caused patellar instability need to be focused in order to reduce the complications and operation failure.

Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade.

Immune checkpoint blockades, such as inhibitors against programmed death 1 (PD-1) and its ligand (PD-L1), have received extensive attention in the past decade because of their dramatic clinical outcomes in advanced malignancies. However, both primary and acquired resistance becomes one of the major obstacles, which greatly limits the long-lasting effects and wide application of PD-1/PD-L1 blockade therapy. PD-1/PD-L1 both regulates and is regulated by cellular signaling pathways and epigenetic modification, thus inhibiting the proliferation and effector function of T and B cells. The lack of tumor antigens and effective antigen presentation, aberrant activation of oncogenic pathways, mutations in IFN-γ signaling, immunosuppressive tumor microenvironment such as regulatory T cells, myeloid-derived suppressor cells, M2 macrophages, and immunoinhibitory cytokines can lead to resistance to PD-1/PD-L1 blockade. In this review, we describe PD-1 related signaling pathways, essential factors contributing to the resistance of PD-1 blockade, and discuss strategies to increase the efficacy of immunotherapy. Furthermore, we discuss the possibility of combined epigenetic therapy with PD-1 blockade as a potential promising approach for cancer treatment.

HLA-DMB restricts human T-cell leukemia virus type-1 (HTLV-1) protein expression via regulation of ATG7 acetylation.

The roles of autophagy in viral infection are complicated. While autophagy has been shown to function in host antiviral defense by eliminating intracellular viruses and regulating adaptive immunity, several viruses have evolved molecular mechanisms to get benefits from it. The deltaretrovirus human T-cell leukemia virus type-1 (HTLV-1) has been reported to profit its replication from enhancing autophagosome accumulation. Here, we reported that HLA-DMB (generally referred to here as DMB), the beta chain of the non-classical MHC-II protein HLA-DM, had strong expression in HTLV-1-transformed T-cell lines and could be induced in Hela, PMA-differentiated THP1 (PMA-THP1) or primary human monocytes by HTLV-1 infection. Immunoblot and real-time PCR assays demonstrated that overexpression of DMB decreased HTLV-1 protein expression while the knockdown of DMB increased HTLV-1 protein expression. Immunoblot and confocal microscopy assays indicated that overexpression of DMB decreased HTLV-1 induced autophagosome accumulation while the knockdown of DMB yielded the opposite effects. Coimmunoprecipitation and immunoprecipitation experiments suggested DMB interacted with autophagy-related gene (ATG) 7 and increased the acetylation of ATG7. Taken together, these results suggested DMB modulated HTLV-1 protein expression through regulation of autophagosome accumulation and our findings suggested a new mechanism by which the host cells defended against HTLV-1 infection.

Interferon-λ1 induces G1 phase cell cycle arrest and apoptosis in gastric carcinoma cells in vitro.

The aim of the present study was to examine the potential antitumor action of IFN-λ1 in human gastric carcinoma cell lines and the possible interaction between IFN-λ1 and human gastric carcinoma cells. Gastric carcinoma HGC-27 and SGC-7901 cells were treated with IFN-λ1 (0, 10, 100, 1000 ng/ml) for 48 h. Cytotoxicity was examined using an MTT method. Cell cycle distribution was examined using propidium iodide staining. Apoptosis was examined using the Annexin V-FITC/PI apoptosis kit. By using flow cytometry and JC-1 probe, the mitochondrial membrane potential of cells following treatment with IFN-λ1 was also examined. Expression levels of representative apoptosis­related proteins were evaluated by western blot analysis. IFN-λ1 inhibited the proliferation of gastric carcinoma cells in a concentration­dependent manner. IFN-λ1 increased the accumulation of cells in the sub-G0 phase and arrested the cells in the G1 phase. Exposure to IFN­λ1 decreased the mitochondrial membrane potential and increased apoptosis. Moreover, IFN­λ1 exposure upregulated the expression of p21, p27 and Bax, downregulated the expression of Bcl­2, increased the release of cytochrome c and apoptosis-inducing factor (AIF) and activated caspase-3 and caspase-9. In conclusion, IFN-λ1 inhibits the proliferation of gastric carcinoma cells by arresting the cells in the G1 phase and by inducing mitochondrial­mediated apoptosis.

Knockdown of Bcl-3 inhibits cell growth and induces DNA damage in HTLV-1-infected cells.

Oncoprotein Bcl-3 is perceived as an unusual member of IκB family since it can both stimulate and suppress NF-κB activation. Aberrant Bcl-3 results in increased cell proliferation and survival, suggesting a contribution to malignant potential and elevated levels of Bcl-3 have been observed in many HTLV-1-infected T cell lines and ATL cells. To investigate the specific roles of Bcl-3 in HTLV-1-infected cells, we knocked down Bcl-3 expression using shRNA and then examined the consequences with regard to DNA damage and cell proliferation, as well as NF-κB activation. The HTLV-1 encoded protein Tax promotes Bcl-3 expression and nuclear translocation. In HTLV-1-infected cells, Bcl-3 knockdown obviously induced DNA damage. Cell growth and NF-κB activation were reduced in HTLV-1-infected or Tax positive cells when Bcl-3 expression was decreased. Together, our results revealed positive roles of Bcl-3 in DNA stabilization, growth and NF-κB activation in HTLV-1-infected cells.

Bcl-3 suppresses Tax-induced NF-κB activation through p65 nuclear translocation blockage in HTLV-1-infected cells.

Human T cell leukemia virus type 1 (HTLV-1) Tax-induced persistent activation of the NF-κB pathway is perceived as the primary cause of adult T cell leukemia (ATL), an aggressive leukemia caused by HTLV-1. Although elevated oncoprotein Bcl-3 levels are found in many HTLV-1-infected T cell lines and ATL cells, the role of Bcl-3 in the malignant progression caused by HTLV-1 retrovirus remains poorly understood. We confirmed, in the present study, that the Tax-induced NF-κB activation involves the regulation of Bcl-3. Both knockdown and overexpression of Bcl-3 inhibit the Tax-induced NF-κB activation. Similarly, excessive Bcl-3 inhibits the NF-κB/DNA binding activity and significantly decreases Tax-induced p65 nuclear translocation. The present results demonstrate the pleiotropic roles of Bcl-3 in Tax-induced NF-κB activation and indicate that a balance in the aberrant Bcl-3 expression may be established to play an important role in the maintenance of proliferation and inhibition of apoptosis in HTLV-1-infected and ATL cells.

[Recombinant human IL-16 inhibits proliferation and induces apoptosis in MT-4 cells].

OBJECTIVE: To investigate the effects of recombinant human IL-16 (rhIL-16) on the proliferation and apoptosis of MT-4 cells. METHODS: MT-4 cells were infected with adenovirus expressing rhIL-16 at different time points. Then the proliferation of MT-4 cells was measured by the MTT assay. The apoptosis of the MT-4 cells was evaluated by flow cytometry. The expression of two molecular markers for apoptosis, Bax and Bcl-2, were analyzed by Western blotting. RESULTS: The MTT assay results showed that pAd-IL-16 transfectants had inhibitory effect on the proliferation of MT-4 cells, compared with untreated cells at various time points. Flow cytometry revealed that apoptotic rate of MT-4 cells was higher than that of control group. Furthermore, Western blotting indicated that the Bax protein expression increased while Bcl-2 protein expression decreased in a time-dependent manner in MT-4 cells infected with the rhIL-17-expressing adenovirus. CONCLUSION: These results demonstrated that IL-16 plays an important role in the proliferation and apoptosis of MT-4 cells, and the molecular mechanism underlying this phenomenon may involve the modulation of Bax and Bcl-2 expression.