METTL8 links mt-tRNA m3C modification to the HIF1α/RTK/Akt axis to sustain GBM stemness and tumorigenicity.

Epitranscriptomic RNA modifications are crucial for the maintenance of glioma stem cells (GSCs), the most malignant cells in glioblastoma (GBM). 3-methylcytosine (m3C) is a new epitranscriptomic mark on RNAs and METTL8 represents an m3C writer that is dysregulated in cancer. Although METTL8 has an established function in mitochondrial tRNA (mt-tRNA) m3C modification, alternative splicing of METTL8 can also generate isoforms that localize to the nucleolus where they may regulate R-loop formation. The molecular basis for METTL8 dysregulation in GBM, and which METTL8 isoform(s) may influence GBM cell fate and malignancy remain elusive. Here, we investigated the role of METTL8 in regulating GBM stemness and tumorigenicity. In GSC, METTL8 is exclusively localized to the mitochondrial matrix where it installs m3C on mt-tRNAThr/Ser(UCN) for mitochondrial translation and respiration. High expression of METTL8 in GBM is attributed to histone variant H2AZ-mediated chromatin accessibility of HIF1α and portends inferior glioma patient outcome. METTL8 depletion impairs the ability of GSC to self-renew and differentiate, thus retarding tumor growth in an intracranial GBM xenograft model. Interestingly, METTL8 depletion decreases protein levels of HIF1α, which serves as a transcription factor for several receptor tyrosine kinase (RTK) genes, in GSC. Accordingly, METTL8 loss inactivates the RTK/Akt axis leading to heightened sensitivity to Akt inhibitor treatment. These mechanistic findings, along with the intimate link between METTL8 levels and the HIF1α/RTK/Akt axis in glioma patients, guided us to propose a HIF1α/Akt inhibitor combination which potently compromises GSC proliferation/self-renewal in vitro. Thus, METTL8 represents a new GBM dependency that is therapeutically targetable.

Enhancing antitumor efficacy of NIR-I region zinc phthalocyanine@upconversion nanoparticle through lysosomal escape and mitochondria targeting.

Accurately visualizing the intracellular trafficking of upconversion nanoparticles (UCNPs) loaded with phthalocyanines and achieving precise photodynamic therapy (PDT) using near-infrared (NIR) laser irradiation still present challenges. In this study, a novel NIR laser-triggered upconversion luminescence (UCL) imaging-guided nanoparticle called FA@TPA-NH-ZnPc@UCNPs (FTU) was developed for PDT. FTU consisted of UCNPs, folic acid (FA), and triphenylamino-phenylaniline zinc phthalocyanine (TPA-NH-ZnPc). Notably, TPA-NH-ZnPc showcases aggregation-induced emission (AIE) characteristic and NIR absorption properties at 741 nm, synthesized initially via molybdenum-catalyzed condensation reaction. The UCL emitted by FTU enable real-time visualization of their subcellular localization and intracellular trafficking within ovarian cancer HO-8910 cells. Fluorescence images revealed that FTU managed to escape from lysosomes due to the "proton sponge" effect of TPA-NH-ZnPc. The FA ligands on the surface of FTU further directed their transport and accumulation within mitochondria. When excited by a 980 nm laser, FTU exhibited UCL and activated TPA-NH-ZnPc, consequently generating cytotoxic singlet oxygen (1O2), disrupted mitochondrial function and induced apoptosis in cancer cells, which demonstrated great potential for tumor ablation.

Comparison of endoscopic resection therapies for rectal neuroendocrine tumors.

AIMS: This study was to evaluate and compare the efficacy and safety of endoscopic mucosal resection (EMR), clip-and-snare assisted endoscopic mucosal resection (CS-EMR), and endoscopic submucosal dissection (ESD) for the endoscopic resection of rectal NETs. MATERIAL AND METHODS: A retrospective analysis was performed on 47 patients with rectal NETs who underwent endoscopic treatment in The Second Affiliated Hospital of Soochow University. Manifestations of clinic pathological characteristics, complications, procedure time and hospitalization costs were studied. RESULTS: The complete resection rates with CS-EMR and ESD were significantly higher than those with EMR (CS-EMR vs. EMR, p = 0.038; ESD vs. EMR, p = 0.04), but no significant difference was found between the CS-EMR and ESD groups (p = 0.383). The lateral margin was less distant in the CS-EMR group than in the ESD group and there was no difference with regard to vertical margin (lateral margin distance, 1500 ± 3125 vs.3000 ± 3000 µm; vertical margin distance, 400 ± 275 vs.500 ± 500 µm). Compared to ESD, CS-EMR required less operation time (p < 0.01) and money (p < 0.01) and reduced the length of hospital stays (p < 0.01). CONCLUSIONS: The CS-EMR technique is more effective and efficient than EMR for small rectal NETs. In addition, CS-EMR reduces procedure time, duration of post-procedure hospitalization and decreases patients' cost compared to ESD while ensuring sufficient vertical margin distances.

Mechanistic insights and the clinical prospects of targeted therapies for glioblastoma: a comprehensive review.

Glioblastoma (GBM) is a fatal brain tumour that is traditionally diagnosed based on histological features. Recent molecular profiling studies have reshaped the World Health Organization approach in the classification of central nervous system tumours to include more pathogenetic hallmarks. These studies have revealed that multiple oncogenic pathways are dysregulated, which contributes to the aggressiveness and resistance of GBM. Such findings have shed light on the molecular vulnerability of GBM and have shifted the disease management paradigm from chemotherapy to targeted therapies. Targeted drugs have been developed to inhibit oncogenic targets in GBM, including receptors involved in the angiogenic axis, the signal transducer and activator of transcription 3 (STAT3), the PI3K/AKT/mTOR signalling pathway, the ubiquitination-proteasome pathway, as well as IDH1/2 pathway. While certain targeted drugs showed promising results in vivo, the translatability of such preclinical achievements in GBM remains a barrier. We also discuss the recent developments and clinical assessments of targeted drugs, as well as the prospects of cell-based therapies and combinatorial therapy as novel ways to target GBM. Targeted treatments have demonstrated preclinical efficacy over chemotherapy as an alternative or adjuvant to the current standard of care for GBM, but their clinical efficacy remains hindered by challenges such as blood-brain barrier penetrance of the drugs. The development of combinatorial targeted therapies is expected to improve therapeutic efficacy and overcome drug resistance.

PF-04449913 Inhibits Proliferation and Metastasis of Colorectal Cancer Cells by Down-regulating MMP9 Expression through the ERK/p65 Pathway.

INTRODUCTION: Colorectal cancer remains a life-threatening malignancy with increasing morbidity and mortality worldwide. Therefore, new and effective anti-colorectal cancer therapeutics are urgently needed. METHOD: In this study, we have studied the anti-tumor properties and potential mechanisms of PF-04449913. Colorectal cancer cell viability was reduced by PF-04449913 in a dose-dependent manner. The migration and invasion ability of malignant colon cells were attenuated by the drug, as demonstrated by the Transwell test. Moreover, PF-04449913 repressed the phosphorylation levels of ERK and other proteins, and the expression levels of MMP9. The anti-tumor effects of the drug in vivo were demonstrated in BALB/c-nude mice models, and PF-04449913 inhibited the malignant phenotype of colorectal cancer cells, including reduction of tumor size and promotion of apoptosis. At the molecular level, PF-04449913 induced a significant decrease in ERK and p65 protein phosphorylation levels and inhibited MMP9 protein expression. RESULTS: Both in vivo and in vitro results showed PF-04449913 to demonstrate antitumor effects, which have been proposed to be mediated through blockade of the ERK/p65 signaling pathway, and subsequent repression of MMP9 expression. CONCLUSION: Our study provides a new perspective on the potential clinical application of PF-04449913 in the treatment of colorectal cancer.

Fluorinated triphenylamine silicon phthalocyanine nanoparticles with two-color imaging guided in vitro photodynamic therapy through lysosomal dysfunction.

Lysosome-targeting therapy has emerged as a promising strategy for combating drug-resistant tumors. However, the synthesis of nanodrugs to achieve efficient lysosome targeting remains a challenging task. In this study, a nanoparticle DSPE@TPA-FBPA-SiPc was developed for lysosome targeting therapy. The nanoparticle was prepared by loading 2-[4-(diphenylamino)-1-diphenicacid-1-carbobenzoxy-4-(1,1,1,3,3,3-hexafluoropropane-4-phenoxy) silicon phthalocyanine (TPA-FBPA-SiPc) into 1,2-distearoyl-sn­glycero-3-phosphoethanolamine-N-[succinyl(polyethyleneglycol)-2000] (DSPE). DSPE@TPA-FBPA-SiPc demonstrated remarkable capabilities such as two-color imaging, lysosome targeting and in vitro photodynamic therapy functions. The results revealed that DSPE@TPA-FBPA-SiPc efficiently accumulated in lysosomes, leading to generation of a high amount of reactive oxygen species upon irradiation. This induced apoptosis in MCF-7 cells by disrupting lysosomal function. Consequently, DSPE@TPA-FBPA-SiPc holds great potential as a photosensitizer for photodynamic therapy, utilizing the lysosomal-mediated cell death pathway.

Characteristics of ginsenoside Rd-induced effects on rat intestinal contractility with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a very common refractory disease. Its exact pathophysiological mechanism is still unclear. Despite the availability of plentiful drugs to control IBS, most patients do not respond well. Ginsenoside Rd is one of the major active components of Panax ginseng, which has been verified to produce various pharmacological actions. However, the role of ginsenoside Rd in modulating smooth muscle contractility is still undefined. The aim of this study is to investigate the effects of ginsenoside Rd on intestinal contractility and related mechanisms in IBS.

The geriatric nutritional risk index is an effective tool to detect GLIM-defined malnutrition in rectal cancer patients.

Background: This study aimed to investigate the value of the Geriatric Nutritional Risk Index (GNRI), prognostic nutritional index (PNI), and advanced lung cancer inflammation index (ALI) scores in detecting malnutrition in patients with rectal cancer; the Global Leadership Initiative on Malnutrition (GLIM) was used as the reference criterion. Materials and methods: This study included patients with rectal cancer who underwent proctectomy. GNRI, PNI, and ALI were calculated to detect the GLIM-defined malnutrition using the Receiver operating characteristic (ROC) curves. Univariate and multivariate logistic regression analyses were used to evaluate the association between the nutritional tools and postoperative complications. Kaplan-Meier survival curves, log-rank tests, and univariate and multivariate Cox regression analyses were used to clarify the relationship between nutritional tools and overall survival (OS). Results: This study enrolled 636 patients with rectal cancer. The GNRI demonstrated the highest sensitivity (77.8%), pretty specificity (69.0%), and the largest AUC (0.734). The GNRI showed good property in predicting major postoperative complications. All three nutritional tools were independent predictors of OS. Conclusion: The GNRI can be used as a promising alternative to the GLIM and is optimal in perioperative management of patients with rectal cancer.

A smartphone-based platform for ratiometric visualization of SARS-CoV-2 via an oligonucleotide probe.

COVID-19 necessitates the development of reliable and convenient diagnostic tools. In this work, a facile 3D-printed smartphone platform was constructed that achieved reliable visual detection of SARS-CoV-2 by eliminating the effect of ambient light and fixing the camera position relative to the sample. The oligonucleotide probe is modified with orange-red-emitting TAMRA working as an internal standard and green-emitting FAM serving as a sensitive sensing agent. Under 365-nm UV excitation, the emission wavelengths of TAMRA and FAM are 580 nm and 518 nm, respectively. When the probes interact with the targets, the green fluorescence gradually restores while the orange-red fluorescence remains stable. Thus, a striking color transition from orange-red to green could be observed by the naked eye. The detection limit of SARS-CoV-2 nucleic acid is 0.23 nM, and the entire process of color change could be completed in 25 min. Furthermore, the RGB value analysis of the sample solution was conducted using a smartphone for reliable and reproducible discrimination of SARS-CoV-2. The proposed smartphone platform might establish a general method for visual detection of SARS-CoV-2 nucleic acid as well as other virus-related diseases.

Effect of combined arsenic and lead exposure on their uptake and translocation in Indian mustard.

Phytoremediation makes use of hyperaccumulating plants to remove potentially toxic elements (PTEs) from soil selectively. Most researches examining hyperaccumulators focused on how they act on a single PTE contaminant. However, there is more than one kind of PTEs in most contaminated soils. Phytoremediation approaches could be less effective in environments containing multiple PTEs contaminants. Here we examine arsenic (As) and lead (Pb) accumulation in Indian Mustard (Brassica juncea) from solutions with one or both pollutants. Indian mustard accumulates As or Pb when exposed in the single liquid exposure of As or Pb, and the highest concentrations of As and Pb in Indian Mustard reach 1,786 mg/kg and 47,200 mg/kg, respectively. But the absorption efficiencies of As and Pb decrease (by >90% for As, and ∼10-30% for Pb) when both As and Pb are present. The translocation of As and Pb from the root to leaf is also impeded by 36%-88% for As and 55-85% for Pb when treated with both PTEs. In As and Pb co-treatment, significant negative correlations between As (V) and P and between Pb and other elements (including K, Mg and Ca) were found in Indian mustard. X-ray absorption near edge (XANES) spectroscopy and subcellular extraction experiments indicate that much of the accumulated Pb bound within lead phosphate particles, and often located within the cell wall. Pb could decrease the percentage of water-soluble As and increase protein combined As in subcellular levels within Indian mustard. Based on these data, we suggest that the competition between Pb and monovalent and divalent nutrients (e.g., Ca(II), Mg(II) and K(I)), and the formation of lead phosphates within cell walls play critical roles in decreasing As and Pb co-uptake efficiencies for Indian mustard.

Deep brain stimulation in the medial septum attenuates temporal lobe epilepsy via entrainment of hippocampal theta rhythm.

AIMS: Temporal lobe epilepsy (TLE), often associated with cognitive impairment, is one of the most common types of medically refractory epilepsy. Deep brain stimulation (DBS) shows considerable promise for the treatment of TLE. However, the optimal stimulation targets and parameters of DBS to control seizures and related cognitive impairment are still not fully illustrated. METHODS: In the present study, we evaluated the therapeutic potential of DBS in the medial septum (MS) on seizures and cognitive function in mouse acute and chronic epilepsy models. RESULTS: We found that DBS in the MS alleviated the severity of seizure activities in both kainic acid-induced acute seizure model and hippocampal-kindled epilepsy model. DBS showed antiseizure effects with a wide window of effective stimulation frequencies. The antiseizure effects of DBS were mediated by the hippocampal theta rhythm, as atropine, which reversed the DBS-induced augmentation of the hippocampal theta oscillation, abolished the antiseizure effects of DBS. Further, in the kainic acid-induced chronic TLE model, DBS in the MS not only reduced spontaneous seizures, but also improved behavioral performance in novel object recognition. CONCLUSION: DBS in the MS is a promising approach to attenuate TLE probably through entrainment of the hippocampal theta rhythm, which may be therapeutically significant for refractory TLE treatment.

Aquifer-Scale Observations of Iron Redox Transformations in Arsenic-Impacted Environments to Predict Future Contamination.

Iron oxides control the mobility of a host of contaminants in aquifer systems, and the microbial reduction of iron oxides in the subsurface is linked to high levels of arsenic in groundwater that affects greater than 150 million people globally. Paired observations of groundwater and solid-phase aquifer composition are critical to understand spatial and temporal trends in contamination and effectively manage changing water resources, yet field-representative mineralogical data are sparse across redox gradients relevant to arsenic contamination. We characterize iron mineralogy using X-ray absorption spectroscopy across a natural gradient of groundwater arsenic contamination in Vietnam. Hierarchical cluster analysis classifies sediments into meaningful groups delineating weathering and redox changes, diagnostic of depositional history, in this first direct characterization of redox transformations in the field. Notably, these groupings reveal a signature of iron minerals undergoing active reduction before the onset of arsenic contamination in groundwater. Pleistocene sediments undergoing postdepositional reduction may be more extensive than previously recognized due to previous misclassification. By upscaling to similar environments in South and Southeast Asia via multinomial logistic regression modeling, we show that active iron reduction, and therefore susceptibility to future arsenic contamination, is more widely distributed in presumably pristine aquifers than anticipated.

MiR-15a/16-1 deficiency induces IL-10-producing CD19+ TIM-1+ cells in tumor microenvironment.

IL-10-producing B cells (B10) are associated with autoimmune diseases, infection and tumours. MiR-15a/16 as a tumour-suppressive gene is down-regulated in several tumours, such as chronic lymphocytic leukaemia, pituitary adenomas and prostate carcinoma. Here, increased frequency of IL-10-producing CD19+ Tim-1+ cells was seen in both aged miR-15a/16-/- mice (15-18 months) with the onset of B cell leukaemia and young knockout mice (8-12 weeks) transplanted with hepatic cancer cells. CD19+ Tim-1+ cells down-regulated the function of effector CD4+ CD25low T cells ex vivo dependent on IL-10 production, and adoptive transfer of CD19+ Tim-1+ cells promoted tumour growth in mice. IL-10 production by CD19+ Tim-1+ cells was involved with the STAT3 activation. Bioinformatics analysis shows that miR-16 targets the 3'-untranslating region (3'-UTR) of STAT3 mRNA. Overexpression of miR-16 in CD19+ Tim-1+ cells inhibited STAT3 transcription and its protein expression. Thus, the loss of miR-15a/16 promoted induction of regulatory CD19+ Tim-1+ cells in tumour microenvironment. These results confirmed that miR-15a/16 could be used in tumour therapy due to its inhibition of tumour and regulatory B cells.

Interaction with AEG-1 and MDM2 is associated with glioma development and progression and correlates with poor prognosis.

Glioma is the most common central nervous system tumor with poor prognosis. The AEG-1 (Astrocyte Elevated Gene 1) gene displays oncogenic characteristics, including proliferation, metastasis, chemoresistance, invasion, and evasion of apoptosis, and is strongly linked to the occurrence of glioma. Here, we elucidated the potential contribution of AEG-1 in human glioma pathogenesis. In glioma cells, AEG-1 could directly interact with Murine Double Minute-2 (MDM2) protein resulting in MDM2-p53-mediated cell proliferation and apoptosis. MDM2 is being revealed as an oncoprotein, which is involved in many human cancers progression. By immunohistochemical and a multivariate analysis, expressions of AEG-1 and MDM2 were elevated in glioma and high AEG-1 and MDM2 expressions were showed to be correlated with poor prognosis. AEG-1-MDM2 interaction prolonged stabilization of MDM2 where AEG-1 inhibited ubiquitination and subsequent proteasome-mediated degradation of MDM2 protein. Moreover, slicing AEG-1 blocked MDM2 expression and then impacted MDM2-p53 pathway that influenced cell proliferation and apoptosis. These findings uncover a novel AEG-1-MDM2 interplay by which AEG-1 augments glioma progression and reveal a viable potential therapy for the treatment of glioma patients.

Pharmaco-genetic therapeutics targeting parvalbumin neurons attenuate temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common type of epilepsy and is often medically refractory. Previous studies suggest that selective pharmaco-genetic inhibition of pyramidal neurons has therapeutic value for the treatment of epilepsy, however there is a risk of disrupting normal physical functions. Here, we test whether pharmaco-genetic activation of parvalbumin neurons, which are transgenetically transduced with the modified muscarinic receptor hM3Dq can attenuate TLE. We found that pharmaco-genetic activation of hippocampal parvalbumin neurons in epileptogenic zone not only significantly extends the latency to different seizure stages and attenuates seizure activities in acute seizure model, but also greatly alleviates the severity of seizure onsets in two chronic epilepsy models. This manipulation did not affect the normal physical function evaluated in various cognitive tasks. Further, the activation of parvalbumin neurons produced an inhibition on parts of surrounding pyramidal neurons, and the direct inactivation of pyramidal neurons via the viral expression of a modified muscarinic receptor hM4Di produced a similar anti-ictogenic effect. Interestingly, pharmaco-genetic inactivation of pyramidal neurons was more sensitive to impair cognitive function. Those data demonstrated that pharmaco-genetic seizure attenuation through targeting parvalbumin neurons rather than pyramidal neurons may be a novel and relatively safe approach for treating refractory TLE.

Phytoavailability, bioaccumulation, and human health risks of metal(loid) elements in an agroecosystem near a lead-zinc mine.

Soil near a Pb-Zn-Mn mine was polluted by mining, which may have an impact on human health via the food chain. To evaluate the pollution effects, arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), manganese (Mn), lead (Pb), and zinc (Zn) in vegetables were determined by inductively coupled plasma atomic emission and mass spectrometry. Lead species were analyzed by X-ray absorption near-edge structure (XANES). Phytoavailability of the elements was evaluated by bioaccumulation of the elements, the sequential extraction procedure, Pb species, and plant uptakes. The target health quotient (THQ) was calculated to evaluate the human health risks. It was found that (1) high concentrations of As, Cd, Cr, and Pb were detectable in vegetables, and bioaccumulation was in the order of Mn > Zn > Cr > Pb > Cu > As > Cd; (2) phytoavailability of the elements was controlled mainly by the soluble fraction, and a linear relationship observed between the soluble fraction and bioaccumulation; (3) a new Pb-fulvic acid complex (Pb-FA) was identified by XANES in rhizosphere soil, and high content of Pb organic matter (60%) and soluble Pb (18%) were found; (4) both Cd and Zn accumulated in both of the Amaranthaceae and the Apiaceae families, indicating that the plants in the same family have the same bioaccumulation trend for the elements in the same group; (5) agricultural activities and plant growing increased phytoavailability of As, Cd, Cu, Pb, and Zn by decreasing the residual and raising the soluble and extractable fractions; (6) arsenic is top of the high health risks, followed by Pb, Cd, and Mn. Coriander, celery, and spinach were the top three highest health risks in the area.

[Effects of Clostridium butyricum on serum uric acid and inflammatory mediators in rats with hyperuricemia].

OBJECTIVE: To investigate the effects of intragastric administration of Clostridium butyricum in regulating serum uric acid, lipopolysaccharides (LPS), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in rats with hyperuricemia rats. METHODS: Forty SD rats were randomized into 4 equal groups, namely the normal control group, hyperuricemia model group, benzbromarone (3 mg/kg daily) intervention group and live Clostridium butyricum group (1.5×107 CFU/day). Except for those in the control group, the rats were subjected to intragastric administration of yeast extract and oteracil potassium once daily for 12 weeks to induce hyperuricemia with corresponding treatments. The changes in serum uric acid, lipopolysaccharides , IL-6 and TNF-α in each group were detected. RESULTS: The serum level of uric acid was significantly higher in rats fed with high-purine diet than in the control rats (P<0.01), demonstrating the successful establishment of hyperuricemia models. In rats with hyperuricemia, serum uric acid level was positively correlated with the levels of LPS, IL-6 and TNF-α, and their serum levels decreased significantly and progressively with time in Benzbromarone group and Clostridium butyricum group. Benzbromarone was more effective in decreasing serum uric acid in the rats, while Clostridium butyricum produced a stronger effect in down-regulating the inflammatory mediators. CONCLUSION: Chronic inflammatory reaction exists in rats with hyperuricemia. Intragastric administration of Clostridium butyricum can effectively decrease serum uric acid level and inhibit the inflammatory cytokines, and thus contributes to immune homeostasis in the intestines.

MiR-16 regulates mouse peritoneal macrophage polarization and affects T-cell activation.

MiR-16 is a tumour suppressor that is down-regulated in certain human cancers. However, little is known on its activity in other cell types. In this study, we examined the biological significance and underlying mechanisms of miR-16 on macrophage polarization and subsequent T-cell activation. Mouse peritoneal macrophages were isolated and induced to undergo either M1 polarization with 100 ng/ml of interferon-γ and 20 ng/ml of lipopolysaccharide, or M2 polarization with 20 ng/ml of interleukin (IL)-4. The identity of polarized macrophages was determined by profiling cell-surface markers by flow cytometry and cytokine production by ELISA. Macrophages were infected with lentivirus-expressing miR-16 to assess the effects of miR-16. Effects on macrophage-T cell interactions were analysed by co-culturing purified CD4(+) T cells with miR-16-expressing peritoneal macrophages, and measuring activation marker CD69 by flow cytometry and cytokine secretion by ELISA. Bioinformatics analysis was applied to search for potential miR-16 targets and understand its underlying mechanisms. MiR-16-induced M1 differentiation of mouse peritoneal macrophages from either the basal M0- or M2-polarized state is indicated by the significant up-regulation of M1 marker CD16/32, repression of M2 marker CD206 and Dectin-1, and increased secretion of M1 cytokine IL-12 and nitric oxide. Consistently, miR-16-expressing macrophages stimulate the activation of purified CD4(+) T cells. Mechanistically, miR-16 significantly down-regulates the expression of PD-L1, a critical immune suppressor that controls macrophage-T cell interaction and T-cell activation. MiR-16 plays an important role in shifting macrophage polarization from M2 to M1 status, and functionally activating CD4(+) T cells. This effect is potentially mediated through the down-regulation of immune suppressor PD-L1.