Effect of Single Particle High-Speed Impingement on the Electrochemical Step Characteristics of a Stainless-Steel Surface.

In the process of particle erosion and electrochemical corrosion interaction, the electrolyte flow state change, product film destruction, and matrix structure change caused by particle impact affect the electrochemical corrosion process. Such transient, complex physical and electrochemical changes are difficult to capture because of the short duration of action and the small collision area. The peak, step time, and recovery time in this transient step cycle can indirectly reflect the smoothness and reaction rate of the electrochemical reaction system, and thus characterize the resistance to scouring corrosion coupling damage of metals in liquid-solid two-phase flow. In this study, in order to obtain the electrochemical response at the moment of particle impact, electrochemical monitoring experiments using a specially designed miniature three-electrode system were used to test step-critical values, including step potential, current, and resistance, among others. Meanwhile, an electrochemical step model under particle impact considering boundary layer perturbation was developed. The experimental results reflect the effect law of particle impact velocity and particle size on the peak step and recovery period. Meanwhile, the effect of particle impingement on the electrochemical step of stainless steel in different electrolyte solutions was obtained by comparing the step curves in distilled water and Cl-containing water. The connection between the parameters in the electrochemical step model and in the particle impact, as well as the effect of the variation of these parameters on the surface repassivation process are discussed in this paper. By fitting and modeling the test curves, a new mathematical model of electrochemical step-decay under single-particle impact was obtained, which can be used to characterize the change pattern of electrochemical parameters on the metal surface before and after the impingement.

Phenylethanoid glycosides from Michelia champaca leaves.

Chemical investigation on the leaves of Michelia champaca L. (Magnoliaceae) led to the isolation of five previously undescribed phenylethanoid glycosides (PhGs), 4-O-ß-d-glucopyranosyl-acteoside (1), 4‴-O-(6-O-E-caffeoyl)-ß-d-glucopyranosyl-acteoside (2), 4‴-O-(6-O-E-caffeoyl)-ß-d-glucopyranosyl-isoacteoside (3), 6""-O-E-feruloyl-echinacoside (4), and 6""-O-p-E-coumaroyl-echinacoside (5), together with eighteen known PhGs. Their structures were determined by spectroscopic and chemical methods. All the known PhGs except acteoside (8) were not previously reported in the genus. Twenty-one PhGs exhibited more potent DPPH radical scavenging activity and FRAP than l-ascorbic acid (l-AA), and twenty-two PhGs showed better ABTS radical cation scavenging activity than l-AA. In addition, twelve PhGs displayed more potent cellular reactive oxygen species scavenging activity than curcumin. The results revealed that the leaves of M. champaca are a rich source of phenylethanoid glycosides and antioxidants.

Ginsenoside Rd attenuated hyperglycemia via Akt pathway and modulated gut microbiota in streptozotocin-induced diabetic rats.

Ginsenoside Rd is a protopanaxadiol abundant in Panax ginseng and Panax notoginseng. It has been reported that ginsenoside Rd possesses various health benefits, such as anti-diabetic, anti-tumor and anti-inflammatory. This work explored the effects of ginsenoside Rd on hyperglycemia and gut microbiota in streptozotocin-induced diabetic rats. Results showed that 5-week ginsenoside Rd (20 mg/kg) treatment significantly improved hyperglycemia in diabetic rats. Besides, ginsenoside Rd promoted glycogen synthesis via activating Akt pathway. It also inhibited hepatic gluconeogenesis, which was associated with inhibiting phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. We further found that ginsenoside Rd treatment increased the diversity of gut microbiota, increased the abundance of beneficial bacteria, such as SMB53, rc4-4 and Ruminococcus, and reduced the abundance of conditional pathogenic bacteria. These results indicated that ginsenoside Rd has the potential for diabetic intervention.

Envafolimab combined with chemotherapy in the treatment of combined small cell lung cancer: A case report.

BACKGROUND: Combined small cell lung cancer (C-SCLC) is a special subtype of small cell lung cancer that is relatively rare, aggressive, and prone to early metastasis and has a poor prognosis. Currently, there are limited studies on C-SCLC, and there is no uniform standard treatment, especially for extensive C-SCLC, which still faces great challenges. In recent years, the development and progress of immunotherapy have provided more possibilities for the treatment of C-SCLC. We used immunotherapy combined with first-line chemotherapy to treat extensive-stage C-SCLC to explore its antitumor activity and safety. CASE SUMMARY: We report a case of C-SCLC that presented early with adrenal, rib, and mediastinal lymph node metastases. The patient received carboplatin and etoposide with concurrent initiation of envafolimab. After 6 cycles of chemotherapy, the lung lesion was significantly reduced, and the comprehensive efficacy evaluation showed a partial response. No serious drug-related adverse events occurred during the treatment, and the drug regimen was well tolerated. CONCLUSION: Envafolimab combined with carboplatin and etoposide in the treatment of extensive-stage C-SCLC has preliminary antitumor activity and good safety and tolerability.

Zeaxanthin prevents ferroptosis by promoting mitochondrial function and inhibiting the p53 pathway in free fatty acid-induced HepG2 cells.

Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder worldwide and a risk factor for obesity and diabetes. Emerging evidence has shown that ferroptosis is involved in the progression of NAFLD. Zeaxanthin (ZEA) is a carotenoid found in human serum. It has been reported that ZEA can ameliorate obesity, prevent age-related macular degeneration, and protect against non-alcoholic steatohepatitis. However, no study has focused on the protective effects of ZEA against NAFLD. In this study, free fatty acid (FFA) induced HepG2 cells were used as a cell model for NAFLD. Our results suggest that ZEA exerts antioxidative and anti-inflammatory effects in FFA-induced HepG2 cells. Moreover, ZEA acted as a ferroptosis inhibitor, significantly reducing reactive oxygen species (ROS) generation and iron overload and improving mitochondrial dysfunction in FFA-induced HepG2 cells. In addition, ZEA downregulated the expression of p53 and modulated downstream targets, such as GPX4, SLC7A11, SAT1, and ALOX15, which contributed to the reduction in cellular lipid peroxidation. Our findings suggest that ZEA has the potential for NAFLD intervention.

Characterization of the synergistic inhibitory effect of cyanidin-3-O-glucoside and catechin on pancreatic lipase.

This study aimed to identify novel pancreatic lipase (PL) inhibitors using affinity ultrafiltration combined with spectroscopy and molecular docking. Cyanidin-3-O-glucoside (C3G; IC50: 0.268 mg/mL) and catechin (IC50: 0.280 mg/mL) were shown to be potent PL inhibitors extracted from black rice and adzuki bean coat extracts. Isobologram analysis revealed that the combined use of C3G and catechin at a ratio of 2:3 had a remarkable synergistic effect (IC50 of the mixture: 0.201 mg/mL). The inhibitory mechanism of C3G-catechin mixture was of mixed type. The C3G-catechin mixture had a great impact on PL secondary structures. Molecular docking analysis further demonstrated that these polyphenols formed hydrophobic interactions and hydrogen bonds with amino acid residues in the binding pocket of PL. Collectively, C3G and catechin were shown to inhibit PL in a synergistic manner and can be potentially used for the development of food supplements for obesity prevention.

Fraxetin protects rat brains from the cerebral stroke via promoting angiogenesis and activating PI3K/Akt pathway.

OBJECTIVE: Fraxetin has antioxidant, anti-inflammation and neuroprotective functions, however, its role in ischemic stroke is still vague. Herein, this study delves into the underlying mechanism. METHODS: Ischemia and reperfusion operation were performed to establish the cerebral stroke rat models. The brain functions were evaluated with neurological score. The brain infarcted volume in fraxetin group was measured by 2,3,5-triphenyltetrazolium chloride staining. The blood-brain barrier permeability, CD34 enrichment, and the brain water content were measured by Evans blue staining, immunofluorescence staining, and wet-dry method, respectively. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) were applied to examine the levels of angiogenesis- and PI3K/Akt pathway-related factors. MTT and tube formation assays were used to measure the viability and tube formation of HUVECs. RESULTS: Fraxetin decreased the brain injury-related neurological score, brain infarction, and cerebral edema and maintained blood-brain barrier permeability, whereas it promoted the angiogenesis in ischemia-damaged brain via enhancing CD34 enrichment, the expressions of VEGF, Ang-1, Tie-2, and CD-31, viability of HUVECs, as well as activating the phosphorylation of PI3K and Akt. Importantly, wortmannin (a specific PI3K inhibitor) impeded the fraxetin-induced cell viability, angiogenesis, and phosphorylation of Akt and PI3K in HUVECs. CONCLUSIONS: Fraxetin has protective effects on the brain ischemia-reperfusion injury and promotes angiogenesis for cerebral repair via phosphorylation of PI3K and Akt.

Lipid oxidation and in vitro digestion of pickering emulsion based on zein-adzuki bean seed coat polyphenol covalent crosslinking nanoparticles.

This study first used adzuki bean seed coat polyphenol (ABSCP) to modify zein and form covalent nanoparticles (ZAP) and used ZAP as an emulsifier to stabilize Pickering emulsion (ZAE). The results showed that the ratio of zein-ABSCP controlled the physicochemical properties of the two compounds. ZAP could be absorbed on the water-oil surface and stabilized ZAE, which presented as a non-Newtonian fluid state with good rheological properties. The addition of ABSCP inhibited lipid oxidation in a dose-dependent manner, as verified through the analysis of accelerated oxidation experiments (50 °C, 20 days). In in vitro gastrointestinal digestion of ZAE showed that free fatty acids (FFA) release gradually decreased with ABSCP concentration increasing. Moreover, ABSCP gave ZAE a strong red-yellow color, which allowed ZAE to be used for specific applications (e.g., natural pigments). Our findings make it feasible to develope functional food and food-grade delivery systems made of protein-plant polyphenols nanoparticles.

Cardiac myxomas as great imitators: A rare case series and review of the literature.

Myxoma is the most common type of primary cardiac tumors, accounting for 50%-80% of them. Cardiac myxomas are difficult to detect due to the lack of specific signs and symptoms and even benign tumors can cause serious consequences. Cardiac failure, atrio-ventricular valve obstruction or the embolization phenomenon can quietly occur in patients with cardiac myxomas. Here, we report three extraordinary cases, each of which vary in the first symptom. One case involved a 66-year-old man who had no underlying heart disease but suddenly developed chest tightness and got out of breath after exercising. One case was a 36-year-old young woman with a two-year history of low blood pressure but suddenly suffered a stroke. The third case was a 42-year-old middle-aged woman who accidentally discovered a cardiac myxoma during the diagnosis and treatment of acute pancreatitis. Echocardiography revealed huge masses floating in their atriums. Under general anesthesia, all the patients underwent open-heart surgery and hematoxylin and eosin-stained sections of the samples confirmed myxomas. Although most patients with cardiac myxomas lack of specific systemic symptoms, typical myxomas are relatively easy to diagnose. There are currently no effective medical therapeutic to inhibit tumor growth and surgical resection is the mainstay of treatment, which prevents a dreaded complication resulted from systemic and pulmonary embolisms.

Vedolizumab-associated diffuse interstitial lung disease in patients with ulcerative colitis: A case report.

BACKGROUND: Vedolizumab, a newer class of integrin antagonist biological agents, has been applied to treat patients with moderate-to-severe Crohn's disease (CD) and ulcerative colitis (UC), especially for patients who are refractory to traditional therapies and tumor necrosis factor antagonists. However, some rare but life-threatening adverse effects warrant pharmacovigilance. We describe the first fatal case of vedolizumab-associated severe diffuse interstitial lung disease in China. CASE SUMMARY: We present a case of new-onset diffuse parenchymal lung disease developing under treatment with vedolizumab in a patient with UC. After two doses of vedolizumab, he developed persistent fever and progressively worsening dyspnea. Extensive workups, including bronchoalveolar lavage, transbronchial lung biopsy and metagenomic next-generation sequencing, identified no infectious causes, and other potential causes (such as tumors and cardiogenic pulmonary edema) were also excluded. As a result, a diagnosis of vedolizumab-related interstitial lung disease was established. Unfortunately, although corticosteroids and empiric antibiotics were administered, the patient eventually died of respiratory failure. CONCLUSION: Vedolizumab-related interstitial lung disease in patients with UC is rare but potentially lethal. Gastroenterologists and pulmonologists should be aware of vedolizumab-related adverse drug reactions.

Protective effect of rosuvastatin against the formation of benign esophageal stricture.

BACKGROUND: Benign esophageal strictures result from caustic or radiation injury or surgical procedures. Statins have anti-inflammatory and anti-fibrotic activities. We examined the role of rosuvastatin in preventing benign esophageal fibrosis and stricture formation in a rabbit model. METHODS: Twenty-six rabbits were assigned to control and rosuvastatin groups. The rabbits in the rosuvastatin group were administered rosuvastatin 5 mg/day, 2 weeks prior to the esophageal stricture phase. Esophageal strictures were established by applying 4% sodium hydroxide solution to the middle esophagus. Esophagography was performed to evaluate the degree of esophageal stenosis, and histopathologic assessment of esophageal tissue damage was performed with hematoxylin-eosin and Masson staining. The expressions of transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) were examined by immunohistochemistry. RESULTS: The incidence of strictures was significantly lower in the rosuvastatin group. Esophagography demonstrated mild stenosis in the narrowest inner esophageal diameter in the rosuvastatin group than in the control group, and Masson staining demonstrated significantly less collagen deposition in the rosuvastatin group. In addition, immunohistochemistry results showed that the expressions of TGF-ß1, CTGF, and α-SMA significantly reduced in the rosuvastatin group. CONCLUSIONS: The present study demonstrated that rosuvastatin prevents benign esophageal stricture formation. This effect may be exerted through the anti-fibrotic activity of rosuvastatin, which may be exerted by the inhibition of CTGF and α-SMA production induced by TGF-ß1.

Dietary Antioxidant Anthocyanins Mitigate Type II Diabetes through Improving the Disorder of Glycometabolism and Insulin Resistance.

Insulin resistance (IR) is one of the pathological reasons for type II diabetes mellitus (T2DM). Therefore, it is important to prevent the body from developing T2DM by improving IR and maintaining glucose homeostasis. Anthocyanins (ACNs) are water-soluble pigments and are widely distributed in natural products. This article summarizes research on the bioavailability and metabolism of ACNs. Moreover, we further elaborate on how ACNs reduce IR and hyperglycemia during the development of T2DM based on studies over the past 20 years. Many studies have demonstrated that ACNs are small molecules that target the pancreatic, liver, muscle, and adipose tissues, preventing IR and hyperglycemia. However, the molecular mechanisms are still unclear. Therefore, we envision whether the molecular mechanism of reducing T2DM by ACNs could be more deeply investigated.

Zeaxanthin promotes browning by enhancing mitochondrial biogenesis through the PKA pathway in 3T3-L1 adipocytes.

Obesity is closely associated with maintaining mitochondrial homeostasis, and mitochondrial dysfunction can lead to systemic lipid metabolism disorders. Zeaxanthin (ZEA) is a kind of carotenoid with potent antioxidant activity and has been reported to promote mitochondrial biogenesis. Nevertheless, the molecular mechanism has not been explained. In this study, we first discovered that ZEA stimulated 3T3-L1 adipocyte browning by increasing the expression of specific markers (Cd137, Tbx1, Sirt1, Cidea, Ucp1, Tmem26, and Cited1), thereby reducing lipid accumulation. Besides, ZEA promoted mitochondrial biogenesis by increasing the expression of PRDM16, UCP1, NRF2, PGC-1α, and SIRT1. Moreover, the uncoupled oxygen consumption rate (OCR) of protons leaked in 3T3-L1 adipocytes was rapidly increased by ZEA treatment, which improved mitochondrial respiration and energy metabolism. Furthermore, we found that ZEA promotes browning by enhancing mitochondrial biogenesis partly through the protein kinase A (PKA) pathway. This study provided new insight into the promotion of browning and mitochondrial biogenesis by ZEA, suggesting that ZEA probably has potential therapeutic effects on obesity.

Glycolysis-Related Genes Serve as Potential Prognostic Biomarkers in Clear Cell Renal Cell Carcinoma.

Metabolic rearrangement is a marker of cancer that has been widely studied in recent years. One of the major metabolic characteristics of tumor cells is the high levels of glycolysis, even under aerobic conditions, a phenomenon that is called the "Warburg effect." We investigated the expression and copy number variation (CNV) frequency of all glycolysis-related genes in multiple cancer types and found many differentially expressed genes, particularly in clear cell renal cell carcinoma (ccRCC). Single nucleotide variants (SNVs) showed that the overall average mutation frequency for all genes was low. The purpose of this study was to establish a predictive model by studying glycolysis-related genes in ccRCC. We compared the expression of glycolysis-related genes in 539 ccRCC tissues and 72 normal renal tissues from The Cancer Genome Atlas dataset and identified 17 upregulated and 26 downregulated genes. Pathway analysis revealed that PSAT1 and SDHB could activate the cell cycle, RPIA could activate the DNA damage response, and HK3 could activate apoptosis and EMT signaling, while PDK2 could inhibit apoptosis. The results of the drug sensitivity analysis suggested that some of these differentially expressed genes were positively correlated with drug sensitivity. Thirteen genes were selected from the gene coexpression network and the LASSO regression analysis. The Kaplan-Meier overall survival curves showed that the expression of upregulated genes in ccRCC patients was associated with lower overall survival. We established a predictive model consisting of 13 genes (RPIA, G6PD, PSAT1, ENO2, HK3, IDH1, PDK4, PGM2, PGK1, FBP1, OGDH, SUCLA2, and SUCLG2). This predictive model correlated well with the development and progression of ccRCC. Thus, it is of great value in the diagnosis and prognostic evaluation of ccRCC and may aid the identification of potential prognostic biomarkers and drug targets.

Identification of a New Prognostic Risk Signature of Clear Cell Renal Cell Carcinoma Based on N6-Methyladenosine RNA Methylation Regulators.

As the most prevalent internal eukaryotic modification, N6-methyladenosine (m6A) is installed by methyltransferases, removed by demethylases, and recognized by readers. However, there are few studies on the role of m6A in clear cell renal cell carcinoma (ccRCC). In this study, we researched the RNA-seq transcriptome data of ccRCC in the TCGA dataset and used bioinformatics analyses to detect the relationship between m6A RNA methylation regulators and ccRCC. First, we compared the expression of 18 m6A RNA methylation regulators in ccRCC patients and normal tissues. Then, data from ccRCC patients were divided into two clusters by consensus clustering. LASSO Cox regression analysis was used to build a risk signature to predict the prognosis of patients with ccRCC. An ROC curve, univariate Cox regression analysis, and multivariate Cox regression analysis were used to verify this risk signature's predictive ability. Then, we internally validated this signature by random sampling. Finally, we explored the role of the genes in the signature in some common pathways. Gene distribution between the two subgroups was different; cluster 2 was gender-related and had a worse prognosis. IGF2BP3, IGF2BP2, HNRNPA2B1, and METTL14 were chosen to build the risk signature. The overall survival of the high- and low-risk groups was significantly different (p = 7.47e - 12). The ROC curve also indicated that the risk signature had a decent predictive significance (AUC = 0.72). These results imply that the risk signature has a potential value for ccRCC treatment.

Functional characterization of myeloid-derived suppressor cell subpopulations during the development of experimental arthritis.

Recent evidence indicates the existence of subpopulations of myeloid-derived suppressor cells (MDSCs) with distinct phenotypes and functions. Here, we characterized the role of MDSC subpopulations in the pathogenesis of autoimmune arthritis in a collagen-induced arthritis (CIA) mouse model. The splenic CD11b(+) Gr-1(+) MDSC population expanded in CIA mice, and these cells could be subdivided into polymorphonuclear (PMN) and mononuclear (MO) MDSC subpopulations based on Ly6C and Ly6G expression. During CIA, the proportion of splenic MO-MDSCs was increased in association with the severity of joint inflammation, while PMN-MDSCs were decreased. MO-MDSCs expressed higher levels of surface CD40 and CD86 protein, but lower levels of Il10, Tgfb1, Ccr5, and Cxcr2 mRNA. PMN-MDSCs exhibited a more potent capacity to suppress polyclonal T-cell proliferation in vitro, compared with MO-MDSCs. Moreover, the adoptive transfer of PMN-MDSCs, but not MO-MDSCs, decreased joint inflammation, accompanied by reduced levels of serum cytokine secretion and the frequencies of Th1 and Th17 cells in draining lymph nodes. These results suggest that there could be a shift from potently suppressive PMN-MDSCs to poorly suppressive MO-MDSCs during the development of experimental arthritis, which might reflect the failure of expanded MDSCs to suppress autoimmune arthritis.

A mutant retroviral receptor restricts virus superinfection interference and productive infection.

BACKGROUND: Both cell-free and cell-associated infection routes are important for retroviral dissemination. Regardless of the mechanism, the driving force of retroviral entry is the interaction between the viral envelope and its receptor. To date it remains unclear how decreased affinity of viruses for their receptors affects viral cell-free infection, cell-cell transmission, and spreading kinetics. We have previously characterized a mutant form of the amphotropic murine retrovirus receptor human phosphate transporter 2 (PiT2) wherein the single substitution of a glutamic acid for the lysine residue at position 522 of this receptor is sufficient to render it to function as a gibbon ape leukemia virus (GALV) receptor. RESULTS: In this study we analyzed the binding affinity of the mutant receptor PiT2K522E and determined that it has a 1000 fold decreased GALV envelope binding affinity compared to the GALV wild type receptor. The decreased affinity does not restrict the initiation of cell-free GALV infection. The diminished binding affinity does, however, correlate with a decrease in the ability of GALV to spread in cells expressing this mutant receptor. CONCLUSIONS: The reduced ability of GALV to subsequently spread among cells expressing PiT2K522E is likely resulted from reduced cell-cell transmission, the decreased ability of PiT2K522E-expressing cells to establish superinfection interference, and attendant cytopathic affects.

Role of human endogenous retroviral long terminal repeats (LTRs) in maintaining the integrity of the human germ line.

Retroviruses integrate a reverse transcribed double stranded DNA copy of their viral genome into the chromosomal DNA of cells they infect. Occasionally, exogenous retroviruses infect germ cells and when this happens a profound shift in the virus host dynamic occurs. Retroviruses maintained as hereditable viral genetic material are referred to as endogenous retroviruses (ERVs). After millions of years of co-evolution with their hosts many human ERVs retain some degree of function and a few have even become symbionts. Thousands of copies of endogenous retrovirus long terminal repeats (LTRs) exist in the human genome. There are approximately 3000 to 4000 copies of the ERV-9 LTRs in the human genome and like other solo LTRs, ERV-9 LTRs can exhibit distinct promoter/enhancer activity in different cell lineages. It has been recently reported that a novel transcript of p63, a primordial member of the p53 family, is under the transcriptional control of an ERV-9 LTR [1]. The expression of different p63 transcript isoforms has been previously shown to have an important role in replenishing cutaneous epithelial stem cells and maintaining the fidelity of the female germ line [2]. In this recent report, a novel p63 transcript, designated GTAp63, is described as specifically expressed in healthy human testes and germ cell precursors of human testes but not in testicular cancer cells. The ability of ERV-9 regulatory regions to contribute to the maintenance of male germ line stability is yet another example of how ERVs have evolved to serve an important function in the physiology of their human hosts.

The receptors for gibbon ape leukemia virus and amphotropic murine leukemia virus are not downregulated in productively infected cells.

BACKGROUND: Over the last several decades it has been noted, using a variety of different methods, that cells infected by a specific gammaretrovirus are resistant to infection by other retroviruses that employ the same receptor; a phenomenon termed receptor interference. Receptor masking is thought to provide an earlier means of blocking superinfection, whereas receptor down regulation is generally considered to occur in chronically infected cells. RESULTS: We used replication-competent GFP-expressing viruses containing either an amphotropic murine leukemia virus (A-MLV) or the gibbon ape leukemia virus (GALV) envelope. We also constructed similar viruses containing fluorescence-labeled Gag proteins for the detection of viral particles. Using this repertoire of reagents together with a wide range of antibodies, we were able to determine the presence and availability of viral receptors, and detect viral envelope proteins and particles presence on the cell surface of chronically infected cells. CONCLUSIONS: A-MLV or GALV receptors remain on the surface of chronically infected cells and are detectable by respective antibodies, indicating that these receptors are not downregulated in these infected cells as previously proposed. We were also able to detect viral envelope proteins on the infected cell surface and infected cells are unable to bind soluble A-MLV or GALV envelopes indicating that receptor binding sites are masked by endogenously expressed A-MLV or GALV viral envelope. However, receptor masking does not completely prevent A-MLV or GALV superinfection.

Induction of p21(CIP1/WAF1) expression by human T-lymphotropic virus type 1 Tax requires transcriptional activation and mRNA stabilization.

HTLV-1 Tax can induce senescence by up-regulating the levels of cyclin-dependent kinase inhibitors p21(CIP1/WAF1) and p27(KIP1). Tax increases p27(KIP1) protein stability by activating the anaphase promoting complex/cyclosome (APC/C) precociously, causing degradation of Skp2 and inactivation of SCF(Skp2), the E3 ligase that targets p27(KIP1). The rate of p21(CIP1/WAF1) protein turnover, however, is unaffected by Tax. Rather, the mRNA of p21(CIP1/WAF1) is greatly up-regulated. Here we show that Tax increases p21 mRNA expression by transcriptional activation and mRNA stabilization. Transcriptional activation of p21(CIP1/WAF1) by Tax occurs in a p53-independent manner and requires two tumor growth factor-beta-inducible Sp1 binding sites in the -84 to -60 region of the p21(CIP1/WAF1) promoter. Tax binds Sp1 directly, and the CBP/p300-binding activity of Tax is required for p21(CIP1/WAF1) trans-activation. Tax also increases the stability of p21(CIP1/WAF1) transcript. Several Tax mutants trans-activated the p21 promoter, but were attenuated in stabilizing p21(CIP1/WAF1) mRNA, and were less proficient in increasing p21(CIP1/WAF1) expression. The possible involvement of Tax-mediated APC/C activation in p21(CIP1/WAF1) mRNA stabilization is discussed.