Perioperative remedial antiviral therapy in hepatitis B virus-related hepatocellular carcinoma resection: How to achieve a better outcome.

BACKGROUND: Although the benefits of antiviral therapy for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) have been proven, researchers have not confirmed the differences in patient outcomes between patients who received preoperative antiviral therapy for a period of time (at least 24 wk) and patients who received remedial antiviral therapy just before radical resection for HBV-related HCC. AIM: To investigate the efficacy of perioperative remedial antiviral therapy in patients with HBV-related HCC. METHODS: A retrospective study of patients who underwent radical resection for HBV-related HCC at the First Affiliated Hospital of Xi'an Jiaotong University from January 2016 to June 2019 was conducted. Considering the history of antiviral therapy, patients were assigned to remedial antiviral therapy and preoperative antiviral therapy groups. RESULTS: Kaplan-Meier analysis revealed significant differences in overall survival (P < 0.0001) and disease-free survival (P = 0.035) between the two groups. Multivariate analysis demonstrated that a history of preoperative antiviral treatment was independently related to improved survival (hazard ratio = 0.27; 95% confidence interval: 0.08-0.88; P = 0.030). CONCLUSION: In patients with HBV-related HCC, it is ideal to receive preoperative long-term antiviral therapy, which helps patients tolerate more extensive hepatectomy; however, remedial antiviral therapy, which reduces preoperative HBV-DNA levels to less than 4 Log10 copies DNA/mL, can also result in improved outcomes.

Chitosan-Delivered Chlorantraniliprole for Pest Control: Preparation Optimization, Deposition Behavior, and Application Potential.

Chitosan has emerged as a promising biopolymer carrier for the sustained release of pesticides owing to its good biocompatibility, biodegradability, and bioactivity. In this work, a controlled-release formulation of insecticide chlorantraniliprole was fabricated through coprecipitation-based synchronous encapsulation with chitosan, where the optimum preparation conditions, storage stability, deposition behavior, and application potential were investigated. Preparation of optimization data from response surface methodology showed high correlation coefficient (R2) of 0.9875 and adjusted coefficient (Radj2) of 0.9715. The resulting formulation displayed good loading content of 28.39%, high encapsulation efficiency of 75.71%, and good storage stability. Compared with the commercial suspension concentrate, the formulation exhibited better wettability and retention behaviors on plant leaves. Excitingly, effective control against one species of mealybug genus Paraputo Laing (outside the killing spectrum) on the Hippeastrum reticulatum plant was successfully achieved by spraying the controlled-release formulation at different time intervals. This work indicates the good potential of the developed formulation in expanding the application scope of chlorantraniliprole, which shows a new strategy for sustainable pest management.

Unity of heaven and humanity: Mediating role of the relational-interdependent self in the relationship between Confucian values and holistic thinking.

As the primary value system in Chinese culture for almost 2,000 years, Confucianism has profoundly influenced the mindset of Chinese people. Cultural psychology studies have highlighted that individuals with different cultural backgrounds vary in their preferences for certain personality traits, such as self-construal, and their metacognitive characteristics, such as thinking modes. Compared with Western cultures, Chinese culture shows a preference for the interdependent self and holistic thinking. To investigate the relationship between the relational-interdependent self, holistic thinking, and traditional Chinese values (which are represented by Confucian values), we surveyed 327 Chinese adults using the Confucian Traditional Values Survey, Holistic Thinking Scale, and Relational-Interdependent Self-Construal Scale. The results show that Confucian values positively influence both holistic thinking and the relational-interdependent self, the latter of which partially mediates the positive relationship between Confucian values and holistic thinking. This study deepens the understanding of the psychological features of Chinese culture.

Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model.

Alzheimer's disease (AD) is a neurodegenerative disease in which oxidative stress and neuroinflammation were demonstrated to be associated with neuronal loss and cognitive deficits. However, there are still no specific treatments that can prevent the progression of AD. In this study, a screening of anti-inflammatory hits from 4207 natural compounds of two different molecular libraries indicated 1,6-O,O-diacetylbritannilactone (OABL), a 1,10-seco-eudesmane sesquiterpene lactone isolated from the herb Inula britannica L., exhibited strong anti-inflammatory activity in vitro as well as favorable BBB penetration property. OABL reduced LPS-induced neuroinflammation in BV-2 microglial cells as assessed by effects on the levels of inflammatory mediators including NO, PGE2, TNF-α, iNOS, and COX-2, as well as the translocation of NF-κB. Besides, OABL also exhibited pronounced neuroprotective effects against oxytosis and ferroptosis in the rat pheochromocytoma PC12 cell line. For in vivo research, OABL (20 mg/kg B.W., i.p.) for 21 d attenuated the impairments in cognitive function observed in 6-month-old 5xFAD mice, as assessed with the Morris water maze test. OABL restored neuronal damage and postsynaptic density protein 95 (PSD95) expression in the hippocampus. OABL also significantly reduced the accumulation of amyloid plaques, the Aß expression, the phosphorylation of Tau protein, and the expression of BACE1 in AD mice brain. In addition, OABL attenuated the overactivation of microglia and astrocytes by suppressing the expressions of inflammatory cytokines, and increased glutathione (GSH) and reduced malondialdehyde (MDA) and super oxide dismutase (SOD) levels in the 5xFAD mice brain. In conclusion, these results highlight the beneficial effects of the natural product OABL as a novel treatment with potential application for drug discovery in AD due to its pharmacological profile.

The comparison of the wisdom view in Chinese and Western cultures.

Wisdom views in different cultural contexts are closely connected with the corresponding culture's worldview. Some results are found by comparing the wisdom concepts in Chinese and Western cultures: Firstly, the early wisdom concepts, both in China and the West, contain the elements of intelligence and virtue. Whereas, from the Enlightenment to the Piagetian school, the western concept of wisdom has then shifted to the role of cognition and knowledge; By contrast, the traditional Chinese wisdom concept has been treating wisdom as a virtue. Modern Chinese and western wisdom psychologists are inclined to accept the wisdom meta-theory of "integration of intelligence and virtue". Secondly, both Chinese and the Western philosophy advocate using wisdom to solve real-life problems. Western thinkers focus on practical problems in the material world, i.e. reconciling conflicts between people and the world through understanding and changing the environment. However, Chinese philosophers focus on internal spiritual problems, i.e. improving the individual realm to solve the contradictions inside oneself. Thirdly, both China and the West highlight the comprehensive application of multiple thinking modes. While comparing with the west, which is excelled in using logical and analytical thinking modes and utilizing rational cognition, China is far better at using dialectical and holistic thinking modes and applying intuitive comprehension.

Alkylated Salicylaldehydes and Prenylated Indole Alkaloids from the Endolichenic Fungus Aspergillus chevalieri and Their Bioactivities.

Sixteen metabolites, including seven C7-alkylated salicylaldehyde derivatives (1-7) and nine prenylated indole alkaloids (8-16), three of which are new, namely, asperglaucins A and B (1 and 2) and neoechinulin F (8), were separated from the endolichenic fungus Aspergillus chevalieri SQ-8. Asperglaucin A (1) represents an unusual phthalide-like derivative with a benzo[c]thiophen-1(3H)-one scaffold. All compounds were assessed in vitro for antibacterial, antineuroinflammatory, and antioxidant activities. Notably, asperglaucins A and B exhibited potent antibacterial activities against two plant pathogens Pseudomonas syringae pv actinidae (Psa) and Bacillus cereus, with an MIC value of 6.25 µM; further SEM analyses illustrated that the possible bacteriostatic mechanisms for compounds 1 and 2 were to alter the external structure of B. cereus and Psa, and to cause the rupture or deformation of the cell membranes, respectively, and the results suggest that compounds 1 and 2 may serve as potential promising candidates for lead compounds of agrochemical bactericides. Furthermore, compounds 6 and 10 significantly inhibited nitric oxide production with an IC50 value of ca. 12 µM, and the possible anti-inflammatory mechanisms involved were also studied by molecular docking. Finally, the tested phenolics 3-5 showed significant antioxidative effects. Thus, strain SQ-8 represents a novel resource of these bioactive metabolites to be utilized.

Regulation of RDN on Th1/ILC1 cell imbalance in HFMD patients caused by EV71 infection.

Enterovirus 71 (EV71) infection is more likely to cause hand, foot and mouth disease (HFMD) in children, which can lead to neurogenic complications and higher mortality. As a commonly used clinical medicine, Reduning injection (RDN) helps to shorten the symptoms of patients with HFMD and facilitate the early recovery of children. However, the regulatory mechanism of RDN on the HFMD immune system disorder caused by EV71 remains to be discussed. This study collected detailed treatment data of 56 children with HFMD who entered the affiliated Children's Hospital of Nanjing Medical University during 2019. Retrospective analysis of clinical data showed that the symptoms of the RDN treatment group were improved compared with the untreated group. To explore its mechanism, the relevant detection indicators were detected by flow cytometry, enzyme-linked immunosorbent assay and real-time quantitative PCR. It was found that the number and function of innate immune (ILCs) and adaptive immunity (Th1, Th2 and secreted cytokines) were reduced, suggesting that RDN plays a role by regulating cellular immunity. The in vitro differentiation inhibition test further confirmed that RDN affected Th1 differentiation by inhibiting the expression of transcription factors on the basis of Th1 cell differentiation in vitro.

Minimally Invasive Pedicle Screw Fixation Combined with Percutaneous Kyphoplasty Under O-Arm Navigation for the Treatment of Metastatic Spinal Tumors with Posterior Wall Destruction.

OBJECTIVE: To evaluate the safety and efficacy of O-arm-guided minimally invasive pedicle screw fixation combined with percutaneous kyphoplasty for metastatic spinal tumors with posterior wall destruction. METHODS: Patients who underwent minimally invasive pedicle screw fixation combined with percutaneous kyphoplasty for pathological vertebral fractures with posterior wall defects from January 2015 to December 2017 were followed up for 1 year. Visual analogue scale (VAS), SF-36 scores, middle vertebral height, posterior vertebral height, and the accuracy of pedicle screws were assessed preoperatively, postoperatively, and 1 year after surgery. The operation time, time from operation to discharge, blood loss, volume of bone cement, and leakage of bone cement were recorded. RESULTS: Twenty-three patients (13 females and 10 males) who met our criteria were followed up for 1 year. The operation time of these patients was 162.61 ± 33.47 min, the amount of bleeding was 230.87 ± 93.76 mL, the time from operation to discharge was 4.35 ± 2.42 days, and the volume of bone cement was 3.67 ± 0.63 mL. The VAS score decreased from 7.04 ± 1.07 to 2.65 ± 0.93 before surgery (P = 0.000) and remained at 2.57 ± 0.79 1 year after surgery. Compared with the preoperative SF-36 scores for physical pain, physiological function, energy, and social function, the postoperative scores were significantly improved (P = 0.000). The height of the middle vertebral body increased from 14.47 ± 2.96 mm before surgery to 20.18 ± 2.94 mm (P = 0.000), and remained at 20.44 to 3.01 mm 1 year after surgery. The height of the posterior vertebral body increased from 16.56 ± 3.07 mm before operation to 22.79 ± 4.00 mm (P = 0.000), and 22.45 ± 3.88 mm 1 year after surgery. The 23 patients had a total of 92 pedicle screws; 85 screws were Grade A and 7 screws were Grade B. There was no leakage of bone cement after surgery. CONCLUSION: In the short term, O-arm-guided minimally invasive pedicle screw fixation combined with kyphoplasty is safe and effective in the treatment of metastatic spinal tumors with posterior wall destruction.

Role and mechanism of matrine alone and combined with acitretin for HaCaT cells and psoriasis-like murine models.

BACKGROUND: Acitretin and matrine have been used in the treatment of psoriasis in China. This study was designed to investigate the role and related mechanisms of matrine alone and in combination with acitretin in the treatment of psoriasis in vitro and in vivo. METHODS: HaCaT cells were treated with matrine at different concentrations of 0 (blank control), 0.2, 0.4, 0.8, and 1.6 mg/mL for 24, 48, 72 h, respectively. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium cell viability assay was used to assess the growth and proliferation of HaCaT cells. Cell cycle and apoptosis were detected by flow cytometry. Expression of protein was detected by Western blotting. Autophagy was observed by transmission electron microscopy. Then HaCaT cells were assigned to normal saline (NS) control group, matrine (0.4 mg/mL) group, acitretin (10 µmol/L) group, and matrine plus acitretin group, and the above methods were repeated. In animal experiments, the cumulative score (erythema, scaling, thickening) as a measure of the severity of inflammation was used to measure the skin performance of mice after treated with matrine 50 mg/kg, acitretin 4.5 mg/kg or combination of the two drugs on the psoriasis-like mouse models, respectively. Pathological findings of the lesions were observed, and the protein expressions in the lesions were detected by immunohistochemistry. RESULTS: Cell proliferation inhibition was seen in HaCaT cells with treatment of matrine in a dose- and time-dependent manner (P < 0.01, respectively). Cell cycle G0/G1 phase arrest was observed in a dose-dependent way (P < 0.01). The expression of p21 (P < 0.05), LC3II/I (P < 0.01), and Beclin 1 (P < 0.01) increased and the expression of cyclin D1 (P < 0.05) decreased with increasing doses of matrine. Compared with the blank control, more autophagosomes were seen in HaCaT cells treated with matrine at 0.4 mg/mL by transmission electron microscopy (2.667 ±â€Š1.202 vs. 21.33 ±â€Š1.453, t = 9.899, P < 0.01). Cell proliferation inhibition and degree of the G0/G1 phase arrest was significantly higher in matrine plus acitretin group than those in matrine, acitretin, or the NS control group (P < 0.01, respectively). Compared with matrine or acitretin group, the expression of p21 (P < 0.05, P < 0.05) and LC3II/I (P < 0.01, P < 0.05) in matrine plus acitretin group increased significantly and the expression of cyclin D1 (P < 0.01, P < 0.05) and p62 (P < 0.05, P < 0.05) was reduced significantly. Compared with matrine or acitretin, matrine plus acitretin significantly down-regulated the phosphorylation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway (P < 0.05) and its downstream p-p70S6K (P < 0.05). In addition, the cumulative score of mice in the matrine plus acitretin group was significantly better than that in the matrine or acitretin group (1.480 ±â€Š0.230 vs. 2.370 ±â€Š0.241, P < 0.01; 1.480 ±â€Š0.230 vs. 2.888 ±â€Š0.341, P < 0.01). The expression of LC3 protein in the matrine plus acitretin group was also higher than that in the matrine, acitretin, or the NS control group (P < 0.05, respectively). CONCLUSIONS: Matrine has therapeutic potentials for psoriasis. Matrine and acitretin show synergistic effect via cell cycle arrest and autophagy induction by PI3K/Akt/mTOR pathway.

Defining the short-term effects of pharmacological 5'-AMP activated kinase modulators on mitochondrial polarization, morphology and heterogeneity.

BACKGROUND: Under aerobic growth conditions, mitochondria are the major producers of cellular ATP and crucial for the proper performance of organs and tissues. This applies especially to cells with high energy demand, such as the renal proximal tubule epithelium. Mitochondrial dysfunction contributes to the pathology of human health conditions, including various kidney diseases. The improvement of mitochondrial function ameliorates some of these pathologies. This can potentially be achieved with pharmacological compounds. For example, long-term treatment with activators of 5'-AMP activated kinase (AMPK) enhances mitochondrial biogenesis. However, pharmacological damage control during acute cell injury requires that the short-term effects of these compounds and the impact on healthy cells are also understood. It was our objective to define the changes elicited by established modulators of AMPK activity in healthy renal proximal tubule cells. METHODS: Our work combines confocal microscopy with quantitative image analysis, 3D image reconstruction and Western blotting to provide novel insights into the biology of mitochondria. Specifically, we evaluated the effects of pharmacological AMPK modulators (compound C, AICAR, phenformin, resveratrol) on mitochondrial polarization, morphology and heterogeneity. Microscopic studies generated information at the single cell and subcellular levels. Our research focused on LLC-PK1 cells that are derived from the renal proximal tubule. Mitochondrial heterogeneity was also examined in MCF7 breast cancer cells. RESULTS: Pharmacological agents that affect AMPK activity in renal proximal tubule cells can alter mitochondrial organization and the electrochemical potential across the inner mitochondrial membrane. These changes were compound-specific. Short-term incubation with the AMPK inhibitor compound C caused mitochondrial hyperpolarization. This was accompanied by mitochondrial fragmentation. By contrast, AMPK activators AICAR, phenformin and resveratrol had little impact. We further show that the biological properties of mitochondria are determined by their subcellular location. Mitochondria at the cell periphery displayed higher MitoTracker/Tom70 values as compared to organelles located in the vicinity of the nucleus. This was not limited to renal proximal tubule cells, but also observed in MCF7 cells. Pharmacological AMPK modulators altered these location-dependent properties in a compound-specific fashion. While the region-dependent differences were enhanced with phenformin, they were ameliorated by resveratrol. DISCUSSION: We evaluated the rapid changes in mitochondrial characteristics that are induced by pharmacological AMPK modulators. Our research supports the concept that pharmacological agents that target AMPK can rearrange mitochondrial networks at the single cell level. Collectively, these insights are relevant to the development of proper strategies for the short-term adjustment of mitochondrial performance.

MicroR-760 suppresses cancer stem cell subpopulation and breast cancer cell proliferation and metastasis: By down-regulating NANOG.

BACKGROUND AND OBJECTIVE: Emerging evidences suggest that cancer stem cells are responsible for tumor aggressive, metastasis and therapeutic resistance. To data, the mechanism underlying breast cancer stem cell (BCSC) population within tumor metastasis remains to be fully elucidated. The current study was to investigate the potential role of microRNA-760 (miR-760) and its associated target gene in population and metastasis of BCSC. METHODS: Characteristic BCSCs surface markers (CD44(+)/CD24(-/low)) were determined by flow cytometry in breast cancer MCF-7 and BT-549 cells. Quantitative RT-PCR was used to evaluate miR-760 and NANOG mRNA expression. Expression of NANOG protein was determined using western blot. Cell proliferation was determined by MTT assay. The model of breast cancer cell xenograft was used to evaluate the effect of miR-760 on tumor growth. RESULTS: BT-549 cell has substantially more CD44(+)/CD24(-/low) subpopulation than MCF-7 cell. Moreover, BT-549 cell expressed lower level of miR-760 and higher level of NANOG than MCF-7cell. By result from cellular miR-760 modulation, we found that miR-760 overexpression suppressed CD44(+)/CD24(-/low) population as well as inhibited cell proliferation and migration of BT-549. On the contrary, knockdown of miR-760 promoted CD44(+)/CD24(-/low) population and migration of MCF-7 cells. By luciferase reporter assay, miR-760 was proved to be functional associated with NANOG via regulating its expression. This functional interaction was showed to be involved in controlling proliferation and migration of MCF-7 and BT-549 cell. CONCLUSION: These data suggest that the target of miR-760/NANOG axis may represent a new therapeutic approach to suppress breast cancer stem cell subpopulation thereby prevent cancer metastasis.

Cripto-1 modulates macrophage cytokine secretion and phagocytic activity via NF-κB signaling.

Cripto-1 is an oncogenic protein belonging to the epidermal growth factor­Cripto-1/FRL-1/Cryptic family. It has important roles in tumor formation and metastasis, but its effects on the immune system are unclear. In the present study, we investigated the effects of Cripto-1 overexpression on macrophage activities and examined the underlying mechanisms. A cell line stably overexpressing Cripto-1 was developed. The culture supernatant from this cell line was collected and used to condition macrophages (RAW264.7, THP-1, and primary mouse macrophages) for various times. Exposure to this supernatant significantly increased the mRNA and protein expression levels of the anti-inflammatory cytokine interleukin (IL)-10 and of three pro-inflammatory cytokines (tumor necrosis factor-α, IL-6, and IL-1ß), but did not affect the expression of transforming growth factor-ß, another anti-inflammatory cytokine. Exposure to this supernatant also enhanced macrophage phagocytosis of chicken erythrocytes and yeast cells. Similar effects were observed in macrophages stimulated with purified Cripto-1 protein. Mechanistic experiments revealed that Cripto-1 activated nuclear factor (NF)-κB signaling by inducing IκB kinase phosphorylation and p65 nuclear translocation. Pretreatment with ammonium pyrrolidine dithiocarbamate, a specific NF-κB inhibitor, inhibited Cripto-1-induced cytokine secretion and phagocytosis of macrophages. Taken together, our present findings suggest that Cripto-1 enhances macrophage phagocytic activity and upregulates the production of anti- and pro-inflammatory cytokines via the NF-κB signaling pathway.

N-Acetyl cysteine (NAC)-mediated reinforcement of alpha-tricalcium phosphate/silk fibroin (α-TCP/SF) cement.

Calcium phosphate cements (CPCs) are popular bone filling materials and drug carriers. However poor mechanical properties and lack of osteoinduction restrict their clinical applications. Recent studies suggested the osteogenic properties of NAC. In our study, we incorporated NAC with α-TCP/SF. We found that the compressive strength of α-TCP/SF-NAC composites increased with increase in NAC concentration, possibly due to complex three-dimensional networks of SF induced by NAC, which was large and chemically heterogeneous and induced compact oriented growth of HA crystals. However the setting time increased slightly with the addition of NAC, due to the ruptured disulfide bonds in SF. The α-TCP/SF-NAC composites also showed decent biocompatibility in vitro. As a result, these composites hold great potential as bone filling materials for clinical applications, including minimally invasive surgeries.

Off to the organelles - killing cancer cells with targeted gold nanoparticles.

Gold nanoparticles (AuNPs) are excellent tools for cancer cell imaging and basic research. However, they have yet to reach their full potential in the clinic. At present, we are only beginning to understand the molecular mechanisms that underlie the biological effects of AuNPs, including the structural and functional changes of cancer cells. This knowledge is critical for two aspects of nanomedicine. First, it will define the AuNP-induced events at the subcellular and molecular level, thereby possibly identifying new targets for cancer treatment. Second, it could provide new strategies to improve AuNP-dependent cancer diagnosis and treatment. Our review summarizes the impact of AuNPs on selected subcellular organelles that are relevant to cancer therapy. We focus on the nucleus, its subcompartments, and mitochondria, because they are intimately linked to cancer cell survival, growth, proliferation and death. While non-targeted AuNPs can damage tumor cells, concentrating AuNPs in particular subcellular locations will likely improve tumor cell killing. Thus, it will increase cancer cell damage by photothermal ablation, mechanical injury or localized drug delivery. This concept is promising, but AuNPs have to overcome multiple hurdles to perform these tasks. AuNP size, morphology and surface modification are critical parameters for their delivery to organelles. Recent strategies explored all of these variables, and surface functionalization has become crucial to concentrate AuNPs in subcellular compartments. Here, we highlight the use of AuNPs to damage cancer cells and their organelles. We discuss current limitations of AuNP-based cancer research and conclude with future directions for AuNP-dependent cancer treatment.

Shape selectivity extending to ordered supermicroporous aluminosilicates.

In the synthesis of polyoxymethylene dimethyl ethers (PODEn) catalyzed by ordered supermicroporous aluminosilicates, shape selectivity was observed and the high selectivity for target products (PODE3-8) was attributed to the particular pore diameter.

Asymmetric epoxidation of cis/trans-ß-methylstyrene catalysed by immobilised Mn(salen) with different linkages: heterogenisation of homogeneous asymmetric catalysis.

Immobilised Mn(salen) catalysts with two different linkages were studied in the asymmetric epoxidation of cis/trans-ß-methylstyrene using NaClO as oxidant. The immobilised Mn(salen) complexes inside nanopores can lead to different catalytic behaviour compared with that of homogeneous Jacobsen catalyst. The rigidity of the linkage was found to be a key factor affecting the catalytic performance of immobilised catalysts. The immobilised catalyst with a rigid linkage exhibited comparable chemical selectivity, enantioselectivity and cis/trans ratio of product formation to that obtained with homogeneous Jacobsen catalysts. In contrast, the immobilised catalyst with a flexible linkage gave remarkably lower chemical selectivity, enantioselectivity and inverted cis/trans ratio compared with the results obtained with the homogeneous Jacobsen catalyst and the immobilised catalyst with rigid linkage. Thus, for immobilised Mn(salen) catalysts, a rigid linkage connecting active centres to the support is essential to obtain activity and enantioselectivity as high as those obtained in homogeneous systems.

Pharmacological AMP kinase activators target the nucleolar organization and control cell proliferation.

AIMS: Phenformin, resveratrol and AICAR stimulate the energy sensor 5'-AMP activated kinase (AMPK) and inhibit the first step of ribosome biogenesis, de novo RNA synthesis in nucleoli. Nucleolar activities are relevant to human health, because ribosome production is crucial to the development of diabetic complications. Although the function of nucleoli relies on their organization, the impact of AMPK activators on nucleolar structures is not known. Here, we addressed this question by examining four nucleolar proteins that are essential for ribosome biogenesis. METHODS: Kidney cells were selected as model system, because diabetic nephropathy is one of the complications associated with diabetes mellitus. To determine the impact of pharmacological agents on nucleoli, we focused on the subcellular and subnuclear distribution of B23/nucleophosmin, fibrillarin, nucleolin and RPA194. This was achieved by quantitative confocal microscopy at the single-cell level in combination with cell fractionation and quantitative Western blotting. RESULTS: AMPK activators induced the re-organization of nucleoli, which was accompanied by changes in cell proliferation. Among the compounds tested, phenformin and resveratrol had the most pronounced impact on nucleolar organization. For B23, fibrillarin, nucleolin and RPA194, both agents (i) altered the nucleocytoplasmic distribution and nucleolar association and (ii) reduced significantly the retention in the nucleus. (iii) Phenformin and resveratrol also increased significantly the total concentration of B23 and nucleolin. CONCLUSIONS: AMPK activators have unique effects on the subcellular localization, nuclear retention and abundance of nucleolar proteins. We propose that the combination of these events inhibits de novo ribosomal RNA synthesis and modulates cell proliferation. Our studies identified nucleolin as a target that is especially sensitive to pharmacological AMPK activators. Because of its response to pharmacological agents, nucleolin represents a potential biomarker for the development of drugs that diminish diabetic renal hypertrophy.

Antitumor and scavenging radicals activities of some polyphenols related to dehydroabietylamine derivatives.

A novel series of polyphenols 4-9 were synthesized by the reaction of catechol with dehydroabietylamine derivatives. The antitumor activities of these compounds against L02 and HepG2 cells were investigated. Among them, compounds 4, 5, and 9 can inhibit HepG2 cells viability, but have lower inhibitory effect on L02 cells in the same concentration, indicating their potential for further development. Meanwhile, the novel series of polyphenols exhibited stronger radical-scavenging activities than the control groups.