All-natural hydrogel composed of carboxymethyl chitosan and oxidized dextran for promoting wound healing by immune-microenvironment regulation.

Chronic wound treatment has always been a major clinical challenge owing to complex and dynamic wound microenvironment. The design and development of effective management with antimicrobial activity, ROS-scavenging and regulation immune response is vital for tissue repair. Herein, we developed puerarin (PUE) loaded a double network hydrogel consisting of methacrylated carboxymethyl chitosan and oxidized dextran with Schiff base and photo-crosslinking reaction. The composite hydrogel presented fast self-healing and outstanding compressive performance to bear deformation. The hydrogel exhibits a cumulative drug release pattern with biphasic release, which offers great potential for accelerating tissue healing at all stages of wounding. In addition, the hydrogel has good biocompatibility, antimicrobial ability and tube-forming ability in vitro. The full-thickness skin wound model of Staphylococcus aureus infection showed that the hydrogel dressing can accelerate tissue repair. This study demonstrated that the design of combing natural biomacromolecules with traditional Chinese medicine could be severed as a promising candidate biomaterial for skin tissue recovery.

Polydopamine-coated polycaprolactone/carbon nanotube fibrous scaffolds loaded with basic fibroblast growth factor for wound healing.

Image 1.

Pelvic organ-preserving radical cystectomy versus standard radical cystectomy in female patients diagnosed with bladder cancer.

BACKGROUND: Pelvic organ-preserving radical cystectomy (POPRC) has been reported to result in a better postoperative quality of life in female with bladder cancer compared to standard radical cystectomy (SRC). However, its oncological outcomes remain a concern. PATIENTS AND METHODS: Female patients with bladder cancer who underwent POPRC or SRC were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was used to identify predictors of POPRC usage. To avoid the potential impact of baseline differences between groups on survival, a 1:2 propensity score matching (PSM) was implemented. After that, Kaplan-Meier curves and Log-rank tests were used to determine the significance of overall survival (OS) differences between patients in the SRC group and POPRC group. Finally, subgroup analysis based on predetermined indicators was performed. RESULTS: A total of 2193 patients were included with a median follow-up of 53 months, of whom 233 (10.6%) received POPRC and 1960 (89.4%) received SRC. No definitive predictors of POPRC were identified. Before PSM, POPRC resulted in comparable OS to SRC (HR = 1.09, p = 0.309), while after PSM, POPRC was associated with significantly worse OS (HR = 1.23, p = 0.038). In subgroup analyses, POPRC led to non-inferior OS (HR = 1.18, 95%CI 0.71-1.95, p = 0.531) in patients with non-muscle invasive bladder cancer (NMIBC) and T2 patients (HR = 1.07, p = 0.669), but significantly worse OS in T3 patients (HR = 1.41, p = 0.02). CONCLUSION: Currently, patients undergoing POPRC have not undergone strict screening, and candidates for POPRC should have more stringent criteria in the future to achieve satisfactory oncological outcomes. However, flaws in the study make more evidence needed to support our findings.

Immunogenicity of 4-dose Essen intramuscular regimen for rabies post-exposure prophylaxis: A multi-center cross-sectional study in China.

BACKGROUND: The 4-dose Essen intramuscular (IM) regimen for rabies post-exposure prophylaxis (PEP) has been recommended by Advisory Committee on Immunization Practices (ACIP) and World Health Organization (WHO), but the large-sample clinical evidence is still limited. METHOD: Rabies virus neutralizing antibodies of 11,752 patients were detected from 409 rabies prevention clinics in 27 provinces in China. Patients with serum collected before or no later than 1 h after injection on the day of the fifth dose (day 28) of 5-dose Essen regimen were included in Group A to observe the immune efficacy of 4-dose Essen IM regimen, and patients with serum collected 14-28 days after injection of the fifth dose were included in Group B to observe the immune efficacy of 5-dose Essen IM regimen. RESULTS: Finally, 2351 cases met the inclusion and exclusion criteria, including 2244 cases in Group A and 107 cases in Group B. The antibody titer of Group A was higher than that of Group B [12.21 (4.15, 32.10) IU/ml vs. 9.41 (3.87, 27.38) IU/ml] (P = 0.002). In Group A, the median antibody titers were 4.01IU/ml, 11.63IU/ml and 29.46IU/ml in patients vaccinated with purified hamster kidney cell vaccine (PHKCV), purified Vero cell vaccine (PVRV), and human diploid cell rabies vaccine (HDCV), respectively, with statistical significance (P < 0.001). CONCLUSIONS: The 4-dose Essen IM regimen could provide satisfactory immune effect, and HDCV induced higher antibody titer than PHKCV or PVRV.

[Relationship between GTSE1 and Cell Cycle and Potential Regulatory Mechanisms 
in Lung Cancer Cells].

The regulation of the cell cycle is essential for maintaining normal cellular function, especially in the development of diseases such as lung cancer. The cell cycle consists of four major phases (G1, S, G2 and M phases), which are characterized by a series of precise molecular events to ensure proper cell proliferation and division. In lung cancer cells, cell cycle dysregulation can lead to disordered proliferation and increased invasiveness of cancer cells. G2 and S-phase expressed 1 (GTSE1) is a regulatory protein found in the cytoplasm of the cell, which plays a key role in the cell cycle distribution of a wide range of cancer cells and is involved in life processes such as cell proliferation and apoptosis. GTSE1 affects cell cycle progression by interacting with cyclin-dependent kinase inhibitor 1A (p21) and maintaining the stability of p21, which in turn inhibits the activity of cyclin-dependent kinase 1/2 (CDK1/2). In addition, GTSE1 is also involved in the regulation of tumor protein 53 (p53) signaling pathway. With the assistance of mouse double minute 2 homolog (MDM2), GTSE1 is able to transport p53 from the nucleus to the cytoplasm and promote its ubiquitination and degradation, thus affecting cell cycle and cell death-related signaling pathways. This paper reviews the expression of GTSE1 in lung cancer cells and its effects on lung cancer, as well as its potential mechanisms involved in cell cycle regulation.
.

A sodium alginate - silk fibroin biosponge loaded with thrombin: Effective hemostasis and wound healing.

In trauma first aid, rapid hemostasis is a priority, extricating patients from hemorrhagic shock and infection risks. This paper explores novel hemostatic materials, using ion-crosslinking and freeze-drying techniques. Iterative experiments determined optimal conditions for the temperature-variable mixing-freeze-drying chemical reaction of sodium alginate (SA)/silk fibroin (SF). We used SA, SA/SF, SA/SF-TB and commercial hemostatic sponge control samples to perform hemostasis experiments on rat liver injury and femoral artery injury models, and to perform wound healing experiments on rat back full-layer skin. The results showed that the hemostatic time and blood loss of SA/SF-TB group rats (liver hemorrhage model: 397.17 ± 34.80 mg, 77.83 ± 7.41 s; Femoral artery bleeding model: 940.33 ± 41.93 mg, 96.83 ± 4.07 s) was significantly better than other experimental groups, and similar to the commercial group. The wound healing experiment showed that the new granulation tissue thickness of SA/SF-TB group was thicker (380.39 ± 28.56 µm) at day 14. In addition, the material properties and biocompatibility of sponges were characterized by cell experiments and in vivo embedding experiments. All the results showed that the SA/SF-TB hemostatic sponge prepared in this study could not only seal the wound quickly and stop bleeding, but also promote the growth of epidermal cells and fibroblasts and accelerate wound healing. This new material solves the shortcomings of traditional materials such as low stability, limited shelf life, high unit price, and has good biocompatibility, easy preparation, rapid hemostasis and other excellent properties. Therefore, this innovative hemostatic material has great prospects and potential in clinical applications.

Gain deeper insights into traditional Chinese medicines using multidimensional chromatography combined with chemometric approaches.

Traditional Chinese medicines (TCMs) possess a rich historical background, unique theoretical framework, remarkable therapeutic efficacy, and abundant resources. However, the modernization and internationalization of TCMs have faced significant obstacles due to their diverse ingredients and unknown mechanisms. To gain deeper insights into the phytochemicals and ensure the quality control of TCMs, there is an urgent need to enhance analytical techniques. Currently, two-dimensional (2D) chromatography, which incorporates two independent separation mechanisms, demonstrates superior separation capabilities compared to the traditional one-dimensional (1D) separation system when analyzing TCMs samples. Over the past decade, new techniques have been continuously developed to gain actionable insights from complex samples. This review presents the recent advancements in the application of multidimensional chromatography for the quality evaluation of TCMs, encompassing 2D-gas chromatography (GC), 2D-liquid chromatography (LC), as well as emerging three-dimensional (3D)-GC, 3D-LC, and their associated data-processing approaches. These studies highlight the promising potential of multidimensional chromatographic separation for future phytochemical analysis. Nevertheless, the increased separation capability has resulted in higher-order data sets and greater demands for data-processing tools. Considering that multidimensional chromatography is still a relatively nascent research field, further hardware enhancements and the implementation of chemometric methods are necessary to foster its robust development.

Combination of in silico prediction and convolutional neural network framework for targeted screening of metabolites from LC-HRMS fingerprints: A case study of "Pericarpium Citri Reticulatae - FructusAurantii".

In this study, a novel approach is introduced, merging in silico prediction with a Convolutional Neural Network (CNN) framework for the targeted screening of in vivo metabolites in Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) fingerprints. Initially, three predictive tools, supplemented by literature, identify potential metabolites for target prototypes derived from Traditional Chinese Medicines (TCMs) or functional foods. Subsequently, a CNN is developed to minimize false positives from CWT-based peak detection. The Extracted Ion Chromatogram (EIC) peaks are then annotated using MS-FINDER across three levels of confidence. This methodology focuses on analyzing the metabolic fingerprints of rats administered with "Pericarpium Citri Reticulatae - Fructus Aurantii" (PCR-FA). Consequently, 384 peaks in positive mode and 282 in negative mode were identified as true peaks of probable metabolites. By contrasting these with "blank serum" data, EIC peaks of adequate intensity were chosen for MS/MS fragment analysis. Ultimately, 14 prototypes (including flavonoids and lactones) and 40 metabolites were precisely linked to their corresponding EIC peaks, thereby providing deeper insight into the pharmacological mechanism. This innovative strategy markedly enhances the chemical coverage in the targeted screening of LC-HRMS metabolic fingerprints.

Polydopamine-Coated Polycaprolactone Electrospun Nanofiber Membrane Loaded with Thrombin for Wound Hemostasis.

Hemorrhagic shock is the primary cause of death in patients with severe trauma, and the development of rapid and efficient hemostatic methods is of great significance in saving the lives of trauma patients. In this study, a polycaprolactone (PCL) nanofiber membrane was prepared by electrospinning. A PCL-PDA loading system was developed by modifying the surface of polydopamine (PDA), using inspiration from mussel adhesion protein, and the efficient and stable loading of thrombin (TB) was realized to ensure the bioactivity of TB. The new thrombin loading system overcomes the disadvantages of harsh storage conditions, poor strength, and ease of falling off, and it can use thrombin to start a rapid coagulation cascade reaction, which has the characteristics of fast hemostasis, good biocompatibility, high safety, and a wide range of hemostasis. The physicochemical properties and biocompatibility of the PCL-PDA-TB membrane were verified by scanning electron microscopy, the cell proliferation test, the cell adhesion test, and the extract cytotoxicity test. Red blood cell adhesion, platelet adhesion, dynamic coagulation time, and animal models all verified the coagulation effect of the PCL-PDA-TB membrane. Therefore, the PCL-PDA-TB membrane has great potential in wound hemostasis applications, and should be widely used in various traumatic hemostatic scenarios.

Hungatella hathewayi impairs the sensitivity of colorectal cancer cells to 5-FU through decreasing CDX2 expression.

Hungatella hathewayi (H. hathewayi), also known as Clostridium hathewayi, has been reported to be accumulated in the colorectal cancer (CRC) samples. In addition, evidence has demonstrated that inoculation with H. hathewayi promotes the proliferation of colonic epithelial cells in mice. Herein, we explored H. hathewayi role in regulating the 5-fluorouracil (5-FU) resistance in CRC cells, and investigated the underlying mechanisms. H. hathewayi abundance in CRC tissues and the corresponding adjacent normal tissues was tested using qRT-PCR. Both parental and 5-FU resistance CRC cell lines were used to assess H. hathewayi role in regulating the 5-FU resistance of CRC cells using CCK-8, flow cytometry and animal experiments. H. hathewayi abundance was significantly increased in CRC tissues, and the high level of H. hathewayi was linked to lower overall survival rate. H. hathewayi treatment significantly weakened 5-FU effects on inhibiting cell growth and inducing cell apoptosis in CRC HCT116 and HT29 cells. In addition, H. hathewayi enhanced the 5-FU resistance of HCT116/5-FU and HT29/5-FU cells (the 5-FU resistance cell lines). In mechanism, H. hathewayi decreased the expression of CDX2, and increased the expression of nuclear accumulation of ß-catenin. Overexpression of CDX2 abolished H. hathewayi-mediated enhancement in cell growth and inhibition in cell apoptosis in HCT116/5-FU and HT29/5-FU cells, as well as inhibited the expression and nuclear accumulation of ß-catenin. In conclusion, H. hathewayi abundance was increased in CRC tissues, and the high level of H. hathewayi was linked to lower overall survival rate. In mechanisam, H. hathewayi treatment enhanced the 5-FU resistance of CRC cells through modulating CDX2/ß-catenin signaling.

GTSE1 promotes the growth of NSCLC by regulating microtubule-associated proteins through the ERK/MAPK pathway.

The role of G2 and S phase-expressed-1 (GTSE1), a microtubule-localized protein, in non-small-cell lung cancer (NSCLC) remains unknown. We explored its role in NSCLC growth. GTSE1 was detected in NSCLC tissues and cell lines using quantitative real-time polymerase chain reaction. The clinical significance of GTSE1 levels was evaluated. Biological and apoptotic effects of GTSE1 were evaluated using transwell, cell-scratch, and MTT assays, and flow cytometry and western blotting, respectively. Its association with cellular microtubules was shown by western blotting and immunofluorescence. GTSE1 expression was upregulated in NSCLC tissues and cell lines. GTSE1 levels correlated with lymph node metastasis. Higher GTSE1 mRNA expression correlated with shorter progression-free survival. GTSE1-knockdown decreased proliferation, colony formation, invasion, and migration of NSCLC cells, and inhibited tau and stathmin-1 microtubule-associated protein expression, via the extracellular-regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway, and microtubule disruption. GTSE1 may promote NSCLC growth by regulating tau and stathmin-1 through the ERK/MAPK signaling pathway.

Does Digitization Promote Green Innovation? Evidence from China.

Green innovation is an important strategy in seeking sustainable competitive advantages. This paper investigates the impact of enterprise digitization on green innovation and its mechanisms. We find that enterprise digital transformation has a significant effect on the promotion of green innovation. This positive effect mainly stems from the advantage of resource reallocation generated by enterprise digitalization that can alleviate financing constraints and raise risk-taking levels. Furthermore, the level of economic development strengthens the impact of enterprise digitization on green innovation, and the positive relationship between enterprise digitization and green innovation is stronger in regions with stronger environmental regulation and higher intellectual property protection, as well as in state-owned and heavily polluting enterprises. Digitization can optimize resource utilization, strengthen the capacity of green innovation in pollution reduction and promote the clean production of enterprises. Our results show that enterprise digitization plays a positive role in innovation activities. Furthermore, our results show that enterprise digitization plays a positive role in innovation activities.

Natural phytochemicals prevent side effects in BRCA-mutated ovarian cancer and PARP inhibitor treatment.

Ovarian cancer is among the most common malignant tumors in gynecology and is characterized by insidious onset, poor differentiation, high malignancy, and a high recurrence rate. Numerous studies have shown that poly ADP-ribose polymerase (PARP) inhibitors can improve progression-free survival (PFS) in patients with BRCA-mutated ovarian cancer. With the widespread use of BRCA mutation and PARP inhibitor (PARPi) combination therapy, the side effects associated with BRCA mutation and PARPi have garnered attention worldwide. Mutations in the BRCA gene increase KEAP1-NRF2 ubiquitination and reduce Nrf2 content and cellular antioxidant capacity, which subsequently produces side effects such as cardiovascular endothelial damage and atherosclerosis. PARPi has hematologic toxicity, producing thrombocytopenia, fatigue, nausea, and vomiting. These side effects not only reduce patients' quality of life, but also affect their survival. Studies have shown that natural phytochemicals, a class of compounds with antitumor potential, can effectively prevent and treat the side effects of chemotherapy. Herein, we reviewed the role of natural phytochemicals in disease prevention and treatment in recent years, including sulforaphane, lycopene, catechin, and curcumin, and found that these phytochemicals have significant alleviating effects on atherosclerosis, nausea, and vomiting. Moreover, these mechanisms of action significantly correlated with the side-effect-producing mechanisms of BRCA mutations and PARPi. In conclusion, natural phytochemicals may be effective in alleviating the side effects of BRCA mutant ovarian cancer cells and PARP inhibitors.

Clinical Significance of Serum-Derived Exosomal LINC00917 in Patients With Non-Small Cell Lung Cancer.

Background: In this study, we aimed to explore the diagnostic potential of serum-based exosomal long intergenic noncoding RNA 917 (LINC00917) in non-small cell lung cancer (NSCLC). Methods: Exosomes were extracted from NSCLC patients' serum samples. Exosomal LINC00917 expression levels were compared, by qRT-PCR, between cancer patients and healthy controls, as well as sub-populations of cancer patients. The association between exosomal LINC00917 expression and NSCLC patients' clinicopathologic factors were investigated, and receiver operating characteristic (ROC) curves were drawn. In addition, NSCLC patients' overall survivals (OSs) was examined based on exosomal LINC00917 expression and further evaluated by the cox regression analysis. Results: Serum-derived exosomal LINC00917 was highly expressed in NSCLC patients, and further upregulated in stage III/IV cancer patients. Exosomal LINC00917 yielded modestly good under the curve (AUC) values. Upregulated exosomal LINC00917 expression was closely associated with cancer patients' advanced stages and shorter OSs. Conclusion: Serum-derived exosomal LINC00917 may hold diagnostic potential for patients with non-small cell lung cancer.

Approaching autonomous driving with cautious optimism: analysis of road traffic injuries involving autonomous vehicles based on field test data.

OBJECTIVES: To examine the patterns and associated factors of road traffic injuries (RTIs) involving autonomous vehicles (AVs) and to discuss the public health implications and challenges of autonomous driving. METHODS: Data were extracted from the reports of traffic crashes involving AVs. All the reports were submitted to the California Department of Motor Vehicles by manufacturers with permission to operate AV test on public roads. Descriptive analysis and χ2 analysis or Fisher's exact test was conducted to describe the injury patterns and to examine the influencing factors of injury outcomes, respectively. Binary logistic regression using the Wald test was employed to calculate the OR, adjusted OR (AOR) and 95% CIs. A two-tailed probability (p<0.05) was adopted to indicate statistical significance. RESULTS: 133 reports documented 24 individuals injured in 19 crashes involving AVs, with the overestimated incidence rate of 18.05 per 100 crashes. 70.83% of the injured were AV occupants, replacing vulnerable road users as the leading victims. Head and neck were the most commonly injured locations. Driving in poor lighting was at greater risk of RTIs (AOR 6.37, 95% CI 1.47 to 27.54). Collisions with vulnerable road users or incidents happening during commute periods led to a greater number of victims (p<0.05). Autonomous mode cannot perform better than conventional mode in road traffic safety to date (p=0.468). CONCLUSIONS: Poor lighting improvement and the regulation of commute-period traffic and vulnerable road users should be strengthened for AV-related road safety. So far AVs have not demonstrated the potential to dramatically reduce RTIs. Cautious optimism about AVs is more advisable, and multifaceted efforts, including legislation, smarter roads, and knowledge dissemination campaigns, are fairly required to accelerate the development and acceptance.

Synthesis and biological evaluation of all possible inosine-mixed cyclic dinucleotides that activate different hSTING variants.

Cyclic dinucleotides (CDNs) could activate stimulator of interferon genes (STING) protein to produce type I interferon and other pro-inflammation cytokines in mammalian cells. To explore new types of potentially efficient STING activators targeting all five major hSTING variants (WT, R232H, HAQ, AQ and R293Q), we here reported the synthesis of a total of 19 inosine-containing CDNs based on the combinations of hypoxanthine with four natural bases (A, G, C and U) and three phosphodiester linkage backbones (3'-3', 2'-3', 2'-2'). The IFN-ß induction results showed that all of the 2'-3' and 2'-2' CDNs linked by inosine and purine nucleosides favored the stacking interaction with Y167 and R238 residues of hSTING protein, and several CDNs constructed by hypoxanthine and pyrimidine like c[I(2',5')U(2',5')] could also activate all five hSTING variants. The molecular dynamic simulation and the isothermal titration calorimetric (ITC) assay further demonstrated the potential of cAIMP isomers with 2'-5' phosphate to form the hydrogen binding with R232 and R238 residues of hSTING in an entropically driven manner compared to cGAMP isomers. It would be promising to exploit novel inosine-mixed CDNs as activators of hSTING variants in immune therapy.

Assessment of the content, usability, and benefits of the WeChat-based programme for dog bite victims in China: A prospective observation study.

WeChat in China has been used for public health education and the prevention of diseases. This study introduced a WeChat-based program for rabies prevention and evaluated the users' satisfaction with the program using the technology acceptance model.An online satisfaction questionnaire was used to survey 315 users who had followed the WeChat official account in China, and their satisfaction scores were assessed and analyzed.The users were generally satisfied with the WeChat-based program as an educational and instructional tool with the mean satisfaction score for each item ranging from 3.9 to 4.6 out of a maximum of 5.0 and the total mean satisfaction score of 41.5 out of a maximum of 50.0 (SD = 4.3). Urban users showed more satisfaction than rural users (P = .03). Users who were satisfied also reported that they intended to recommend WeChat to others (P = .00).Findings from the present study indicated that WeChat was considered a useful educational and instructional tool for dog-bite victims among young and urban population. This model of a WeChat-based program for rabies prevention should be expanded to other areas in China.

Analyzing the distribution of rabies clinics and achievements of standardized rabies clinics implementation in mainland China.

BACKGROUND: For rabies prevention and treatment, the Chinese government has been establishing standardized rabies clinics since 2016. This study aimed to investigate the distribution of rabies clinics and the achievements of newly-implemented standardized rabies clinics in mainland China, for the purpose of providing further rabies control strategies. METHODS: The number of rabies clinics, including per million inhabitants in each region, was determined. We sampled 1200 clinics from 8 provinces by multi-stage stratified sampling, and a questionnaire survey was carried out to record each clinic's achievements. Data collected from 1185 questionnaires were analyzed. RESULTS: We found that rabies clinics were mostly located in the southwest, central, and eastern regions of China; these accounted for 67.1% of all clinics. The eastern and south regions showed the lowest number of rabies clinics per million inhabitants (0.15 and 0.12, respectively). The total standard-reaching rate of rabies clinics in mainland China was only 11.0%, with significant differences in the rate among regions (X2 = 33.004, p <  0.001). Specifically, the qualified rates of supporting facilities and functional areas were 13.9% (X2 = 34.003, p <  0.001) and 56.1% (X2 = 9.943, p = 0.019), respectively. Vaccines with 2 different substrates and professional flushing equipment were provided by 40.5% (X2 = 27.935, p = 0.001) and 37.7% (X2 = 54.922, p = 0.001) of clinics, respectively. CONCLUSION: Regional differences do exist in the distribution of rabies clinics in mainland China, with relative low number per million population in south and eastern China. There are few standardized rabies clinics in mainland China. Efforts are needed to establish supporting facilities, especially for wound treatment and vaccination. Future research should focus on the improvement of rabies clinics standardization.

Pharmacological AMPK activation induces transcriptional responses congruent to exercise in skeletal and cardiac muscle, adipose tissues and liver.

Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.

Inhibition of tankyrase by a novel small molecule significantly attenuates prostate cancer cell proliferation.

Tankyrase (TNKS) is a crucial mediator of Wnt signal transduction and has been recognized as a novel molecular target for Wnt-pathway dependent cancer. TNKS is stabilized by the ubiquitin-specific protease 25 (USP25). The effect of disruption of the interaction between TNKS and USP25 by small molecules on prostate cancer proliferation is unknown. In this study we conducted a hierarchical virtual screening with more than 200,000 compounds on the characterized structures of the USP25/TNKS-ARC5 protein complex. In silico analysis and in vitro validation revealed that a small molecule, called C44, binds to the protein-protein interaction (PPI) interface of TNKS and USP25. We show that C44 disrupts the interaction between TNKS and USP25 leading to a higher half-life of AXIN and the breakdown of -catenin protein. We also show that the selective inhibition of the TNKS-USP25 interaction by C44 significantly reduces proliferation of prostate cancer cells in vitro and in vivo. Our study reveals a new PPI inhibitor that lowers the stability of TNKS protein and inhibits Wnt pathway signaling. C44 is a promising new drug for the treatment of Wnt-pathway dependent prostate cancer.