Tea polyphenol-engineered hybrid cellular nanovesicles for cancer immunotherapy and androgen deprivation therapy.

Androgen deprivation therapy (ADT) is a crucial and effective strategy for prostate cancer, while systemic administration may cause profound side effects on normal tissues. More importantly, the ADT can easily lead to resistance by involving the activation of NF-κB signaling pathway and high infiltration of M2 macrophages in tumor microenvironment (TME). Herein, we developed a biomimetic nanotherapeutic platform by deriving cell membrane nanovesicles from cancer cells and probiotics to yield the hybrid cellular nanovesicles (hNVs), loading flutamide (Flu) into the resulting hNVs, and finally modifying the hNVs@Flu with Epigallocatechin-3-gallate (EGCG). In this nanotherapeutic platform, the hNVs significantly improved the accumulation of hNVs@Flu-EGCG in tumor sites and reprogramed immunosuppressive M2 macrophages into antitumorigenic M1 macrophages, the Flu acted on androgen receptors and inhibited tumor proliferation, and the EGCG promoted apoptosis of prostate cancer cells by inhibiting the NF-κB pathway, thus synergistically stimulating the antitumor immunity and reducing the side effects and resistance of ADT. In a prostate cancer mouse model, the hNVs@Flu-EGCG significantly extended the lifespan of mice with tumors and led to an 81.78% reduction in tumor growth compared with the untreated group. Overall, the hNVs@Flu-EGCG are safe, modifiable, and effective, thus offering a promising platform for effective therapeutics of prostate cancer.

Acid-base transformative HADLA micelles alleviate colitis by restoring adaptive immunity and gut microbiome.

Inflammatory bowel disease (IBD) is a worldwide public health issue with an increasing number of patients annually. However, there is no curative drug for IBD, and the present medication for IBD generally focuses on suppressing hyperactive immune responses, which can only delay disease progression but inevitably induce off-target side effects, including infections and cancers. Herein, late-model orally administered nanotherapeutic micelles (HADLA) were developed based on a conjugate of hyaluronic acid (HA) and dehydrolithocholic acid (DLA), which was simple to achieve and obtained satisfactory therapeutic efficacy in a murine colitis model with a full safety profile. HADLA is capable of targeting inflammatory colon tissues, restoring intestinal barrier function and reducing intestinal epithelial cell death. Moreover, it modulates the adaptive immune system by inhibiting the activation of pathogenic T helper 17 (Th17) cells, and it exhibits more remarkable effects in preventing colitis than DLA alone. Finally, HADLA exhibits a remarkable ability to modulate dysregulated gut microbiomes by increasing beneficial probiotics and decreasing pathogenic bacteria, such as Turicibacter. Compared with the current systemic or subcutaneous administration of biologics, this study opens new avenues in the oral delivery of immune-modulating nanomedicine and introduces DLA as a new medication for IBD treatment.

Targeted glycan degradation potentiates cellular immunotherapy for solid tumors.

Immune cell-based cancer therapies, such as chimeric antigen receptor T (CAR-T)-cell immunotherapy, have demonstrated impressive potency against hematological tumors. However, the efficacy of CAR-T cells against solid tumors remains limited. Herein, we designed tumor-targeting molecule-sialidase conjugates that potently and selectively stripped different sialoglycans from a variety of cancer cells. Desialylation enhanced induced pluripotent stem cell-derived chimeric antigen receptor-macrophage (CAR-iMac) infiltration and activation. Furthermore, the combination of cancer cell desialylation and CAR-iMac adoptive cellular therapy exerted a dramatic therapeutic effect on solid tumors and significantly prolonged the survival of tumor-bearing mice; these effects were mainly dependent on blockade of the checkpoint composed of sialic acid-binding immunoglobulin-like lectin (Siglec)-5 and Siglec-10 on the macrophages, and knockout of the glycoimmune checkpoint receptors could construct a CAR-iMac cell with stronger anticancer activity. This strategy that reverts the immune escape state ("cold tumor") to a sensitive recognition state ("hot tumor") has great significance for enhancing the effect of cellular immunotherapy on solid tumors. Therefore, desialylation combined with CAR-iMac cellular immunotherapy is a promising approach to enhance treatment with cellular immunotherapy and expand the valid indications among solid tumors, which provides inspiration for the development of cellular immunotherapies with glycoimmune checkpoint inhibition for the treatment of human cancer.

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid-Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates.

Chemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α-linked glycoconjugates via a RhII /chiral phosphoric acid (CPA)-cocatalyzed dynamic kinetic anomeric O-alkylation of sugar-derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2-carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2-OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.

Soil enzyme activities, soil physical properties, photosynthetic physical characteristics and water use of winter wheat after long-term straw mulch and organic fertilizer application.

Introduction: Inappropriate residue and nutrient management leads to soil degradation and the decline of soil quality and water storage capacity. Methods: An ongoing field experiment has been conducted since 2011 to investigate the effects of straw mulching (SM), and straw mulching combined with organic fertilizer (SM+O), on winter wheat yield, including a control treatment (CK, no straw). We studied the effects of these treatments on soil microbial biomass nitrogen and carbon, soil enzyme activity in 2019, photosynthetic parameters, evapotranspiration (ET), water use efficiency (WUE), and yields over five consecutive years (2015-2019). We also analyzed the soil organic carbon, soil structure, field capacity, and saturated hydraulic conductivity in 2015 and 2019. Results: Results indicate that compared with CK, SM and SM+O treatments increased the proportion of >0.25mm aggregates, soil organic carbon, field capacity, and saturated hydraulic conductivity, but decreased the soil bulk density. In addition, the SM and SM+O treatments also increased soil microbial biomass nitrogen and carbon, the activity of soil enzymes, and decreased the carbon-nitrogen ratio of microbial biomass. Therefore, SM and SM+O treatments both increased the leaf water use efficiency (LWUE) and photosynthetic rate (Pn), and improved the yields and water use efficiency (WUE) of winter wheat. The combination SM (4.5 t/ha)+O (0.75 t/ha) was more effective than SM alone, and both treatments were superior to the control. Conclusion: Based on the results of this study, SM+O is recommended as the most effective cultivation practice.

Chemoimmunological Cascade Cancer Therapy Using Fluorine Assembly Nanomedicine.

Classical chemotherapeutic drugs may cause immunogenic cell death (ICD), followed by activating CD8+ T cells to promote cell-mediated antitumor immune responses. However, CD8+ T cells become exhausted due to tumor antigens' continuous stimulation, creating a major obstacle to effectively suppressing tumor growth and metastasis. Here, we develop an approach of chemo-gene combinational nanomedicine to bridge and reprogram chemotherapy and immunotherapy. The dually loaded nanomedicine induces ICD in tumor cells through doxorubicin and reverses the antitumor effects of exhausted CD8+ T cells through the small interfering RNA. The synergistic chemo-gene and fluorine assembly nanomedicine enriched in reactive oxygen species and acid-sensitive bonds results in enhanced cancer immunotherapy to inhibit tumor growth and the lung metastasis of breast cancer in a mouse model of breast cancer and melanoma. This study provides an efficient strategy and insights into chemoimmunological cascade therapy for combating malignant metastatic tumors.

Effect of long term application of super absorbent polymer on soil structure, soil enzyme activity, photosynthetic characteristics, water and nitrogen use of winter wheat.

Introduction: Water scarcity and seasonal drought are major constraints on agricultural development globally. Super absorbent polymer (SAP) is a good amendment that can improve soil structure, increase soil water retention, and promote crop growth even with less soil moisture. We hypothesize that long term application of SAP has a better effect on soil organic carbon, soil enzyme activity, photosynthetic characteristics, yield, and water and nitrogen use than short term application. Methods: A long term field experiment with different application rates (0 (CK), 15 (L), 30 (M), 45 (H) kg ha-1) of SAP was conducted at the Yuzhou water conservation agriculture base of the Henan Academy of Agricultural Sciences from 2011 to 2019. Results and Discussion: The results indicate that applying SAP increases > 0.25 mm aggregates and decreased<0.25 mm aggregates in the soil after one year (2011) and 9 years (2019) of application. In addition, soil organic carbon, soil microbial biomass carbon, soil sucrase and cellulase activities, soil water consumption, water consumption, net photosynthetic rate (Pn), leaf water use efficiency (LWUE) of wheat and yield, all increased after SAP application. SAP also boosts water use efficiency and nitrogen use efficiency. Correlation analyses show that SAP promotes the growth of wheat, and improves the utilization rate of soil water and nutrients by improving the soil structure and increasing soil organic carbon and microbial enzyme activity. Conclusion: Based on our research, SAP treatment at a dosage of 45 kg ha-1 is most effective and is thus recommended.

Dynamic ginsenoside-sheltered nanocatalysts for safe ferroptosis-apoptosis combined therapy.

Chemodynamic therapy (CDT)-activated apoptosis is a potential anticancer strategy. However, CDT encounters a bottleneck in clinical translation due to its serious side effects and low efficacy. Here, we first reveal that surface engineering of ginsenoside Rg3 dramatically alters the organ distribution and tumor enrichment of systematically administered nanocatalysts using the orthotopic pancreatic tumor model while avoiding toxicity and increasing efficacy in vivo to address the key and universal toxicity problems encountered in nanomedicine. Compared with nanocatalysts alone, Rg3-sheltered dynamic nanocatalysts form hydrophilic nanoclusters, prolonging their circulation lifespan in the blood, protecting the internal nanocatalysts from leakage while allowing their specific release at the tumor site. Moreover, the nanoclusters provide a drug-loading platform for Rg3 so that more Rg3 reaches the tumor site to achieve obvious synergistic effect with nanocatalysts. Rg3-sheltered dynamic nanocatalysts can simultaneously activate ferroptosis and apoptosis to significantly improve anticancer efficacy. Systematic administration of ginsenoside Rg3-sheltered nanocatalysts inhibited 86.6% of tumor growth without toxicity and prolonged the survival time of mice. This study provides a promising approach of nanomedicine with high biosafety and a new outlook for catalytic ferroptosis-apoptosis combined antitumor therapies. STATEMENT OF SIGNIFICANCE: Chemodynamic therapy (CDT) has limited clinical efficacy in cancer. In this study, we developed Rg3-sheltered dynamic nanocatalysts, which could simultaneously activate ferroptosis based on CDT-activated apoptosis, and ultimately form a combined therapy of ferroptosis-apoptosis to kill tumors. Studies have shown that the nanocatalysts after Rg3 surface engineering dramatically alters the pharmacokinetics and organ distribution of the nanocatalysts after being systematically administered, resulting in avoiding the toxicity of the nanocatalysts. Nanocatalysts also act as a drug-loading platform, guiding more Rg3 into the tumor site. This study emphasizes that nanocatalysts after Rg3 surface engineering improve the safety and effectiveness of ferroptosis-apoptosis combined therapy, providing an effective idea for clinical practices.

Virus Dynamics and Decay in Evaporating Human Saliva Droplets on Fomites.

The transmission of most respiratory pathogens, including SARS-CoV-2, occurs via virus-containing respiratory droplets, and thus, factors that affect virus viability in droplet residues on surfaces are of critical medical and public health importance. Relative humidity (RH) is known to play a role in virus survival, with a U-shaped relationship between RH and virus viability. The mechanisms affecting virus viability in droplet residues, however, are unclear. This study examines the structure and evaporation dynamics of virus-containing saliva droplets on fomites and their impact on virus viability using four model viruses: vesicular stomatitis virus, herpes simplex virus 1, Newcastle disease virus, and coronavirus HCoV-OC43. The results support the hypothesis that the direct contact of antiviral proteins and virions within the "coffee ring" region of the droplet residue gives rise to the observed U-shaped relationship between virus viability and RH. Viruses survive much better at low and high RH, and their viability is substantially reduced at intermediate RH. A phenomenological theory explaining this phenomenon and a quantitative model analyzing and correlating the experimentally measured virus survivability are developed on the basis of the observations. The mechanisms by which RH affects virus viability are explored. At intermediate RH, antiviral proteins have optimal influence on virions because of their largest contact time and overlap area, which leads to the lowest level of virus activity.

Tacrolimus Loaded Cationic Liposomes for Dry Eye Treatment.

Eye drops are ophthalmic formulations routinely used to treat dry eye. However, the low ocular bioavailability is an obvious drawback of eye drops owing to short ocular retention time and weak permeability of the cornea. Herein, to improve the ocular bioavailability of eye drops, a cationic liposome eye drop was constructed and used to treat dry eye. Tacrolimus liposomes exhibit a diameter of around 300 nm and a surface charge of +30 mV. Cationic liposomes could interact with the anionic ocular surface, extending the ocular retention time and improving tacrolimus amount into the cornea. The cationic liposomes notably prolonged the ocular retention time of eye drops, leading to an increased tacrolimus concentration in the ocular surface. The tacrolimus liposomes were also demonstrated to reduce reactive oxygen species and dry eye-related inflammation factors. The use of drug-loaded cationic liposomes is a good formulation in the treatment of ocular disease; the improved ocular retention time and biocompatibility give tremendous scope for application in the treatment of ocular disease, with further work in the area recommended.

General Strategy for the Synthesis of Rare Sugars via Ru(II)-Catalyzed and Boron-Mediated Selective Epimerization of 1,2-trans-Diols to 1,2-cis-Diols.

Human glycans are primarily composed of nine common sugar building blocks. On the other hand, several hundred monosaccharides have been discovered in bacteria and most of them are not readily available. The ability to access these rare sugars and the corresponding glycoconjugates can facilitate the studies of various fundamentally important biological processes in bacteria, including interactions between microbiota and the human host. Many rare sugars also exist in a variety of natural products and pharmaceutical reagents with significant biological activities. Although several methods have been developed for the synthesis of rare monosaccharides, most of them involve lengthy steps. Herein, we report an efficient and general strategy that can provide access to rare sugars from commercially available common monosaccharides via a one-step Ru(II)-catalyzed and boron-mediated selective epimerization of 1,2-trans-diols to 1,2-cis-diols. The formation of boronate esters drives the equilibrium toward 1,2-cis-diol products, which can be immediately used for further selective functionalization and glycosylation. The utility of this strategy was demonstrated by the efficient construction of glycoside skeletons in natural products or bioactive compounds.

Calcification-Based Cancer Diagnosis and Therapy.

In nature, calcium deposition is a common biological process in mammals that shapes mechanical structures and creates the functions of bones and teeth, and causes calculi formation. Spontaneous tumor calcification and regional lymph node calcification in colorectal cancer, lung cancer, and glioblastoma have been proven to be benign prognostic factors in the clinic. In line with this concept, we introduce the idea and lead the compound development of artificially inducing bionic calcification around the surface of cancer cells. This process is shown to have excellent effects in the inhibition of growth and metastases of cervical, breast, and lung tumors, as well as superb performance in early-stage diagnosis. Therefore, we predict that this concept may open the door for cancer targeting calcification therapy and diagnosis and provide an outlook for a new avenue in anticancer drug development.

Prussian Blue/Calcium Peroxide Nanocomposites-Mediated Tumor Cell Iron Mineralization for Treatment of Experimental Lung Adenocarcinoma.

Current lung cancer diagnosis methods encounter delayed visual confirmation of tumor foci and low-resolution metrics in imaging findings, which delays the early treatment of tumors. Here, we developed a potent lung cancer imaging and treatment strategy centered around a nanotransformational concept of tumor iron mineralization in situ, which employs Prussian blue/calcium peroxide nanocomposites as a precursor. The resultant iron mineralization in tumor cells greatly facilitates the early and differential diagnosis of lung carcinoma from benign nodules via medical imaging, meanwhile introducing oxidative stress to activate the cellular apoptosis and ferroptosis pathways, resulting in inhibition of the malignant behavior of tumor cells. Tumor-microenvironment-triggered iron mineralization enables integration of the detection and prevention of tumor metastasis at its early stages with no assistance of toxic drugs, which offers a potential solution for the precise management of lung cancer with ideal outcomes.

Impact of Combining Long-Term Subsoiling and Organic Fertilizer on Soil Microbial Biomass Carbon and Nitrogen, Soil Enzyme Activity, and Water Use of Winter Wheat.

Reductions in soil productivity and soil water retention capacity, and water scarcity during crop growth, may occur due to long-term suboptimal tillage and fertilization practices. Therefore, the application of appropriate tillage (subsoiling) and fertilization (organic fertilizer) practices is important for improving soil structure, water conservation and soil productivity. We hypothesize that subsoiling tillage combined with organic fertilizer has a better effect than subsoiling or organic fertilizer alone. A field experiment in Henan, China, has been conducted since 2011 to explore the effects of subsoiling and organic fertilizer, in combination, on winter wheat (Triticum aestivum L.) farming. We studied the effects of conventional tillage (CT), subsoiling (S), organic fertilizer (OF), and organic fertilizer combined with subsoiling (S+OF) treatments on dry matter accumulation (DM), water consumption (ET), water use efficiency (WUE) at different growth stages, yield, and water production efficiency (WPE) of winter wheat over 3 years (2016-2017, 2017-2018, 2018-2019). We also analyzed the soil structure, soil organic carbon, soil microbial biomass carbon and nitrogen, and soil enzymes in 2019. The results indicate that compared with CT, the S, OF and S+OF treatments increased the proportion of >0.25 mm aggregates, and S+OF especially led to increased soil organic carbon, soil microbial biomass carbon and nitrogen, soil enzyme activity (sucrase, cellulose, and urease). S+OF treatment was most effective in reducing ET, and increasing DM and WUE during the entire growth period of wheat. S+OF treatment also increased the total dry matter accumulation (Total DM) and total water use efficiency (total WUE) by 18.6-32.0% and 36.6-42.7%, respectively, during these 3 years. Wheat yield and WPE under S+OF treatment increased by 11.6-28.6% and 26.8-43.6%, respectively, in these 3 years. Therefore, S+OF in combination was found to be superior to S or OF alone, which in turn yielded better results than the CT.

The synthesis of a nanodrug using metal-based nanozymes conjugated with ginsenoside Rg3 for pancreatic cancer therapy.

Nanozymes have limited applications in clinical practice due to issues relating to their safety, stability, biocompatibility, and relatively low catalytic activity in the tumor microenvironment (TME) in vivo. Herein, we report a synergistic enhancement strategy involving the conjugation of metal-based nanozymes (Fe@Fe3O4) with natural bioactive organic molecules (ginsenoside Rg3) to establish a new nanodrug. Importantly, this metal-organic nanocomposite drug ensured the stability and biosafety of the nanozyme cores and the cellular uptake efficiency of the whole nanodrug entity. This nanodrug is based on integrating the biological characteristics and intrinsic physicochemical properties of bionics. The glycoside chain of Rg3 forms a hydrophilic layer on the outermost layer of the nanodrug to improve the biocompatibility and pharmacokinetics. Additionally, Rg3 can activate apoptosis and optimize the activity and status of normal cells. Internal nanozymes enter the TME and release Fe3+ and Fe2+, and the central metal Fe(0) continuously generates highly active Fe2+ under the conditions of the TME and in the presence of Fe3+, maintaining the catalytic activity. Therefore, these nanozymes can effectively produce reactive oxygen species and oxygen in the TME, thereby promoting the apoptosis of cancer cells. Thus, we propose the use of a new type of metal-organic nanocomposite material as a synergistic strategy against cancer.

Tumor circulome in the liquid biopsies for cancer diagnosis and prognosis.

Liquid biopsy is a convenient, fast, non-invasive and reproducible sampling method that can dynamically reflect the changes in tumor gene expression profile, and provide a robust basis for individualized therapy and early diagnosis of cancer. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are the currently approved diagnostic biomarkers for screening cancer patients. In addition, tumor-derived extracellular vesicles (tdEVs), circulating tumor-derived proteins, circulating tumor RNA (ctRNA) and tumor-bearing platelets (TEPs) are other components of liquid biopsies with diagnostic potential. In this review, we have discussed the clinical applications of these biomarkers, and the factors that limit their implementation in routine clinical practice. In addition, the most recent developments in the isolation and analysis of circulating tumor biomarkers have been summarized, and the potential of non-blood liquid biopsies in tumor diagnostics has also been discussed.

Relationship of cultural alienation and mental health on minority students in Han middle schools / 中国学校卫生

Objective@#To explore mental health among minority students in Han middle schools and to analyze the difference of mental health between junior and senior high school students, with the aim of providing a reference for the relationship between cultural alienation and mental health of minority students in Han middle schools.@*Methods@#Participants were 1 679 minority students in two Han middle schools recruited from Datong county in Qinghai province, participants completed cultural alienation and mental health inventroy of middle school students.@*Results@#Prevalence of mental health problems illustrated a‘V’ shape curve for both junior and senior high school minority students in Han middle schools. Junior school students scored lower than senior high school students on obsessive, learning anxiety, learning pressure, maladjustment and emotional imbalance(t=-2.88, -5.17, -2.82, -1.99, -2.60, P<0.05). The detection rate of moderate and mild mental health problems (44.5%, 12.5%) between middle school students of Han nationality and minority nationality (50.3%, 6.9%)(χ2=13.22，P<0.01). The middle school students of minority nationality showed more hostile, interpersonal tension and sensitivity, depressed, maladjustment, psychological imbalance, and lesser obsessive(t=2.86, 1.97, 2.04, 5.11, 5.75, -13.17, P<0.05). After controlling for grade, gender and nationality, cultural isolation(β=0.22, t=5.12), cultural separateness(β=0.19, t=4.54) and discordant sense(β=0.08, t=2.39) was positively associated with mental health，the sense of control(β=-0.09, t=-2.02) was negative associated with mental health(P<0.05).@*Conclusion@#Mental health of middle school students of ethnic minorities in Han area is at a satisfactory level, The junior school students in Han middle schools had higher level of mental health, Cultural alienation is an important factor in keeping mental health.

Site-Selective and Stereoselective O-Alkylation of Glycosides by Rh(II)-Catalyzed Carbenoid Insertion.

Carbohydrates are synthetically challenging molecules with vital biological roles in all living systems. Selective synthesis and functionalization of carbohydrates provide tremendous opportunities to improve our understanding on the biological functions of this fundamentally important class of molecules. However, selective functionalization of seemingly identical hydroxyl groups in carbohydrates remains a long-standing challenge in chemical synthesis. We herein describe a practical and predictable method for the site-selective and stereoselective alkylation of carbohydrate hydroxyl groups via Rh(II)-catalyzed insertion of metal carbenoid intermediates. This represents one of the mildest alkylation methods for the systematic modification of carbohydrates. Density functional theory (DFT) calculations suggest that the site selectivity is determined in the Rh(II)-carbenoid insertion step, which prefers insertion into hydroxyl groups with an adjacent axial substituent. The subsequent intramolecular enolate protonation determines the unexpected high stereoselectivity. The most prevalent trans-1,2-diols in various pyranoses can be systematically and predictably differentiated based on the model derived from DFT calculations. We also demonstrated that the selective O-alkylation method could significantly improve the efficiency and stereoselectivity of glycosylation reactions. The alkyl groups introduced to carbohydrates by OH insertion reaction can serve as functional groups, protecting groups, and directing groups.

Expression pattern and level of ING5 protein in normal and cancer tissues.

Inhibitor of growth family 5 (ING5) functions as a type-II tumor suppressor gene and exerts an important role in DNA repair, apoptotic induction, proliferative inhibition, chromatin remodeling and the invasion process. In the present study, immunohistochemistry was performed to characterize the expression profile of ING5 protein on a tissue microarray containing mouse and human normal tissues, and human cancer tissues, including hepatocellular (n=62), renal clear cell (n=62), pancreatic (n=62), esophageal squamous cell (n=45), cervical squamous cell (n=31), breast (n=144), gastric (n=196), colorectal (n=96), endometrial (n=96) and lung carcinoma (n=192). In the mouse tissues, ING5 expression was detected in the cytoplasm of neurons, the nephric tubule and glomerulus, alveolar epithelium, gastrointestinal glands, squamous epithelium of the skin and skeletal muscles. By contrast, ING5 was localized to the cell nucleus in breast tissues. In human tissues, ING5 protein was primarily localized in the cytoplasm. However, ING5 was detected in the cytoplasm and nucleus in various types of normal tissues, including the tongue, stomach, intestine, lung and breast. In total, ING5 expression was detected in 400/986 cancer tissues (40.6%). In the majority of cases, ING5 expression was observed to be restricted to the cytoplasm. However, ING5 was also detected in the nucleus in a number of cancer tissues, including gastric, colorectal and lung carcinoma. Notably, ING5 was more frequently expressed in breast (79.9%), colorectal (56.3%) and endometrial carcinoma (50.0%). The incidence of ING5 expression in hepatocellular carcinoma (14.5%) and pancreatic carcinoma (22.6%) was low. These findings indicate that ING5 may be involved in cell regeneration and be associated with colorectal carcinogenesis.

C-terminal site-specific PEGylated Exendin-4 analog: A long-acting glucagon like Peptide-1 receptor agonist, on glycemic control and beta cell function in diabetic db/db mice.

PEG modification is a common clinical strategy for prolonging the half-life of therapeutic proteins or polypeptides. In a previous work, we have successfully synthesized PEG-modified Exendin-4 (PE) by conjugating a 20 kDa PEG to the C-terminal of Exendin-4. Then, we introduced an integrative characterization for PE to evaluate its hypoglycemic activity and pharmacokinetic properties. The normoglycemic efficacies and therapeutic activity of PE were investigated in db/db mice. The hypoglycemic time after single administration of PE on db/db mice was prolonged from 8.4 h to 54.9 h. In multiple treatment with PE, the fasting blood glucose in various PE dosages (50, 150, and 250 nmol/kg) were remarkably reduced, and the glycosylated hemoglobin level was decreased to 2.0%. When the in vivo single- and multiple-dose pharmacokinetics of PE were examined in Sprague-Dawley rats, the half-life was prolonged to 31.7 h, and no accumulation effect was observed. Overall, this study provided a novel promising therapeutic approach to improving glucose-controlling ability and extending half-life without accumulation in vivo for long-acting treatment of type-2 diabetes.