Dual N-linked glycosylation at residues 133 and 158 in the hemagglutinin are essential for the efficacy of H7N9 avian influenza virus like particle vaccine in chickens and mice.

H7N9 subtype avian influenza virus (AIV) poses a great challenge to poultry industry. Virus-like particle (VLP) is a prospective alternative for the traditional egg-based influenza vaccines. N-linked glycosylation (NLG) regulates the efficacy of influenza vaccines, whereas the impact of NLG modifications on the efficacy of influenza VLP vaccines remains unclear. Here, H7N9 VLPs were assembled in insect cells through co-infection with the baculoviruses expressing the NLG-modified hemagglutinin (HA), neuraminidase and matrix proteins, and the VLP vaccines were assessed in chickens and mice. NLG modifications significantly enhanced hemagglutination-inhibition and virus neutralization antibody responses in mice, rather than in chickens, because different immunization strategies were used in these animal models. The presence of dual NLG at residues 133 and 158 significantly elevated HA-binding IgG titers in chickens and mice. The VLP vaccines conferred complete protection and significantly suppressed virus replication and lung pathology post challenge with H7N9 viruses in chickens and mice. VLP immunization activated T cell immunity-related cytokine response and inhibited inflammatory cytokine response in mouse lung. Of note, the presence of dual NLG at residues 133 and 158 optimized the capacity of the VLP vaccine to stimulate interleukin-4 expression, inhibit virus shedding or alleviate lung pathology in chickens or mice. Intriguingly, the VLP vaccine with NLG addition at residue 133 provided partial cross-protection against the H5Nx subtype AIVs in chickens and mice. In conclusion, dual NLG at residues 133 and 158 in HA can be potentially used to enhance the efficacy of H7N9 VLP vaccines in chickens and mammals.

Hepatocyte HSPA12A inhibits macrophage chemotaxis and activation to attenuate liver ischemia/reperfusion injury via suppressing glycolysis-mediated HMGB1 lactylation and secretion of hepatocytes.

Rationale: Liver ischemia-reperfusion (LI/R) injury is characterized by two interconnected phases: local ischemia that causes hepatic cell damage to release damage-associated molecular pattern (DAMPs), and DAMPs that recruit immune cells to elicit inflammatory cascade for further injury of hepatocytes. High-mobility group box 1 (HMGB1) is a representative DAMP. Studies in macrophages demonstrated that HMGB1 is secreted after lactylation during sepsis. However, whether lactylation mediates HMGB1 secretion from hepatocytes after LI/R is known. Heat shock protein A12A (HSPA12A) is an atypical member of HSP70 family. Methods: Gene expression was examined by microarray analysis and immunoblotting. The hepatic injury was analyzed using released ALT and AST activities assays. Hepatic macrophage chemotaxis was evaluated by Transwell chemotaxis assays. Inflammatory mediators were evaluated by immunoblotting. HMGB1 secretion was examined in exosomes or serum. HMGB1 lactylation was determined using immunoprecipitation and immunoblotting. Results: Here, we report that LI/R decreased HSPA12A expression in hepatocytes, while hepatocyte-specific HSPA12A overexpression attenuated LI/R-induced hepatic dysfunction and mortality of mice. We also noticed that hepatocyte HSPA12A overexpression suppressed macrophage chemotaxis to LI/R-exposed livers in vivo and to hypoxia/reoxygenation (H/R)-exposed hepatocytes in vitro. The LI/R-increased serum HMGB1 levels of mice and the H/R-increased HMGB1 lactylation and secretion levels of hepatocytes were also inhibited by hepatocyte HSPA12A overexpression. By contrast, HSPA12A knockout in hepatocytes promoted not only H/R-induced HMGB1 lactylation and secretion of hepatocytes but also the effects of H/R-hepatocytes on macrophage chemotaxis and inflammatory activation, while all these deleterious effects of HSPA12A knockout were reversed following hepatocyte HMGB1 knockdown. Further molecular analyses showed that HSPA12A overexpression reduced glycolysis-generated lactate, thus decreasing HMGB1 lactylation and secretion from hepatocytes, thereby inhibiting not only macrophage chemotaxis but also the subsequent inflammatory cascade, which ultimately protecting against LI/R injury. Conclusion: Taken together, these findings suggest that hepatocyte HSPA12A is a novel regulator that protects livers from LI/R injury by suppressing glycolysis-mediated HMGB1 lactylation and secretion from hepatocytes to inhibit macrophage chemotaxis and inflammatory activation. Therefore, targeting hepatocyte HSPA12A may have therapeutic potential in the management of LI/R injury in patients.

Transcriptional regulations of pollen tube reception are associated with the fertility of the ginger species Zingiber zerumbet and Zingiber corallinum.

Zingiber zerumbet and Zingiber corallinum are economically valuable species in the genus Zingiber. While Z. corallinum is sexually active, Z. zerumbet adopts clonal propagation, although it has the potential for sexual reproduction. It is unclear so far at which step during the sexual reproduction of Z. zerumbet inhibition occurs, and what are the regulatory mechanisms underlying this inhibition. Here, by comparing with the fertile species Z. corallinum using microscopy-based methods, we show that rare differences were observed in Z. zerumbet up to the point when the pollen tubes invaded the ovules. However, a significantly higher percentage of ovules still contained intact pollen tubes 24 h after pollination, suggesting pollen tube rupture was impaired in this species. Further RNA-seq analysis generated accordant results, showing that the transcription of ANX and FER, as well as genes for the partners in the same complexes (e.g., BUPS and LRE, respectively), and those putative peptide signals (e.g., RALF34), were timely activated in Z. corallinum, which ensured the pollen tubes being able to grow, reorient to ovules, and receipt by embryo sacs. In Z. zerumbet, genes for these complexes were cooperatively suppressed, which would result in the maintenance of PT integrity due to the disruption of RALF34-ANX/BUPS signaling in PT and the failure of PT reception by an active synergid due to the insufficiency of the synergid-harbored FER/LRE complex. Taking the results from the cytological and RNA-seq studies together, a model is proposed to illustrate the possible regulation mechanisms in Z. zerumbet and Z. corallinum, in which the regulations for pollen tube rupture and reception are proposed as the barrier for sexual reproduction in Z. zerumbet.

[Erythrocytes-camouflaged nanoparticles: a promising delivery system for drugs and vaccines].

Erythrocytes-camouflaged nanoparticles is an in vivo delivery system that uses erythrocytes or erythrocyte membrane nano vesicles as carriers for drugs, enzymes, peptides and antigens. This system has the advantages of good biocompatibility, long circulation cycle and efficient targeting. This review summarizes the type of carriers, their development history, the application of delivery strategies as well as their limitations and future challenges. Lastly, future directions and key issues in the development of this system are discussed.

Immobilization of Pb and Zn in Contaminated Soil Using Alumina-Silica Nano-Amendments Synthesized from Coal Fly Ash.

To apply coal fly ash to the remediation of heavy-metal-contaminated soil, an alumina-silica nano-amendment (ASNA) was synthesized from coal fly ash and was used for the immobilization of lead and zinc in contaminated soil. The investigation on the synthesis of the ASNA shows that the ASNA can be obtained under a roasting temperature of 700 °C, a ratio of alkali to coal fly ash of 1.2:1, and a molar ratio of silicon to aluminum of 1:1. The ASNA could increase the soil pH and cation exchange capacity (CEC) and decrease the bioavailability of Pb and Zn. When the ASNA addition increased from 0 to 2%, the bioavailability (extracted by CaCl2) of Pb and Zn decreased by 47% and 72%, respectively. Moreover, the addition of the ASNA facilitated the transformation of Pb from a reducible fraction to oxidizable and residual fractions and Zn from an exchangeable fraction to a residual fraction. The correlation analysis and cluster analysis verify that the ASNA modulates the chemical speciation of heavy metals by increasing the soil's CEC and pH, thereby immobilizing heavy metals. It is expected that this study can provide a new method for the remediation of Pb- and Zn-contaminated soil.

Genome-Wide Identification and Analysis of FKBP Gene Family in Wheat (Triticum asetivum).

FK506-binding protein (FKBP) genes have been found to play vital roles in plant development and abiotic stress responses. However, limited information is available about this gene family in wheat (Triticum aestivum L.). In this study, a total of 64 FKBP genes were identified in wheat via a genome-wide analysis involving a homologous search of the latest wheat genome data, which was unevenly distributed in 21 chromosomes, encoded 152 to 649 amino acids with molecular weights ranging from 16 kDa to 72 kDa, and was localized in the chloroplast, cytoplasm, nucleus, mitochondria, peroxisome and endoplasmic reticulum. Based on sequence alignment and phylogenetic analysis, 64 TaFKBPs were divided into four different groups or subfamilies, providing evidence of an evolutionary relationship with Aegilops tauschii, Brachypodium distachyon, Triticum dicoccoides, Arabidopsis thaliana and Oryza sativa. Hormone-related, abiotic stress-related and development-related cis-elements were preferentially presented in promoters of TaFKBPs. The expression levels of TaFKBP genes were investigated using transcriptome data from the WheatExp database, which exhibited tissue-specific expression patterns. Moreover, TaFKBPs responded to drought and heat stress, and nine of them were randomly selected for validation by qRT-PCR. Yeast cells expressing TaFKBP19-2B-2 or TaFKBP18-6B showed increased influence on drought stress, indicating their negative roles in drought tolerance. Collectively, our results provide valuable information about the FKBP gene family in wheat and contribute to further characterization of FKBPs during plant development and abiotic stress responses, especially in drought stress.

Covalent Triazine Frameworks and Porous Carbons: Perspective from an Azulene-Based Case.

Covalent triazine frameworks (CTFs) are among the most valuable frameworks owing to many fantastic properties. However, molten salt-involved preparation of CTFs at 400-600 °C causes debate on whether CTFs represent organic frameworks or carbon. Herein, new CTFs based on the 1,3-dicyanoazulene monomer (CTF-Azs) are synthesized using molten ZnCl2 at 400-600 °C. Chemical structure analysis reveals that the CTF-Az prepared at low temperature (400 °C) exhibits polymeric features, whereas those prepared at high temperatures (600 °C) exhibit typical carbon features. Even after being treated at even higher temperatures, the CTF-Azs retain their rich porosity, but the polymeric features vanish. Although structural de-conformation is a widely accepted outcome in polymer-to-carbon rearrangement processes, the study evaluates such processes in the context of CTF systems. A proof-of-concept study is performed, observing that the as-synthesized CTF-Azs exhibit promising performance as cathodes for Li- and K-ion batteries. Moreover, the as-prepared NPCs exhibit excellent catalytic oxygen reduction reaction (ORR) performance; hence, they can be used as air cathodes in Zn-air batteries. This study not only provides new building blocks for novel CTFs with controllable polymer/carbon features but also offers insights into the formation and structure transformation history of CTFs during thermal treatment.

Baculovirus-derived influenza virus-like particle confers complete protection against lethal H7N9 avian influenza virus challenge in chickens and mice.

Currently, highly pathogenic avian influenza (HPAI) H7N9 viruses still pose a potential pandemic threat. Influenza virus-like particle (VLP) is one of the most promising vaccine strategies to complement traditional egg-dependent vaccines. Here, we generated a H7N9 VLP vaccine candidate by baculovirus expression system and evaluated its efficacy in chickens and mice. The H7N9 VLP was produced through co-infection of Sf9 insect cells with three recombinant baculoviruses expressing individual HA, NA and M1 gene of the HPAI H7N9 virus A/chicken/Guangdong/GD15/2016. Intramuscular immunization of the H7N9 VLP elicited robust antibody immune responses and conferred complete clinical protection against lethal H7N9 virus challenge both in chickens and mice. Meanwhile, H7N9 VLP significantly restrained virus shedding and dramatically alleviated pulmonary lesions caused by H7N9 virus infection in birds and mice. Interestingly, chicken antibodies induced by the H7N9 VLP also had a good cross-reactivity with H7N9 field strains isolated in different years. In addition, vaccination with the H7N9 VLP elicited high T cell immunity in mouse lung, evidenced by significantly upregulated expression of IL-2, IL-4 and IFN-γ. Furthermore, the H7N9 VLP significantly decreased the expression of some key inflammatory cytokines, such as IL6, RANTES and TNF-α in mouse lung, which may partially account for its contribution to alleviate lung pathology. Therefore, our study describes the good efficacy of the HA + NA + M1-containing H7N9 VLP both in chicken and mice models, highlighting the potential of VLP-based vaccine as a critical alternative of traditional egg-based vaccine for control of H7N9 influenza virus in both humans and poultry.

Single Dose of Bivalent H5 and H7 Influenza Virus-Like Particle Protects Chickens Against Highly Pathogenic H5N1 and H7N9 Avian Influenza Viruses.

Both H5N1 and H7N9 subtype avian influenza viruses cause enormous economic losses and pose considerable threats to public health. Bivalent vaccines against both two subtypes are more effective in control of H5N1 and H7N9 viruses in poultry and novel egg-independent vaccines are needed. Herein, H5 and H7 virus like particle (VLP) were generated in a baculovirus expression system and a bivalent H5+H7 VLP vaccine candidate was prepared by combining these two antigens. Single immunization of the bivalent VLP or commercial inactivated vaccines elicited effective antibody immune responses, including hemagglutination inhibition, virus neutralizing and HA-specific IgG antibodies. All vaccinated birds survived lethal challenge with highly pathogenic H5N1 and H7N9 viruses. Furthermore, the bivalent VLP significantly reduced viral shedding and virus replication in chickens, which was comparable to that observed for the commercial inactivated vaccine. However, the bivalent VLP was better than the commercial vaccine in terms of alleviating pulmonary lesions caused by H7N9 virus infection in chickens. Therefore, our study suggests that the bivalent H5+H7 VLP vaccine candidate can serve as a critical alternative for the traditional egg-based inactivated vaccines against H5N1 and H7N9 avian influenza virus infection in poultry.

Neuroprotective Effects of Dexmedetomidine on the Ketamine-Induced Disruption of the Proliferation and Differentiation of Developing Neural Stem Cells in the Subventricular Zone.

Background: Ketamine disrupts the proliferation and differentiation of developing neural stem cells (NSCs). Therefore, the safe use of ketamine in pediatric anesthesia has been an issue of increasing concern among anesthesiologists and children's parents. Dexmedetomidine (DEX) is widely used in sedation as an antianxiety agent and for analgesia. DEX has recently been shown to provide neuroprotection against anesthetic-induced neurotoxicity in the developing brain. The aim of this in vivo study was to investigate whether DEX exerted neuroprotective effects on the proliferation and differentiation of NSCs in the subventricular zone (SVZ) following neonatal ketamine exposure. Methods: Postnatal day 7 (PND-7) male Sprague-Dawley rats were equally divided into the following five groups: control group (n = 8), ketamine group (n = 8), 1 µg/kg DEX+ketamine group (n = 8), 5 µg/kg DEX+ketamine group (n = 8) and 10 µg/kg DEX+ketamine group (n = 8). Immediately after treatment, rats received a single intraperitoneal injection of BrdU, and the proliferation and differentiation of NSCs in the SVZ were assessed using immunostaining at 24 h after the BrdU injection. In the olfactory behavioral tests, rats in each group were raised until 2 months old, and the buried food test and olfactory memory test were performed. Results: The proliferation of NSCs and astrocytic differentiation in the SVZ were significantly inhibited at 24 h after repeated ketamine exposure in the neonatal period, and neuronal differentiation was markedly increased. Furthermore, pretreatment with moderately high (5 µg/kg) or high doses (10 µg/kg) of DEX reversed ketamine-induced disturbances in the proliferation and differentiation of NSCs. In the behavior tests, repeated neonatal ketamine exposure induced olfactory cognitive dysfunction in the adult stage, and moderately high and high doses of DEX reversed the olfactory cognitive dysfunction induced by ketamine. Conclusions: Based on the present findings, pretreatment with a moderately high (5 µg/kg) or high dose (10 µg/kg) of DEX may alleviate the developmental neurogenesis disorder in the SVZ at 24 h after repeated ketamine exposure and improve olfactory cognitive dysfunction in adulthood.

Efficacy and safety of ultrasound-guided above-knee lateral approach for popliteal sciatic nerve block in surgeries below the knee: a randomized controlled trial.

BACKGROUND: Ultrasound guidance has become a standard method for detection of nerve structures in regional anesthesia. During ultrasound-guided blockade, to identify anatomical structures is crucial but can be challenging. In clinical practice, we find a wide difference in the visibility score of the sciatic nerve (SN) through different approaches. This study aimed to compare SNB through the anterior and above-knee lateral approach in terms of identification ease, performance efficacy, and safety. METHODS: Patients scheduled for below-knee surgery were randomized to either receive SNB using the above-knee lateral approach (Group L, n=27) or the anterior approach (Group A, n=26). The primary outcome was the visibility score of SN. Secondary outcomes included the time taken to identify the SN, nerve depth, success rate of SN identification, number of needle passes, time to elicit foot flexion, needle depth, and occurrence of SNB complications. Additionally, the sensory block onset and analgesia duration were assessed. RESULTS: We included 53 adult patients. Compared with Group A, Group L showed a higher SN visibility score [3.25 (3.17, 3.67) vs. 2.50 (1.86, 2.68), P<0.001]. The scan time was significantly shorter in Group L [8.70 (6.01) s vs. 31.54 (11.87) s, P<0.001]. The depth of the SN was 3.20 (0.56) cm in Group L and 5.53 (0.84) cm in Group A (P<0.001), and the needle insertion depth was 7.15 (0.90) cm in group L and 8.32 (1.13) cm in Group A (P<0.001). The number of needle passes was less in Group L, as well as the time to elicit foot flexion, and the time taken to perform the SN block (all P<0.001). The success rate of SN identification was non-significantly higher in Group L. There was no significant between-group difference in the onset of sensory block, as well as postoperative analgesia duration. None of the approaches involved acute systemic toxicity and hematoma occurrence. CONCLUSIONS: Based on the visibility score, the above-knee lateral approach allowed easy SN identification and safe SNB. Using the ultrasound-guided above-knee lateral approach for SNB in below-knee surgeries could be a reliable choice.

H7N9 influenza virus-like particle based on BEVS protects chickens from lethal challenge with highly pathogenic H7N9 avian influenza virus.

H7N9 avian influenza virus poses a dual threat to both poultry industry and public health. Therefore, it is highly urgent to develop an effective vaccine to reduce its pandemic potential. Virus-like particles (VLP) represent an effective approach for pandemic vaccine development. In this study, a recombinant baculovirus co-expressing the HA, NA and M1 genes of the H7N9 virus was constructed for generation of H7N9 VLP. Single immunization of chickens with 15 µg of the VLP or the commercial whole virus inactivated vaccine stimulates high hemagglutination inhibition, virus neutralizing and HA-specific IgY antibodies. Moreover, the antiserum had a good cross-reactivity with H7N9 field strains isolated in different years. Within 14 days after a lethal challenge with highly pathogenic (HP) H7N9 virus, no clinical symptoms and death were observed in the vaccinated chickens, and no virus was recovered from the organs. Compared to the non-vaccinated chickens, H7N9 VLP significantly reduced the proportion of animals shedding virus. Only 30 % of the VLP-vaccinated birds shed virus, whereas virus shedding was detected in 50 % of the chickens immunized with the commercial vaccine. Moreover, both vaccines dramatically alleviated pulmonary lesions caused by HP H7N9 virus, with a greater degree observed for the VLP. Altogether, our results indicated that the H7N9 VLP vaccine candidate confers a complete clinical protection against a lethal challenge with HP H7N9 virus, significantly inhibits virus shedding and abolishes viral replication in chickens. The VLP generated in this study represents a promising alternative strategy for the development of novel H7N9 avian influenza vaccines for chickens.

The Effectiveness and Safety of Intravenous Dexmedetomidine of Different Concentrations Combined with Butorphanol for Post-Caesarean Section Analgesia: A Randomized Controlled Trial.

PURPOSE: The present study aimed to determine the effectiveness of intravenous dexmedetomidine of different concentrations and to evaluate its maternal and neonatal safety when combined with butorphanol in parturients undergoing cesarean section. PATIENTS AND METHODS: A total of 114 parturients between 24 and 43 years of age, with singleton pregnancy who underwent elective cesarean section under epidural anesthesia, were randomly allocated to four groups: group C received 0.9% sodium chloride after delivery, followed by butorphanol (3 µg·kg-1·h-1); patients in groups D1, D2, and D3 received 0.5 µg·kg-1·h-1 dexmedetomidine after delivery, followed by butorphanol (3 µg·kg-1·h-1) combined with dexmedetomidine 0.03, 0.05, and 0.08 µg·kg-1·h-1, respectively. The primary outcome was the visual analogue scale (VAS) score at 6 h after delivery when patients were at rest. Secondary outcome measures included VAS after delivery when patients were on movement and uterine cramping, Ramsay sedation scale (RSS), relative infant dose (RID) of dexmedetomidine, satisfaction with analgesia after surgery and symptoms of CNS depression in neonates. RESULTS: There were no significant differences in patient characteristics among the groups (P > 0.05). The VAS at all timepoints after delivery in groups D2 and D3 were significantly lower than in groups C and D1 (P < 0.001). RSS scores were clearly higher in group D3 than in the other three groups at 6 h and 12 h (P < 0.0001). RID in groups D1, D2, and D3 was 0.171%, 0.197%, and 0.370%, respectively. Compared with group D1, RID was higher in group D3 (P = 0.0079). Degree of satisfaction with analgesia was higher in groups D2 and D3 (P < 0.005). CONCLUSION: Continuous intravenous infusion of 0.05 µg·kg-1·h-1 dexmedetomidine combined with 3 µg·kg-1·h-1 butorphanol could be safely applied in healthy parturients with satisfactory analgesia after cesarean section without changes in sedation.

Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells.

The PI3K/AKT/mTOR signaling pathway is constitutively active in PTEN-deficient cancer cells, and its targeted inhibition has significant anti-tumor effects. However, the efficacy of targeted therapies is often limited due to drug resistance. The relevant signaling pathways in PTEN-deficient cancer cells treated with the PI3K/mTOR inhibitor BEZ235 were screened using a phosphokinase array, and further validated following treatment with multiple PI3K/AKT/mTOR inhibitors or AKT knockdown. The correlation between PTEN expression levels and STAT3 kinase phosphorylation in the tissue microarrays of gastric cancer patients was analyzed by immunohistochemistry. Cell proliferation and clonogenic assays were performed on the suitably treated PTEN-deficient cancer cells. Cytokine arrays, small molecule inhibition and knockdown assays were performed to identify related factors. PTEN-deficient tumor xenografts were established in nude mice that were treated with PI3K/AKT/mTOR and/or STAT3 inhibitors. PTEN deficiency was positively correlated with low STAT3 activity. PI3K/mTOR inhibitors increased the expression and secretion of macrophage migration inhibitory factor (MIF) and activated the JAK1/STAT3 signaling pathway. Both cancer cells and in vivo tumor xenografts showed that the combined inhibition of PI3K/AKT/mTOR and STAT3 activity enhanced the inhibitory effect of BEZ235 on the proliferation of PTEN-deficient cancer cells. Our findings provide a scientific basis for a novel treatment strategy in cancer patients with PTEN deficiency.

HSPA12A unstabilizes CD147 to inhibit lactate export and migration in human renal cell carcinoma.

Background: Metastasis accounts for 90% of cancer-associated mortality in patients with renal cell carcinoma (RCC). However, the clinical management of RCC metastasis is challenging. Lactate export is known to play an important role in cancer cell migration. This study investigated the role of heat shock protein A12A (HSPA12A) in RCC migration. Methods: HSPA12A expression was examined in 82 pairs of matched RCC tumors and corresponding normal kidney tissues from patients by immunoblotting and immunofluorescence analyses. The proliferation of RCC cells was analyzed using MTT and EdU incorporation assays. The migration of RCC cells was evaluated by wound healing and Transwell migration assays. Extracellular acidification was examined using Seahorse technology. Protein stability was determined following treatment with protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132. Mass spectrometry, immunoprecipitation, and immunoblotting were employed to examine protein-protein interactions. Results: RCC tumors from patients showed downregulation of HSPA12A, which was associated with advanced tumor node metastasis stage. Intriguingly, overexpression of HSPA12A in RCC cells inhibited migration, whereas HSPA12A knockdown had the opposite effect. Lactate export, glycolysis rate, and CD147 protein abundance were also inhibited by HSPA12A overexpression but promoted by HSPA12A knockdown. An interaction of HSPA12A with HRD1 ubiquitin E3 ligase was detected in RCC cells. Further studies demonstrated that CD147 ubiquitination and proteasomal degradation were promoted by HSPA12A overexpression whereas inhibited by HSPA12A knockdown. Notably, the HSPA12A overexpression-induced inhibition of lactate export and migration were abolished by CD147 overexpression. Conclusion: Human RCC shows downregulation of HSPA12A. Overexpression of HSPA12A in RCC cells unstabilizes CD147 through increasing its ubiquitin-proteasome degradation, thereby inhibits lactate export and glycolysis, and ultimately suppresses RCC cell migration. Our results demonstrate that overexpression of HSPA12A might represent a viable strategy for managing RCC metastasis.

MicroRNA­93 promotes angiogenesis and attenuates remodeling via inactivation of the Hippo/Yap pathway by targeting Lats2 after myocardial infarctionω.

Inactivation of the Hippo pathway protects the myocardium from cardiac ischemic injury. MicroRNAs (miRs) have been reported to play pivotal roles in the progression of myocardial infarction (MI). The present study examined whether miR­93 could promote angiogenesis and attenuate remodeling after MI via inactivation of the Hippo/Yes­associated protein (Yap) pathway, by targeting large tumor suppressor kinase 2 (Lats2). It was identified that transfection of human umbilical vein endothelial cells with miR­93 mimic significantly decreased Lats2 expression and Yap phosphorylation, increased cell viability and migration, and attenuated cell apoptosis following hypoxia/reoxygenation injury. Moreover, increased expression of miR­93 resulted in an improvement of cardiac function, promotion of angiogenesis and attenuation of remodeling after MI. Additionally, miR­93 overexpression significantly decreased intracellular adhesion molecule 1 and vascular cell adhesion protein 1 expression levels, as well as attenuated the infiltration of neutrophils and macrophages into the myocardium after MI. Furthermore, it was found that miR­93 overexpression significantly suppressed Lats2 expression and decreased the levels of phosphorylated Yap in the myocardium after MI. Collectively, the present results suggested that miR­93 may exert a protective effect against MI via inactivation of the Hippo/Yap pathway by targeting Lats2.

Alpha-lipoic acid inhibits lung cancer growth via mTOR-mediated autophagy inhibition.

Lung cancer is the leading cause of cancer-related death, and there remains a need for novel therapies for this malignancy. Here, we examined the effects of alpha-lipoic acid (LA), a drug used for treating human diabetic complications, on lung cancer growth. We report that LA limited lung cancer growth in xenograft mice and reduced lung cancer A549 cell viability. We observed autophagy activation in human lung cancers, and report that LA inactivated autophagy in A549 cells. In addition, LA activated mammalian target of rapamycin (mTOR)/p70S6K signaling. Inhibition of mTOR with rapamycin reversed LA-induced inactivation of autophagy and abolished LA-induced suppression of A549 cell viability. Altogether, the data suggest that LA exerts an anti-lung cancer effect through mTOR-mediated inhibition of autophagy, and thus LA may have therapeutic potential for lung cancer management.

A Comparison of the Immunostimulatory Effects of Polysaccharides from Tetraploid and Diploid Echinacea purpurea.

Polyploidization is an effective means of improving the active components and quality of secondary metabolism in medicinal plants. In the present study, we compared the immunostimulatory effects of crude polysaccharides from tetraploid and diploid Echinacea purpurea. The results showed that the carbohydrate contents of crude polysaccharide of tetraploid E. purpurea (CPE4) and diploid E. purpurea (CPE2) were 85.51% and 44.65%, respectively. 1H-nuclear magnetic resonance (NMR) spectroscopy and gel-permeation chromatography (GPC) analyses showed no major differences in the overall structure and molecular weight of polysaccharides between CPE4 and CPE2. However, some differences in the relative content of the same polysaccharides group were observed between CPE4 and CPE2. In in vitro tests, EP4 could stimulate lymphocyte proliferation and secretion of cytokines maximally at the concentration of 0.0312 mg/mL, and EP2 could stimulate lymphocyte proliferation and secretion of cytokines maximally at the concentration of 0.125 mg/mL. In in vivo tests, EP4 was more effective at promoting the proliferation of lymphocytes and secretion of cytokines in mice immunosuppressed by cyclophosphamide than EP2 at the same concentration. Taken together, these data demonstrated that the relative content of the partial polysaccharides group is increased, and the immunoregulatory effect is enhanced in tetraploid E. purpurea.

Polysaccharide Nanoparticles for Targeted Cancer Therapies.

BACKGROUND: Despite extensive advances have been made in constructing polysaccharide-based nanomedicines for target cancer therapy due to their biocompatibility, easy-functionalizability and high targeting property, there is no review concentrating the significance of the intrinsic targeting properties of polysaccharides. This review mainly focuses on the recent progress on polysaccharide-based nanoparticles which have been applied in gene delivery, drug delivery and theranostics for targeted cancer therapies. Notably, representative polysaccharides with intrinsic targeting capability used as targeting ligand are well discussed. CONCLUSION: It has been found that polysaccharides have become a class of promising biopolymer carrier materials to deliver anti-cancer therapeutic molecules. Among all of polysaccharides, those who are with intrinsic properties of targeting are most frequently used. Therefore, this review revealed the importance of understanding the natural functions of polysaccharides to tailor nanocarrier platforms and ultimately surmount challenges in targeted cancer therapy.

α-Lipoic acid inhibits sevoflurane-induced neuronal apoptosis through PI3K/Akt signalling pathway.

Sevoflurane is a widely used anaesthetic agent, including in anaesthesia of children and infants. Recent studies indicated that the general anaesthesia might cause the cell apoptosis in the brain. This issue raises the concerns about the neuronal toxicity induced by the application of anaesthetic agents, especially in the infants and young children. In this study, we used Morris water maze, western blotting and immunohistochemistry to elucidate the role of α-lipoic acid in the inhibition of neuronal apoptosis. We found that sevoflurane led to the long-term cognitive impairment in the young rats. This adverse effect may be caused by the neuronal death in the hippocampal region, mediated through PI3K/Akt signalling pathway. We also showed that α-lipoic acid offset the effect of sevoflurane on the neuronal apoptosis and cognitive dysfunction. This study elucidated the potential clinical role of α-lipoic acid, providing a promising way in the prevention and treatment of long-term cognitive impairment induced by sevoflurane general anesthesia.