Gedunin induces apoptosis and inhibits HMBG1/PI3K/AKT signaling pathways in a rat model of gastric carcinogenesis induced by methylnitronitrosoguanidine.

Introduction: This study aimed to evaluate the anti-cancer effects of gedunin, a natural compound, in a rat model of gastric carcinogenesis induced by MNNG. Methods: Fifty-four rats were randomly assigned to six groups for a 60-day study on the effects of MNNG and gedunin. Groups 1-4 received 200 mg/kg MNNG (1, 10, or 100 mg/kg), and group 5 had only 100 mg/kg gedunin. Results: Gedunin at low doses exhibited anti-cancer and protective properties against MNNG-induced damage, including reduced inflammation, and apoptosis. Conclusions: Gedunin demonstrates a U-shaped dose-response, with low doses offering protection and high doses promoting tumor growth.

IFN-γ enhances protective efficacy against Nocardia seriolae infection in largemouth bass (Micropterus salmoides).

Introduction: Nocardia seriolae adversely impacts a diverse range of fish species, exhibiting significant pathogenic characteristics that substantially impede the progress of aquaculture. N. seriolae infects in fish has a long incubation period, and clinical symptoms are not obvious in the early stages. There is presently no viable and eco-friendly approach to combat the spread of the disease. According to reports, N. seriolae primarily targets macrophages in tissues after infecting fish and can proliferate massively, leading to the death of fish. Interferon-gamma (IFN-γ) is a crucial molecule that regulates macrophage activation, but little is known about its role in the N. seriolae prevention. Methods: IFN-γ was first defined as largemouth bass (Micropterus salmoides, MsIFN-γ), which has a highly conserved IFN-γ characteristic sequence through homology analysis. The recombinant proteins (rMsIFN-γ) were obtained in Escherichia coli (E. coli) strain BL21 (DE3). The inflammatory response-inducing ability of rMsIFN-γ was assessed in vitro using monocytes/macrophages. Meanwhile, the protective effect of MsIFN-γ in vivo was evaluated by N. seriolae infection largemouth bass model. Results: In the inflammatory response of the monocytes/macrophages activated by rMsIFN-γ, various cytokines were significantly increased. Interestingly, interleukin 1ß (IL-1ß) and tumor necrosis factor alpha (TNF-a) increased by 183- and 12-fold, respectively, after rMsIFN-γ stimulation. rMsIFN-γ improved survival by 42.1% compared with the control. The bacterial load in the liver, spleen and head kidney significantly decreased. rMsIFN-γ was also shown to better induce increased expression of IL-1ß, TNF-α, hepcidin-1(Hep-1), major histocompatibility complex I (MHCI), and MHC II in head kidney, spleen and liver. The histopathological examination demonstrated the transformation of granuloma status from an early necrotic foci to fibrosis in the infection period. Unexpectedly, the development of granulomas was successfully slowed in the rMsIFN-γ group. Discussion: This work paves the way for further research into IFN-γ of largemouth bass and identifies a potential therapeutic target for the prevention of N. seriolae.

Hepcidin contributes to largemouth bass (Micropterus salmoides) against bacterial infections.

The increasing emergence and dissemination of bacterial pathogens in largemouth bass culture accelerate the desire for new treatment measures. Antimicrobial peptides as the host's antimicrobial source dominate the preferred molecules for discovering antibacterial agents. Here, the potential of Hepcidin-1 from largemouth bass (Micropterus salmoides) (MsHep-1) against bacterial infection is demonstrated. MsHep-1 not only improved the survival rate in infection experiments involving Nocardia seriolae (12 %) and Aeromonas hydrophila (18 %) but also coped with iron overload conditions in vivo. Moreover, the antibacterial activity of MsHep-1 in vitro was identified against both gram-negative and gram-positive bacteria. Mechanistic studies show MsHep-1 leads to bacterial death by changing the bacterial membrane potential and disrupting the bacterial membrane structure. These findings demonstrate that MsHep-1 may play an important role in the host response to bacterial infection. It provides promising strategies in the application of immunosuppression prevention and control in fish. AMPs may be a promising and available reservoir for treating the current bacterial diseases.

Effect of Steam Pressure Toasting Duration on Snowbird Faba Bean Seeds and the Impact on the Intestinal and Metabolic Characteristics in Dairy Cows.

The response of feedstuffs to thermal processing depends on the type of feed and the thermal processing methods being applied. Steam pressure toasting (SPT) has been used to modify the nutrient degradability and enhance the nutritional quality of pulses, including faba bean seeds (FBS). Strategic feeding approaches are essential for balancing diets and maintaining adequate nutrition, especially in high-performing ruminants. This research aimed to determine the effects of SPT duration in FBS on the intestinal and metabolic characteristics of dairy cows. Faba Bean seeds (three harvesting years) were processed at 121 °C for 0, 30, 60, 90, and 120 min. Rumen degradation and intestinal digestion were determined using the in situ and modified in vitro three-step techniques. The true protein supplied to the small intestine was also determined using the NRC and DVE systems. Our results showed a reduced total digested DM (TDDM) with longer SPT duration (quadratic, p = 0.02). The intestinally digested crude protein (IADP) increased from 62 to 220 g/kg DM with 0 to 120 min of SPT, respectively (p < 0.01), whereas the total tract digestible starch (TDSt) gradually decreased from 321 to 182 g/kg DM based on SPT time (p < 0.01). On the other hand, the truly digested protein in the small intestine (DVE) and the total metabolizable protein (MP) increased from 138 to 282 g/kg DM and 129 to 282 g/kg DM, respectively, with 0 to 120 min of SPT (quadratic, p < 0.01). The Feed Milk Value (FMV), based on both the DVE/OEB and NRC dairy nutrition systems, also increased with SPT (Quadratic, p < 0.01). The processing of FBS with SPT at 121 °C effectively reduced the highly degradable protein fraction in the rumen, shifting to a higher rumen undegraded protein (RUP) which was able to reach the small intestine. In the current study, the total MP, DVE, and FMV in dairy cows showed an overall increase with SPT in FBS.

Induction therapy with hepatic arterial infusion chemotherapy enhances the efficacy of lenvatinib and pd1 inhibitors in treating hepatocellular carcinoma patients with portal vein tumor thrombosis.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX), lenvatinib and programmed death receptor-1 signaling inhibitors (PD1s) all alone have been proven effective in treating advanced hepatocellular carcinoma (HCC), yet the efficacy and safety of the tri-combination therapy in treating HCC patients with portal vein tumor thrombosis (PVTT) remains unknown. METHODS: In this retrospective study, HCC patients with PVTT received either induction therapy of HAIC and lenvatinib plus PD1s in the initial period of treatment and then dual maintenance therapy of lenvatinib and PD1s (HAIC-Len-PD1) or continuous lenvatinib combined with PD1s (Len-PD1). RESULTS: In total, 53 and 89 patients were enrolled into the Len-PD1 group and HAIC-Len-PD1 group, respectively. The median overall survival times were 13.8 months in the Len-PD1 group and 26.3 months in the HAIC-Len-PD1 group (hazard ratio (HR) = 0.43, P < 0.001). The median progression-free survival (PFS) time was significantly longer in the HAIC-Len-PD1 group than in the Len-PD1 group (11.5 months versus 5.5 months, HR = 0.43, P < 0.001). Induction therapy showed an objective response rate (ORR) 3 times higher than lenvatinib combined with PD1s therapy (61.8% versus 20.8%, P < 0.001), and exhibited inspiring intra- and extra-hepatic tumor control ability. Induction therapy led to more adverse events than lenvatinib combined with PD1s therapy, most of which were tolerable and controllable. CONCLUSION: The induction therapy of FOLFOX-HAIC and lenvatinib plus PD1s is an effective and safe treatment for HCC patients with PVTT. The concept of induction therapy could be applied to other local-regional treatments and drugs combinations in HCC management.

Oral administration of hepcidin and chitosan benefits growth, immunity, and gut microbiota in grass carp (Ctenopharyngodon idella).

Intensive high-density culture patterns are causing an increasing number of bacterial diseases in fish. Hepcidin links iron metabolism with innate immunity in the process of resisting bacterial infection. In this study, the antibacterial effect of the combination of hepcidin (Cihep) and chitosan (CS) against Flavobacterium columnare was investigated. The dosing regimen was also optimized by adopting a feeding schedule of every three days and every seven days. After 56 days of feeding experiment, grass carp growth, immunity, and gut microbiota were tested. In vitro experiments, Cihep and CS can regulate iron metabolism and antibacterial activity, and that the combination of Cihep and CS had the best protective effect. In vivo experiments, Cihep and CS can improve the growth index of grass carp. After challenge with Flavobacterium columnare, the highest survival rate was observed in the Cihep+CS-3d group. By serum biochemical indicators assay and Prussian blue staining, Cihep and CS can increase iron accumulation and decrease serum iron levels. The contents of lysozyme and superoxide dismutase in Cihep+CS-3d group increased significantly. Meanwhile, Cihep and CS can significantly reduce the pathological damage of gill tissue. The 16S rRNA sequencing results showed that Cihep and CS can significantly increase the abundance and diversity of grass carp gut microbiota. These results indicated that the protective effect of consecutive 3-day feeding followed by a 3-day interval was better than that of consecutive 7-day feeding followed by a 7-day interval, and that the protective effect of Cihep in combination with chitosan was better than that of Cihep alone. Our findings optimize the feeding pattern for better oral administration of Cihep in aquaculture.

Understanding the Impact of Neural Variations and Random Connections on Inference.

Recent research suggests that in vitro neural networks created from dissociated neurons may be used for computing and performing machine learning tasks. To develop a better artificial intelligent system, a hybrid bio-silicon computer is worth exploring, but its performance is still inferior to that of a silicon-based computer. One reason may be that a living neural network has many intrinsic properties, such as random network connectivity, high network sparsity, and large neural and synaptic variability. These properties may lead to new design considerations, and existing algorithms need to be adjusted for living neural network implementation. This work investigates the impact of neural variations and random connections on inference with learning algorithms. A two-layer hybrid bio-silicon platform is constructed and a five-step design method is proposed for the fast development of living neural network algorithms. Neural variations and dynamics are verified by fitting model parameters with biological experimental results. Random connections are generated under different connection probabilities to vary network sparsity. A multi-layer perceptron algorithm is tested with biological constraints on the MNIST dataset. The results show that a reasonable inference accuracy can be achieved despite the presence of neural variations and random network connections. A new adaptive pre-processing technique is proposed to ensure good learning accuracy with different living neural network sparsity.

High current density electron wind forces in metallic graphene nanoribbons.

In this study electric current-induced wind forces on a unit lattice of a 10-dimer zigzag graphene nanoribbon (ZGNR) are calculated under different magnitudes of electric field and temperatures. Wind forces are calculated using a semi-classical method where quantum mechanics is integrated into ensemble Monte Carlo simulations by considering energy and momentum conservation in both the transverse and longitudinal directions of graphene nanoribbon (GNR) during the electron-phonon scattering process. First order perturbation theory using the deformation potential approximation was used in the calculation of the scattering rates. The results show that under the same electric field, Joule heating power in a 10-dimer ZGNR is around 3 magnitudes higher than that in metallic single-walled carbon nanotubes and the wind forces are 1 magnitude higher. According to the calculated results, the wind force in the 10-dimer ZNGR is in the order of 0.0073 eV Å-1 under 20 kV at 300 K and it is much lower than the fracture strength of ZGNR based on the results of molecular dynamics simulations. Thus the failure of GNR under an electric current is considered to be mainly due to the Joule heating.

Influence of defects on dissipative transport in graphene nanoribbons tunnel field-effect transistor.

The influence of point defects on the dissipative carrier transport of armchair graphene nanoribbon (GNR) tunnel field effect transistor (TFET) is studied by solving the self-consistent Born approximation problem using the extended lowest order expansion method. The simulation results show that by introducing point defects to the channel region of the armchair GNR-TFET, the OFF state phonon contribution to the carrier transport changes significantly compared with that of the pristine device. The presence of defect would introduce additional optical phonon mode of much higher energy, which facilitates the OFF state phonon-assisted band-to-band tunneling process in a broader energy range and contribute to the dissipative carrier transport. In the ON-state, where the direct source to drain tunneling is at maximum, the electron-phonon interaction has a negligible effect, which is similar to that of the pristine device. Moreover, different defect types and locations are examined, their influence on hole and electron transport are reported.

Extracellular matrix derived by human umbilical cord-deposited mesenchymal stem cells accelerates chondrocyte proliferation and differentiation potential in vitro.

The extracellular matrix (ECM) is a dynamic and intricate three-dimensional (3D) microenvironment with excellent biophysical, biomechanical, and biochemical properties that may directly or indirectly regulate cell behavior, including proliferation, adhesion, migration, and differentiation. Compared with tissue-derived ECM, cell-derived ECM potentially has more advantages, including less potential for pathogen transfer, fewer inflammatory or anti-host immune responses, and a closer resemblance to the native ECM microenvironment. Different types of cell-derived ECM, such as adipose stem cells, synovium-derived stem cells and bone marrow stromal cells, their effects on articular chondrocytes which have been researched. In this study, we aimed to develop a 3D cell culture substrate using decellularized ECM derived from human umbilical cord-derived mesenchymal stem cells (hUCMSCs), and evaluated the effects on articular chondrocytes. We evaluated the morphology and components of hUCMSC-derived ECM using physical and chemical methods. Morphological, histological, immunohistochemical, biochemical, and real-time PCR analyses demonstrated that proliferation and differentiation capacity of chondrocytes using the 3D hUCMSC-derived ECM culture substrate was superior to that using non-coated two-dimensional plastic culture plates. In conclusion, 3D decellularized ECM derived from hUCMSCs offers a tissue-specific microenvironment for in vitro culture of chondrocytes, which not only markedly promoted chondrocyte proliferation but also preserved the differentiation capacity of chondrocytes. Therefore, our findings suggest that a 3D cell-derived ECM microenvironment represents a promising prospect for autologous chondrocyte-based cartilage tissue engineering and regeneration. The hUCMSC-derived ECM as a biomaterial is used for the preparation of scaffold or hybrid scaffold products which need to further study in the future.

Anisotropy of Graphene Nanoflake Diamond Interface Frictional Properties.

Using molecular dynamics (MD) simulations, the frictional properties of the interface between graphene nanoflake and single crystalline diamond substrate have been investigated. The equilibrium distance between the graphene nanoflake and the diamond substrate has been evaluated at different temperatures. This study considered the effects of temperature and relative sliding angle between graphene and diamond. The equilibrium distance between graphene and the diamond substrate was between 3.34 Å at 0 K and 3.42 Å at 600 K, and it was close to the interlayer distance of graphite which was 3.35 Å. The friction force between graphene nanoflakes and the diamond substrate exhibited periodic stick-slip motion which is similar to the friction force within a graphene-Au interface. The friction coefficient of the graphene-single crystalline diamond interface was between 0.0042 and 0.0244, depending on the sliding direction and the temperature. Generally, the friction coefficient was lowest when a graphene flake was sliding along its armchair direction and the highest when it was sliding along its zigzag direction. The friction coefficient increased by up to 20% when the temperature rose from 300 K to 600 K, hence a contribution from temperature cannot be neglected. The findings in this study validate the super-lubricity between graphene and diamond and will shed light on understanding the mechanical behavior of graphene nanodevices when using single crystalline diamond as the substrate.

Academic Career Progression of Chinese-Origin Pharmacy Faculty Members in Western Countries.

Background: The field of Pharmacy education is experiencing a paucity of underrepresented minorities (URMs) faculty worldwide. The aim of this study is to investigate the current professional status of Chinese-origin pharmacy faculty members, who are considered as a good model of URMs at pharmacy academia in western countries, and identify the influencing factors to their academic career progression in academic careers. Methods: An online questionnaire was sent to Chinese-origin academic staffs at pharmacy schools in US, UK, Canada, Australia, and New Zealand. The survey comprised demographic information, educational background, and the influencing factors to academic career progression. Results: The vast majority of Chinese faculty members who worked in US were male. Individuals with junior academic title comprised the largest proportion. Over 75% of Chinese-origin pharmacy academics were involved in scientific disciplines (e.g., pharmaceutics, pharmacology, and medicinal chemistry). Usually, Chinese-origin academic members spent 4 years obtaining their first academic jobs after finishing PhD degree, and need 5⁻6 years to get academic promotion. The contributing factors of academic promotion were high quality publications and external funding. Conclusion: Our research offers a deep insight into academic career progression for URMs and give some valuable advice for their pharmacy academic paths.

Analysis of the Literature and Patents on Solid Dispersions from 1980 to 2015.

Background: Solid dispersions are an effective formulation technique to improve the solubility, dissolution rate, and bioavailability of water-insoluble drugs for oral delivery. In the last 15 years, increased attention was focused on this technology. There were 23 marketed drugs prepared by solid dispersion techniques. Objective: This study aimed to report the big picture of solid dispersion research from 1980 to 2015. Method: Scientific knowledge mapping tools were used for the qualitative and the quantitative analysis of patents and literature from the time and space dimensions. Results: Western Europe and North America were the major research areas in this field with frequent international cooperation. Moreover, there was a close collaboration between universities and industries, while research collaboration in Asia mainly existed between universities. The model drugs, main excipients, preparation technologies, characterization approaches and the mechanism involved in the formulation of solid dispersions were analyzed via the keyword burst and co-citation cluster techniques. Integrated experimental, theoretical and computational tools were useful techniques for in silico formulation design of the solid dispersions. Conclusions: Our research provided the qualitative and the quantitative analysis of patents and literature of solid dispersions in the last three decades.

Big data analysis of global advances in pharmaceutics and drug delivery 1980-2014.

This review provides a comprehensive perspective of the global research advances and frontiers in pharmaceutics from 1980 to 2014. Furthermore, a historical view and future prospects of drug delivery are discussed.

Research Advances in Molecular Modeling in Cyclodextrins.

BACKGROUND: Cyclodextrins (CDs), as one type of the novel pharmaceutical excipients, have been widely used in drug delivery and pharmaceutical industry. Over the past decades, a large amount of molecular modeling studies in CDs were reported for profound understanding of structural, dynamic and energetic features of CDs systems. Thus, this review is focused on qualitative and quantitative analysis of research outputs on molecular modeling in CDs. METHODS: The original data were collected from Web of Science and analyzed by scientific knowledge mapping tools, including Citespace, Science of Science, VOSviewer, GPSvisualizer and Gephi software. Scientific knowledge mapping, as an emerging approach for literature analysis, was employed to identify the knowledge structure and capture the development of the science in a visual way. RESULTS: The results of analysis included research outputs landscape, collaboration patterns, knowledge structure and research frontiers shift with time. China had the largest contributions to the publication number in this area, while USA dominated the high quality research outputs. International collaboration between USA and Europe was much stronger than that within Asia. J American Chemical Society, as one of the most important journals, played a pivotal role in linking different research fields. Furthermore, seven important thematic clusters were identified by the research cluster analysis with visualization tools and demonstrated from three different perspectives including: (1) the mostly-used CD molecules: ß-Cyclodextrin, (2) preferred modeling tools: docking calculation and molecular dynamic, (3) hot research fields: structural properties, solubility, chiral recognition and solidstate inclusion complexes. Moreover, research frontier shift in the past three decades was traced by detecting keywords bursts with high citation. CONCLUSION: The current review provided us a macro-perspective and intellectual landscape to molecular modeling in CDs.

Cell-Derived Extracellular Matrix: Basic Characteristics and Current Applications in Orthopedic Tissue Engineering.

The extracellular matrix (ECM) is a dynamic and intricate microenvironment with excellent biophysical, biomechanical, and biochemical properties, which can directly or indirectly regulate cell proliferation, adhesion, migration, and differentiation, as well as plays key roles in homeostasis and regeneration of tissues and organs. The ECM has attracted a great deal of attention with the rapid development of tissue engineering in the field of regenerative medicine. Tissue-derived ECM scaffolds (also referred to as decellularized tissues and whole organs) are considered a promising therapy for the repair of musculoskeletal defects, including those that are widely used in orthopedics, although there are a few shortcomings. Similar to tissue-derived ECM scaffolds, cell-derived ECM scaffolds also have highly advantageous biophysical and biochemical properties, in particular their ability to be produced in vitro from a number of different cell types. Furthermore, cell-derived ECM scaffolds more closely resemble native ECM microenvironments. The products of cell-derived ECM have a wide range of biomedical applications; these include reagents for cell culture substrates and biomaterials for scaffolds, hybrid scaffolds, and living cell sheet coculture systems. Although cell-derived ECM has only just begun to be investigated, it has great potential as a novel approach for cell-based tissue repair in orthopedic tissue engineering. This review summarizes and analyzes the various types of cell-derived ECM products applied in cartilage, bone, and nerve tissue engineering in vitro or in vivo and discusses future directions for investigation of cell-derived ECM.