Cellular metabolomics study of the antitumor mechanism of Sijunzi decoction combined with mitomycin C.

Mitomycin C (MMC) has an antitumor effect and is considered as a broad-spectrum antibiotic. Sijunzi Decoction (SJZD), a well-known ancient Chinese prescription, is widely used in the treatment of cancer when combined with chemotherapy drugs. Studies have shown that SJZD can be combined with other drugs to enhance the therapeutic effect against cancer and inhibit the toxicity of chemotherapy drugs, but the specific mechanism is not clear. Thus, we hope to further explore the antitumor mechanism of combined SJZD and MMC. 3-(4,5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide assay, flow cytometry, western blot, 1H NMR and HPLC-MS were used to study the mechanism at the cellular level. The results show that the combined administration can have a more significant effect on inhibiting the proliferation of cancer cells, promoting their apoptosis. Based on metabolomics, 38 biomarkers were found in the MMC group and 43 biomarkers were found in the combined administration group. Among them, 18 unique biomarkers were discovered in the combined administration group. Studies have shown that the antitumor mechanism of combined administration is related to amino acid metabolism, energy metabolism, lipid metabolism and nucleotide metabolism, among which amino acid metabolism is the most important. In addition, SJZD achieves the effect of toxin reduction and efficiency enhancement by improving the body's immunity and improving the oxidative stress environment.

Auxins and Cytokinins-The Role of Subcellular Organization on Homeostasis.

Plant hormones are master regulators of plant growth and development. Better knowledge of their spatial signaling and homeostasis (transport and metabolism) on the lowest structural levels (cellular and subcellular) is therefore crucial to a better understanding of developmental processes in plants. Recent progress in phytohormone analysis at the cellular and subcellular levels has greatly improved the effectiveness of isolation protocols and the sensitivity of analytical methods. This review is mainly focused on homeostasis of two plant hormone groups, auxins and cytokinins. It will summarize and discuss their tissue- and cell-type specific distributions at the cellular and subcellular levels.

Advancements in transdermal drug delivery: A comprehensive review of physical penetration enhancement techniques.

Transdermal drug administration has grown in popularity in the pharmaceutical research community due to its potential to improve drug bioavailability, compliance among patients, and therapeutic effectiveness. To overcome the substantial barrier posed by the stratum corneum (SC) and promote drug absorption within the skin, various physical penetration augmentation approaches have been devised. This review article delves into popular physical penetration augmentation techniques, which include sonophoresis, iontophoresis, magnetophoresis, thermophoresis, needle-free injection, and microneedles (MNs) Sonophoresis is a technique that uses low-frequency ultrasonic waves to break the skin's barrier characteristics, therefore improving drug transport and distribution. In contrast, iontophoresis uses an applied electric current to push charged molecules of drugs inside the skin, effectively enhancing medication absorption. Magnetophoresis uses magnetic fields to drive drug carriers into the dermis, a technology that has shown promise in aiding targeted medication delivery. Thermophoresis is the regulated heating of the skin in order to improve drug absorption, particularly with thermally sensitive drug carriers. Needle-free injection technologies, such as jet injectors (JIs) and microprojection arrays, offer another option by producing temporary small pore sizes in the skin, facilitating painless and effective drug delivery. MNs are a painless, minimally invasive method, easy to self-administration, as well as high drug bioavailability. This study focuses on the underlying processes, current breakthroughs, and limitations connected with all of these approaches, with an emphasis on their applicability in diverse therapeutic areas. Finally, a thorough knowledge of these physical enhancement approaches and their incorporation into pharmaceutical research has the potential to revolutionize drug delivery, providing more efficient and secure treatment choices for a wide range of health-related diseases.

Conformational Space Profiling Enhances Generic Molecular Representation for AI-Powered Ligand-Based Drug Discovery.

The molecular representation model is a neural network that converts molecular representations (SMILES, Graph) into feature vectors, and is an essential module applied across a wide range of artificial intelligence-driven drug discovery scenarios. However, current molecular representation models rarely consider the three-dimensional conformational space of molecules, losing sight of the dynamic nature of small molecules as well as the essence of molecular conformational space that covers the heterogeneity of molecule properties, such as the multi-target mechanism of action, recognition of different biomolecules, dynamics in cytoplasm and membrane. In this study, a new model named GeminiMol is proposed to incorporate conformational space profiles into molecular representation learning, which extracts the feature of capturing the complicated interplay between the molecular structure and the conformational space. Although GeminiMol is pre-trained on a relatively small-scale molecular dataset (39290 molecules), it shows balanced and superior performance not only on 67 molecular properties predictions but also on 73 cellular activity predictions and 171 zero-shot tasks (including virtual screening and target identification). By capturing the molecular conformational space profile, the strategy paves the way for rapid exploration of chemical space and facilitates changing paradigms for drug design.

The effect of magnetic fields on tumor occurrence and progression: Recent advances.

Malignancies are the leading human health threat worldwide. Despite rapidly developing treatments, poor prognosis and outcome are still common. Magnetic fields have shown good anti-tumoral effects both in vitro and in vivo, and represent a potential non-invasive treatment; however, the specific underlying molecular mechanisms remain unclear. We here review recent studies on magnetic fields and their effect on tumors at three different levels: organismal, cellular, and molecular. At the organismal level, magnetic fields suppress tumor angiogenesis, microcirculation, and enhance the immune response. At the cellular level, magnetic fields affect tumor cell growth and biological functions by affecting cell morphology, cell membrane structure, cell cycle, and mitochondrial function. At the molecular level, magnetic fields suppress tumors by interfering with DNA synthesis, reactive oxygen species level, second messenger molecule delivery, and orientation of epidermal growth factor receptors. At present, scientific experimental evidence is still lacking; therefore, systematic studies on the biological mechanisms involved are urgently needed for the future application of magnetic fields to tumor treatment.

A Neurorobotic Embodiment for Exploring the Dynamical Interactions of a Spiking Cerebellar Model and a Robot Arm During Vision-Based Manipulation Tasks.

While the original goal for developing robots is replacing humans in dangerous and tedious tasks, the final target shall be completely mimicking the human cognitive and motor behavior. Hence, building detailed computational models for the human brain is one of the reasonable ways to attain this. The cerebellum is one of the key players in our neural system to guarantee dexterous manipulation and coordinated movements as concluded from lesions in that region. Studies suggest that it acts as a forward model providing anticipatory corrections for the sensory signals based on observed discrepancies from the reference values. While most studies consider providing the teaching signal as error in joint-space, few studies consider the error in task-space and even fewer consider the spiking nature of the cerebellum on the cellular-level. In this study, a detailed cellular-level forward cerebellar model is developed, including modeling of Golgi and Basket cells which are usually neglected in previous studies. To preserve the biological features of the cerebellum in the developed model, a hyperparameter optimization method tunes the network accordingly. The efficiency and biological plausibility of the proposed cerebellar-based controller is then demonstrated under different robotic manipulation tasks reproducing motor behavior observed in human reaching experiments.

A high-precision micropipette sensor for cellular-level real-time thermal characterization.

We report herein development of a novel glass micropipette thermal sensor fabricated in a cost-effective manner, which is capable of measuring steady thermal fluctuation at spatial resolution of ∼2 µm with an accuracy of ±0.01 °C. We produced and tested various micrometer-sized sensors, ranging from 2 µm to 30 µm. The sensor comprises unleaded low-melting-point solder alloy (Sn-based) as a core metal inside a pulled borosilicate glass pipette and a thin film of nickel coating outside, creating a thermocouple junction at the tip. The sensor was calibrated using a thermally insulated calibration chamber, the temperature of which can be controlled with an accuracy of ±0.01 °C, and the thermoelectric power (Seebeck coefficient) of the sensor was recorded from 8.46 to 8.86 µV/°C. We have demonstrated the capability of measuring temperatures at a cellular level by inserting our temperature sensor into the membrane of a live retinal pigment epithelium cell subjected to a laser beam with a focal spot of 6 µm. We measured transient temperature profiles and the maximum temperatures were in the range of 38-55 ± 0.5 °C.

Appendage regeneration is context dependent at the cellular level.

Species that can regrow their lost appendages have been studied with the ultimate aim of developing methods to enable human limb regeneration. These examinations highlight that appendage regeneration progresses through shared tissue stages and gene activities, leading to the assumption that appendage regeneration paradigms (e.g. tails and limbs) are the same or similar. However, recent research suggests these paradigms operate differently at the cellular level, despite sharing tissue descriptions and gene expressions. Here, collecting the findings from disparate studies, I argue appendage regeneration is context dependent at the cellular level; nonetheless, it requires (i) signalling centres, (ii) stem/progenitor cell types and (iii) a regeneration-permissive environment, and these three common cellular principles could be more suitable for cross-species/paradigm/age comparisons.

Roadmap on Digital Holography-Based Quantitative Phase Imaging.

Quantitative Phase Imaging (QPI) provides unique means for the imaging of biological or technical microstructures, merging beneficial features identified with microscopy, interferometry, holography, and numerical computations. This roadmap article reviews several digital holography-based QPI approaches developed by prominent research groups. It also briefly discusses the present and future perspectives of 2D and 3D QPI research based on digital holographic microscopy, holographic tomography, and their applications.

Dopamine Receptor-Mediated Binding and Cellular Uptake of Polydopamine-Coated Nanoparticles.

Polydopamine (PDA)-coated nanoparticles (NPs) are emerging carriers of therapeutic agents for nanomedicine applications due to their biocompatibility and abundant entry to various cell types, yet it remains unknown whether their cellular entry engages cell-surface receptors. As monomeric dopamine (DA) is an endogenous ligand of dopamine receptor and raw ingredient of PDA, we elucidate the interaction between polyethylene glycol-stabilized, PDA-coated gold NPs (Au@PDA@PEG NPs) and dopamine receptors, particularly D2 (D2DR). After proving the binding of Au@PDA@PEG NPs to recombinant and cellular D2DR, we employ antibody blocking, gene knockdown, and gene overexpression to establish the role of D2DR in the cellular uptake of Au@PDA@PEG NPs in vitro. By preparing a series of PEG-coated AuNPs that contain different structural analogues of DA (Au@PEG-X NPs), we demonstrate that catechol and amine groups collectively enhance the binding of NPs to D2DR and their cellular uptake. By intravenously injecting Au@PDA@PEG NPs to Balb/c mice, we reveal their in vivo binding to D2DR in the liver by competitive inhibition and immunohistochemistry together with their preferential association to D2DR-rich resident Kupffer cells by flow cytometry, a result consistent with the profuse expression of D2DR by resident Kupffer cells. Catechol and amine groups jointly contribute to the preferential association of NPs to D2DR-rich Kupffer cells. Our data highlight the importance of D2DR expression and DA-related functional groups in mediating the cell-nano interactions of PDA-based nanomedicines.

Cellular activity in insular cortex across seconds to hours: Sensations and predictions of bodily states.

Our wellness relies on continuous interactions between our brain and body: different organs relay their current state to the brain and are regulated, in turn, by descending visceromotor commands from our brain and by actions such as eating, drinking, thermotaxis, and predator escape. Human neuroimaging and theoretical studies suggest a key role for predictive processing by insular cortex in guiding these efforts to maintain bodily homeostasis. Here, we review recent studies recording and manipulating cellular activity in rodent insular cortex at timescales from seconds to hours. We argue that consideration of these findings in the context of predictive processing of future bodily states may reconcile several apparent discrepancies and offer a unifying, heuristic model for guiding future work.

Recent advances in drug delivery systems for targeting cancer stem cells.

Cancer stem cells (CSCs) are a subpopulation of cancer cells with functions similar to those of normal stem cells. Although few in number, they are capable of self-renewal, unlimited proliferation, and multi-directional differentiation potential. In addition, CSCs have the ability to escape immune surveillance. Thus, they play an important role in the occurrence and development of tumors, and they are closely related to tumor invasion, metastasis, drug resistance, and recurrence after treatment. Therefore, specific targeting of CSCs may improve the efficiency of cancer therapy. A series of corresponding promising therapeutic strategies based on CSC targeting, such as the targeting of CSC niche, CSC signaling pathways, and CSC mitochondria, are currently under development. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for CSC targeting are increasingly being developed. In this review, we summarize the advances in CSC-targeted DDSs. Furthermore, we highlight the latest developmental trends through the main line of CSC occurrence and development process; some considerations about the rationale, advantages, and limitations of different DDSs for CSC-targeted therapies were discussed.

A novel method to investigate the effects of gene mutations at the cellular level using a dual expression lentiviral vector.

One of the conventional methods to study the effects of gene mutations is that gene mutants are transfected into mammalian cells, and the dominant effects of gene mutants in the cells are examined. However, the result obtained using this method is not always satisfactory due to the interference of endogenous expression. Whether there is a better method to investigate the effects of gene mutations in cells remains to be examined. In the present study, a novel dual expression lentiviral vector was constructed using a shRNA-expressing lentiviral vector and combined techniques. Using this dual expression system, the vectors expressing both transcription factor IIA γ (TFIIAγ) shRNA and HA-TFIIAγ or its mutants were generated, and the effects of TFIIAγ gene mutations on transcription and protein-DNA interaction were investigated. We show that the transfection of the vector expressing TFIIAγ shRNA and HA-TFIIAγ fusion gene was able to silence the expression of endogenous TFIIAγ gene but not affect that of exogenous HA-TFIIAγ fusion gene in either transiently transfected cells or stable cell lines. Mutations in the conservative domain between AA62 and AA69 in TFIIAγ inhibit the activities of promoters and endogenous gene expression, and reduce TFIIAγ binding to AdML core promoter compared with wild-type (WT) TFIIAγ. ChIP-qPCR data suggest that the TFIIAγ N63A mutant inhibits insulin-like growth factor 2 (IGF2) transcription by reducing the recruitments of TFIIAγ, polymerase II (Pol II), TATA box-binding protein (TBP), and TBP associated factor 1 (250 kDa) (TAF1) at its promoter. Our study provides a novel method that is used to investigate the effects of gene mutations at the cellular level.

Intrapulmonary Cellular-Level Distribution of Inhaled Nanoparticles with Defined Functional Groups and Its Correlations with Protein Corona and Inflammatory Response.

Concerns over the health risks associated with airborne exposure to ultrafine particles [PM0.1, or nanoparticles (NPs)] call for a comprehensive understanding in the interactions of inhaled NPs along their respiratory journey. We prepare a collection of polyethylene glycol-coated gold nanoparticles that bear defined functional groups commonly identified in atmospheric particulates (Au@PEG-X NPs, where X = OCH3, COOH, NH2, OH, or C12H25). Regardless of the functional group, these ∼50 nm NPs remain colloidally stable following aerosolization and incubation in bronchoalveolar lavage fluid (BALF), without pronouncedly crossing the air-blood barrier. The type of BALF proteins adhered onto the NPs is similar, but the composition of protein corona depends on functional group. By subjecting Balb/c mice to inhalation of Au@PEG-X NPs for 6 h, we demonstrate that the intrapulmonary distribution of NPs among the various types of cells (both found in BALF and isolated from the lavaged lung) and the acute inflammatory responses induced by inhalation are sensitive to the functional group of NPs and postinhalation period (0, 24, or 48 h). By evaluating the pairwise correlations between the three variables of "lung-nano" interactions (protein corona, intrapulmonary cellular-level distribution, and inflammatory response), we reveal strong statistical correlations between the (1) fractions of albumin or carbonyl reductase bound to NPs, (2) associations of inhaled NPs to neutrophils in BALF or macrophages in the lavaged lung, and (3) level of total protein in BALF. Our results provide insights into the effect of functional group on lung-nano interactions and health risks associated with inhalation of PM0.1.

Synthesis, characterization and biological activities of imidazo[1,2-a]pyridine based gold(III) metal complexes.

Five imidazo [1,2-a]pyridine derivatives and their Au(III) complexes were synthesized. The compounds were characterized by 1H-NMR, 13C-NMR, IR, mass, UV-visible, elemental analysis, conductivity and magnetic measurement studies. All the compounds were screened for diverse biological activities to check the effect of coordination of Au(III) with imidazo [1,2-a]pyridine heterocycles. The DNA interaction ability of compounds were studied as the change in absorption maxima and position of HS-DNA in presence of compounds and viscosity measurement due to change in DNA length under the influence of compounds. The computational insight of compound-DNA interaction was taken in docking study. All the results suggest intercalation mode of binding. The cellular level cytotoxic nature of compounds was evaluated using trypan blue dye staining of dead cell in cell viability assay. The smearing of DNA was observed, while DNA extracted from S. pombe cells in presence of complexes was subjected to gel electrophoresis, which shows their toxic effect on DNA. The complexes were evaluated for cytotoxicity on human A549 (Lung adenocarcinoma) cell line by MTT assay (IC50 values). The in vitro cytotoxicity in terms of LC50 value was checked on a simple zoological organism, brine shrimp.

Introgression of Physiological Traits for a Comprehensive Improvement of Drought Adaptation in Crop Plants.

Burgeoning population growth, industrial demand, and the predicted global climate change resulting in erratic monsoon rains are expected to severely limit fresh water availability for agriculture both in irrigated and rainfed ecosystems. In order to remain food and nutrient secure, agriculture research needs to focus on devising strategies to save water in irrigated conditions and to develop superior cultivars with improved water productivity to sustain yield under rainfed conditions. Recent opinions accruing in the scientific literature strongly favor the adoption of a "trait based" crop improvement approach for increasing water productivity. Traits associated with maintenance of positive tissue turgor and maintenance of increased carbon assimilation are regarded as most relevant to improve crop growth rates under water limiting conditions and to enhance water productivity. The advent of several water saving agronomic practices notwithstanding, a genetic enhancement strategy of introgressing distinct physiological, morphological, and cellular mechanisms on to a single elite genetic background is essential for achieving a comprehensive improvement in drought adaptation in crop plants. The significant progress made in genomics, though would provide the necessary impetus, a clear understanding of the "traits" to be introgressed is the most essential need of the hour. Water uptake by a better root architecture, water conservation by preventing unproductive transpiration are crucial for maintaining positive tissue water relations. Improved carbon assimilation associated with carboxylation capacity and mesophyll conductance is important in sustaining crop growth rates under water limited conditions. Besides these major traits, we summarize the available information in literature on classifying various drought adaptive traits. We provide evidences that Water-Use Efficiency when introgressed with moderately higher transpiration, would significantly enhance growth rates and water productivity in rice through an improved photosynthetic capacity.

Corrigendum: Introgression of Physiological Traits for a Comprehensive Improvement of Drought Adaptation in Crop Plants.

[This corrects the article DOI: 10.3389/fchem.2018.00092.].

Development of a Surrogate Neutralization Assay for Norovirus Vaccine Evaluation at the Cellular Level.

Noroviruses (NoVs) are the main pathogens responsible for sporadic and epidemic nonbacterial gastroenteritis, causing an estimated 219,000 deaths annually worldwide. There is no commercially available vaccine for NoVs, due partly to the difficulty in establishing NoV cell culture models. The histo-blood group antigen (HBGA) blocking assay is used extensively to assess the protective potential of candidate vaccine-elicited antibodies, but there is still no widely used cellular evaluation model. In this study, we have established a cell line-based NoV vaccine evaluation model through the construction of human α1,2-fucosyltransferase 2-overexpressing 293T (293T-FUT2) cell lines. The 293T-FUT2 cells stably expressed H type 2 and Lewis y antigens. Virus-like particles (VLPs) of the NoV prototype strain genogroup I.1 (GI.1) and the predominant strains GII.4 and GII.17 could attach to the cell line efficiently in a dose-dependent manner. Importantly, antisera against these NoV VLPs could inhibit the attachment of the VLPs, where the inhibitory effects measured by the attachment inhibition assay correlated significantly with the antibody levels determined by the HBGA blocking assay. Collectively, our attachment inhibition assay could serve as a surrogate neutralization assay for the evaluation of NoV vaccines at the cellular level.

Evolution of 1, 3, 5-trisubstituted bipyrazole scaffold based platinum(II) complexes as a biological active agent.

Square planar mononuclear platinum(II) complexes having general formula [Pt(Ln)Cl2], (where, Ln = L1-4) were synthesized with neutral bidentate heterocyclic 1,3,5-trisubstituted bipyrazole based ligands. The synthesized compounds were characterized by physicochemical method such as TGA, molar conductance, micro-elemental analysis and magnetic moment, and spectroscopic method such as, FT-IR, UV-vis, 1H NMR, 13C NMR and mass spectrometry. Biological applications of the compounds were carried out using in vitro brine shrimp lethality bioassay, in vitro antimicrobial study against five different pathogens, and cellular level cytotoxicity against Schizosaccharomyces pombe (S. Pombe) cells. Pt(II) complexes were tested for DNA interaction activities using electronic absorption titration, viscosity measurements study, fluorescence quenching technique and molecular docking assay. Binding constants (Kb) of ligands and complexes were observed in the range of 0.23-1.07 × 105 M-1 and 0.51-3.13 × 105 M-1, respectively. Pt(II) complexes (I-IV) display an excellent binding tendency to biomolecule (DNA) and possess comparatively high binding constant (Kb) values than the ligands. The DNA binding study indicate partial intercalative mode of binding in complex-DNA. The gel electrophoresis activity was carried out to examine DNA nuclease property of pUC19 plasmid DNA.