Allosteric SHP2 inhibition enhances regorafenib's effectiveness in colorectal cancer treatment.

Colorectal cancer (CRC) is the third most common cancer globally. Regorafenib, a multi-target kinase inhibitor, has been approved for treating metastatic colorectal cancer patients who have undergone at least two prior standard anti-cancer therapies. However, regorafenib efficacy as a single agent remains suboptimal. A promising target at the crossroads of multiple signaling pathways is the Src homology 2 domain-containing protein tyrosine phosphatase (SHP2). However, a combination approach using SHP2 inhibitors (SHP099) and anti-angiogenic drugs (Regorafenib) has not been reported in current research. In this study, we conducted in vitro experiments combining SHP099 and regorafenib and established an MC-38 colon cancer allograft mouse model. Our results revealed that co-treatment with SHP099 and regorafenib significantly inhibited cell viability and altered the biological characteristics of tumor cells compared with treatment alone in vitro. Furthermore, the combination strategy demonstrated superior therapeutic efficacy compared to monotherapy with either drug. This was evidenced by reduced tumor size, decreased proliferation, increased apoptosis, normalized tumor microvasculature, and improved antitumor immune response in vivo. These findings suggest that the combination of an SHP2 inhibitor and regorafenib is a promising therapeutic approach for patients with colorectal cancer.

Wide-Field and Real-Time Super-Resolution Optical Imaging By Titanium Dioxide Nanoparticle-Assembled Solid Immersion Lens.

Super-resolution optical imaging techniques can break the optical diffraction limit, thus providing unique opportunities to visualize the microscopic world at the nanoscale. Although near-field optical microscopy techniques have been proven to achieve significantly improved imaging resolution, most near-field approaches still suffer from a narrow field of view (FOV) or difficulty in obtaining wide-field images in real time, which may limit their widespread and diverse applications. Here, the authors experimentally demonstrate an optical microscope magnification and image enhancement approach by using a submillimeter-sized solid immersion lens (SIL) assembled by densely-packed 15 nm TiO2 nanoparticles through a silicone oil two-step dehydration method. This TiO2 nanoparticle-assembled SIL can achieve both high transparency and high refractive index, as well as sufficient mechanical strength and easy-to-handle size, thus providing a fast, wide-field, real-time, non-destructive, and low-cost solution for improving the quality of optical microscopic observation of a variety of samples, including nanomaterials, cancer cells, and living cells or bacteria under conventional optical microscopes. This study provides an attractive alternative to simplify the fabrication and applications of high-performance SILs.

Jasmonate-based warfare between the pathogenic intruder and host plant: who wins?

Plants and microbial pathogens often engage in a fierce war that determines their survival. Host plants have evolved sophisticated regulatory mechanisms to fine-tune defense responses to counter attacks from pathogens, while pathogens often hijack the lipid-derived phytohormone jasmonate to cause hormonal signaling imbalances for efficient infection. This review focuses on the jasmonate-based warfare between host plants and pathogenic intruders, and further discusses approaches to uncouple plant growth and defense tradeoffs in crop breeding.

Simultaneous trapping of high and low refractive index particles using a single-fiber optical trap with coexisting LP01 and LP11 modes.

We propose and demonstrate a fiber optical trap based on the coexistence of LP01 and LP11 modes for the simultaneous trapping of both high refractive index particles and low refractive index particles. Since different mode beams have different propagation constants, they exhibit different focused light fields. We fabricated a tapered fiber probe using thermal fusion to converge the beam, which generates a strong gradient force field near the fiber tip, as well as a dark trap along the axial direction. High refractive index particles are attracted near the fiber tip by a strong gradient force, and low refractive index particles are trapped in the dark cage along the axial direction. The proposed optical trap, which can simultaneously trap particles with different refractive indices, makes it easier to manipulate cells or molecules with different properties and explore multi-molecule interactions, which can facilitate research related to biology and chemistry.

Nanovibration detection based on a microsphere.

We propose a novel, to the best of our knowledge, sensor for nanovibration detection based on a microsphere. The sensor consists of a stretched single-mode fiber and a 2 µm microsphere. The light from the optical fiber passes through the microsphere, forming a photonic nanojet (PNJ) phenomenon at the front of the microsphere. The evanescent field in the PNJ enhances the light reflected from the measured object to the single-mode fiber-microsphere probe (SMFMP). Results showed that the system can detect arbitrary nanovibration waveforms in real time with an SMFMP detection resolution of 1 nm. The voltage signal received and the vibration amplitude showed a good linear relationship within the range of 0-100 nm, with a sensitivity of 0.7 mV/nm and a linearity of more than 99%. The sensor is expected to have potential applications in the field of cell nanovibration detection.

Microsphere-assisted Fabry-Perot interferometry: proof of concept.

We propose a microsphere-assisted Fabry-Perot interferometry (MAFPI) for microstructure measurement. We stretch the single-mode fiber and combine it with microspheres of different sizes and refractive indices, which can form super-focused spots with different characteristics, that is, a photonic nanojet phenomenon. As a proof of principle, we performed scanning imaging of optical discs and holographic gratings by MAFPI. The optical disc image obtained by MAFPI is consistent with the result obtained by a scanning electron microscope, and the obtained grating image is consistent with the actual result.

[Role of ferroptosis in cerebellar injury of mice following lead exposure].

OBJECTIVE: To investigate the role of ferroptosis in cerebellar injury of mice following lead exposure. METHODS: A total of forty SPF C57 mice were randomly divided into control group, low-dose lead exposure group, middle-dose lead exposure group and high-dose lead exposure group, with 10 mice in each group. Mice in three lead exposure groups were given 0.25, 0.50, 1.00 g/L lead acetate through drinking water for twelve weeks respectively. Lead concentration was detected by inductively coupled plasma mass spectrometer. The motor function was detected by beam walking test and open field test. Pathological changes of cerebellum in mice were observed by H&E staining. Western blotting was used to detect the protein expression of transferrin receptor-1(TFR-1), ferroportin(FPN-1), solute carrier family 7 member 11(SLC7 A11), glutathione peroxidase 4(GPX4), NF-E2-related factor 2(Nrf2) and heme oxygenase-1(HO-1). RESULTS: The lead concentration in cerebellum of mice in low lead group, medium lead group and high lead group were(1.05±0.11), (1.21±0.10) and(1.48±0.1) µg/g, respectively, which were significantly higher than that in the control group. The time to traverse the beam in low lead group, medium lead group and high lead group was 1.34, 1.64 and 2.02 folds of that in control group, respectively. Open field test showed that the central residence time and standing times of mice in low lead group, medium lead group and high lead group were significantly lower than that in control. Purkinje cells in the cerebellum of mice exposed to different doses of lead showed irregular arrangement, small cell bodies and deep staining, especially in the high lead group. The relative levels of iron in low lead group, medium lead group and high lead group was 1.77, 2.29 and 3.77 folds of that in control group, respectively. The content of MDA in cerebellum of mice in three lead exposure groups increased significantly, while the GHS decreased significantly. Compared with the control group, the expression of TFR-1 protein increased significantly in the lead exposure group, while the expression of FPN-1 protein decreased significantly only in the medium lead group and high lead group, which was 60% and 50% of the control group. Compared with the control group, the expressions of oxidative stress regulatory proteins SLC7 A11 and GPX4 in medium lead group and high lead group decreased significantly. Lead exposure significantly decreased the expression of Nrf2 and HO-1 protein in cerebellum, especially in high lead group. CONCLUSION: In this experiment condition, lead may induce ferroptosis in cerebellum of mice, of which, Nrf2/HO-1 signaling pathway might be involved in, and then further result in motor dysfunction of mice.

Solid-phase total synthesis and structural confirmation of antimicrobial longicatenamide A.

Longicatenamides A-D are cyclic hexapeptides isolated from the combined culture of Streptomyces sp. KUSC_F05 and Tsukamurella pulmonis TP-B0596. Because these peptides are not detected in the monoculture broth of the actinomycete, they are key tools for understanding chemical communication in the microbial world. Herein, we report the solid-phase total synthesis and structural confirmation of longicatenamide A. First, commercially unavailable building blocks were chemically synthesized with stereocontrol. Second, the peptide chain was elongated via Fmoc-based solid-phase peptide synthesis. Third, the peptide chain was cyclized in the solution phase, followed by simultaneous cleavage of all protecting groups to afford longicatenamide A. Chromatographic analysis corroborated the chemical structure of longicatenamide A. Furthermore, the antimicrobial activity of synthesized longicatenamide A was confirmed. The developed solid-phase synthesis is expected to facilitate the rapid synthesis of diverse synthetic analogues.

Runout tracking in gear motors using a microsensor based on all-fiber Fabry-Perot interferometry.

A novel radial runout measurement method for gear motors using a microsensor based on all-fiber Fabry-Perot interferometry is investigated. In order to achieve the fault diagnosis, in this method, a single-mode fiber is put forward as a sensor to measure radial runout of the rotating shaft. The performance of the proposed sensor has been compared to a Portable Digital Vibrometer-100 laser vibrometer for validation purposes, and the results show that the difference between them is approximately ±0.55µm.

A cross-sectional survey of preschool children: Exploring heavy metal exposure, neurotransmitters, and neurobehavioural relationships and mediation effects.

BACKGROUND: Exposure to heavy metals has been considered harmful and can cause cognitive deficits in preschool children. OBJECTIVE: To investigate the possible mediation effect of neurotransmitters on the relationship of heavy metal exposure with neurobehaviour. METHODS: The levels of blood heavy metals and neurotransmitters, along with the neurobehavioural scores, were determined in preschool children. Multiple linear regression was used to assess the relationship between heavy metals, neurotransmitters, and neurobehavioural scores. Furthermore, the mediating role of neurotransmitters was investigated. RESULTS: An interquartile range (IQR) increase in lead (6.10 µg/L) was associated with a decrease of 8.52%, 30.06%, and 20.10% for Glutamic acid (Glu), Glycine (Gly), and gamma-aminobutyric acid (GABA), respectively. An IQR increase in arsenic (19.37 µg/L) was associated with an increase of 6.32% and 2.09% for Gly and GABA, respectively. Further, an IQR increase in zinc (15.58 µg/L) was associated with an increase of 1.44% for Ser, whereas the IQR increase was associated with a decrease of 2.14%, 2.24%, and 1.89% for Glu, Gly, and GABA, respectively. An IQR increase in selenium (38.75 µg/L) was associated with an increase of 1.88% for GABA. Moreover, both Glu and Gly decreased by 2.87% for an IQR increase in manganese (16.92 µg/L). An IQR increase in mercury (15.22 µg/L) was associated with a decrease of 2.43% for Ser, but the IQR increase was associated with an increase of 4.99% and 3.09% for Gly and GABA, respectively. It was found that Glu and Serine (Ser) have a significant linear relationship with conduct score and impulsivity-hyperactivity index, and that there was a significant linear relationship between Ser and the learning disability index. GABA and conduct score and attention-deficit hyperactivity disorder (ADHD) index have a significant linear relationship. There is a significant linear relationship between Gly and conduct, anxiety, ADHD, and impulsivity-hyperactivity index. The results of the mediating effect analysis indicated that Ser, Glu, Gly, and GABA have a specific mediating effect between blood heavy metals and neurobehaviour. CONCLUSION: We showed the mediating effect of neurotransmitters. The current study may provide valuable information regarding the prevention and management of metal-related neurological disorders in preschool children.

Andrographolide sensitizes Hep-2 human laryngeal cancer cells to carboplatin-induced apoptosis by increasing reactive oxygen species levels.

Andrographolide is a natural diterpenoid from Andrographis paniculata that has been proposed as an anticancer agent as well as a chemosensitizer for use in combination with anticancer drugs. Carboplatin is the first-line chemotherapeutic agent for advanced laryngeal carcinoma. However, the clinical efficacy of carboplatin is limited by drug resistance and side effects. The aim of this study was to investigate whether andrographolide has a synergistic antitumor effect with carboplatin on human laryngeal cancer cells. Hep-2 cells were exposed to andrographolide with or without carboplatin. The effects of indicated therapies were examined using the Cell Counting Kit-8 assay, the colony-forming assay, the Hoechst 33342/PI double staining, and flow cytometry analysis. The molecular mechanism was assessed by reactive oxygen species (ROS) detection and western blot. At the sublethal concentration, andrographolide increased carboplatin sensitivity of Hep-2 cells by increasing carboplatin-induced apoptosis and inhibiting cell viability. Moreover, we found that andrographolide sensitized carboplatin mainly through the induction of ROS generation and apoptotic signaling. Taken together, these results indicate that andrographolide, along with carboplatin, synergistically inhibited cell proliferation and induced mitochondrial apoptosis of Hep-2 cells by increasing the intracellular ROS, regulating the mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3K/AKT) pathways, altering the BCL2/BAX ratio, and ultimately activating the cleavage of Caspase-3 and PARP. These results suggest that andrographolide sensitizes human laryngeal cancer cells to carboplatin-induced apoptosis by increasing ROS levels.

Three-Dimensional NiCo2O4@MnMoO4 Core-Shell Nanoarrays for High-Performance Asymmetric Supercapacitors.

Design of new materials with sophisticated nanostructure has been proven to be an efficient strategy to improve their properties in many applications. Herein, we demonstrate the successful combination of high electron conductive materials of NiCo2O4 with high capacitance materials of MnMoO4 by forming a core-shell nanostructure. The NiCo2O4@MnMoO4 core-shell nanoarrays (CSNAs) electrode possesses high capacitance of 1169 F g-1 (4.24 F cm-2) at a current density of 2.5 mA cm-2, obviously larger than the pristine NiCo2O4 electrode. The asymmetric supercapacitors (ASCs), assembled with NiCo2O4@MnMoO4 CSNAs as binder-free cathode and active carbon (AC) as anode, exhibit high energy density of 15 Wh kg-1 and high power density of 6734 W kg-1. Cycle performance of NiCo2O4@MnMoO4 CSNAs//AC ASCs, conducted at current density of 20 mA cm-2, remain 96.45% of the initial capacitance after 10,000 cycles, demonstrating its excellent long-term cycle stability. Kinetically decoupled analysis reveals that the capacitive capacitance is dominant in the total capacitance of NiCo2O4@MnMoO4 CSNAs electrode, which may be the reason for ultra long cycle stability of ASCs. Our assembled button ASC can easily light up a red LED for 30 min and a green LED for 10 min after being charged for 30 s. The remarkable electrochemical performance of NiCo2O4@MnMoO4 CSNAs//AC ASCs is attributed to its enhanced surface area, abundant electroactive sites, facile electrolyte infiltration into the 3D NiCo2O4@MnMnO4 nanoarrays and fast electron and ion transport path.

Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of alveolar architecture. IPF is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition (EMT). However, there is still a lack of strategies to target EMT for the treatment of IPF. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing pulmonary fibrosis. Here, we explored the therapeutic potential of sunitinib using a mouse model of pulmonary fibrosis. Mice received intratracheal instillation of bleomycin (BLM). Then, the mice were intragastrically administrated with sunitinib or normal saline until the end of the experiment. Distinguished destruction of pulmonary architecture, conspicuous proliferation of fibroblasts and extensive deposition of collagen fibers were found in BLM mice. Sunitinib attenuated the pulmonary fibrosis and inhibited the accumulation of fibroblasts in the lung of BLM mice. To investigate if the inhibition of fibroblast accumulation in the lung by sunitinib was associated with EMT, we used human bronchial epithelial cells (HBEs) and W138 human lung fibroblasts. Sunitinib suppressed the degree of EMT induced by TGF-ß, a profibrotic factor, in HBEs and the proliferation of WI38 fibroblasts. Moreover, sunitinib reduced the degree of phosphorylation of serine residues on Smad2/3 that was induced by TGF-ß in HBEs. As EMT and accumulation of fibroblasts are critical for the development of pulmonary fibrosis, targeting multiple pro-fibrosis signaling pathways with sunitinib may be a novel strategy to treat pulmonary fibrosis.

Self-Assembled Epitaxial Core-Shell Nanocrystals with Tunable Magnetic Anisotropy.

Epitaxial core-shell CoO-CoFe2 O4 nanocrystals are fabricated by using pulsed laser deposition with the aid of melted material (Bi2 O3 ) addition and suitable lattice mismatch provided by substrates (SrTiO3 ). Well aligned orientations among nanocrystals and reversible core-shell sequence reveal tunable magnetic anisotropy. The interfacial coupling between core and shell further engineers the nanocrystal functionality.

CPT-11 activates NLRP3 inflammasome through JNK and NF-κB signalings.

CPT-11 is widely used for cancer therapy as a chemotherapeutic agent. Despite its good efficacy, a large number of side effects appeared during decades of clinical application. Delayed diarrhea, at dose limiting toxicity, happens after 24h of treatment and the rate of occurrence is up to 90%. Although many investments have been made on this negative impact, the real molecular mechanism of delayed diarrhea is poorly understood. In this study, we have discovered that CPT-11 promotes macrophage infiltration into intestinal tissues and activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, resulting in a robust IL-1ß response and colonic inflammation similar to DSS (dextran sodium sulfate) induced experimental colitis. CPT-11 plus LPS primed mouse bone marrow-derived macrophages (BMDMs) and human acute monocytic leukemia cells (THP-1 cells) staying in a highly activated status, showing increased caspase-1 activity and releasing great amounts of IL-1ß and IL-18 as detected by ELISA and western blot. A further mechanism showed that JNK and NF-κB signaling pathways participated in inflammatory responses activated by CPT-11. These results prompted us to suggest that the NLRP3-IL-1ß signaling pathway might play an important role in CPT11-induced colitis. Our findings provide a basis for developing novel strategies that improve clinical implications of CPT-11.

MiR-124 suppresses cell motility and adhesion by targeting talin 1 in prostate cancer cells.

BACKGROUND: MicroRNA is a type of endogenous non-coding RNA implicated in various cellular processes, and has been intensely investigated in the field of cancer research for many years. Here, we investigated the functions and mechanisms of miR-124 in prostate cancer, which is a putative tumor suppressor reported in many carcinomas. METHODS: Using bioinformatics, talin 1 was indicated as a potential target of miR-124. We examined the expression levels of miR-124 and talin 1 in tissue specimens and cell lines. To explore the relationship between miR-124 and talin 1, miR-124 mimics, miR-124 inhibitors, and talin 1 small interfering RNA (siRNA) were transiently transfected into cancer cell lines, followed by analysis using luciferase reporter assays. Next, to investigate the functions of miR-124 in prostate cancer, we performed cell attachment, migration, and invasion assays. A rescue experiment was also conducted to demonstrate whether miR-124 suppressed cell adhesion and motility by targeting talin 1. Finally, we examined the related signaling pathways of miR-124 and talin 1. RESULTS: MiR-124 was down-regulated in prostate cancer specimens and cell lines, while talin 1 was over-expressed in prostate cancer specimens and cell lines. These results showed an inverse correlation of miR-124 and talin 1 expression. Similar to talin 1 siRNA, overexpression of miR-124 by transient transfection of mimics led to a significant decrease in talin 1 levels. Luciferase report assays showed that the seed sequence of the talin 1 3'-untranslated region was a target of miR-124. Functional investigations revealed anti-attachment, anti-migration, and invasion-promoting effects of miR-124 in prostate cancer cells. The rescue experiment confirmed that miR-124 exerted its biological functions by targeting talin 1. Finally, we found that miR-124 and talin 1 impaired cellular adhesion and motility through integrins and the focal adhesion kinase/Akt pathway. CONCLUSIONS: Our study demonstrated biological roles and the related mechanism of miR-124 in prostate cancer. The results indicate that talin 1 is very likely a novel player in the anti-metastatic signaling network of miR-124. By down-regulation of talin 1, miR-124 impairs the adhesion, migration, and invasion of prostate cancer cells.

Atomic-layer-deposited silver and dielectric nanostructures for plasmonic enhancement of Raman scattering from nanoscale ultrathin films.

Plasmonic silver nanostructures and a precise ZnO cover layer prepared by capacitively coupled plasma atomic layer deposition (ALD) were exploited to enhance the Raman scattering from nanoscale ultrathin films on a Si substrate. The plasmonic activity was supported by a nanostructured Ag (nano-Ag) layer, and a ZnO cover layer was introduced upon the nano-Ag layer to spectrally tailor the localized surface plasmon resonance to coincide with the laser excitation wavelength. Because of the optimized dielectric environment provided by the precise growth of ZnO cover layer using ALD, the intensity of Raman scattering from nanoscale ultrathin films was significantly enhanced by an additional order of magnitude, leading to the observation of the monoclinic and tetragonal phases in the nanoscale ZrO2 high-K gate dielectric as thin as ∼6 nm on Si substrate. The excellent agreement between the finite-difference time-domain simulation and experimental measurement further confirms the so-called [absolute value]E(->)[absolute value](4) dependence of the surface-enhanced Raman scattering. This technique of plasmonic enhancement of Raman spectroscopy, assisted by the nano-Ag layer and optimized dielectric environment prepared by ALD, can be applied to characterize the structures of ultrathin films in a variety of nanoscale materials and devices, even on a Si substrate with overwhelming Raman background.

The effects of diosgenin in the regulation of renal proximal tubular fibrosis.

Fibrosis is the important pathway for end-stage renal failure. Glucose has been demonstrated to be the most important fibrogenesis-inducing agent according to previous studies. Despite diosgenin has been demonstrated to be anti-inflammatory, the possible role in fibrosis regulation of diosgenin remain to be investigated. In this study, renal proximal tubular epithelial cells (designated as HK-2) were treated with high concentration of glucose (HG, 27.5mM) to determine whether diosgenin (0.1, 1 and 10 µM) has the effects to regulate renal cellular fibrosis. We found that 10 µM of diosgenin exert optimal inhibitory effects on high glucose-induced fibronectin expression in HK-2 cells. In addition, diosgenin markedly inhibited HG-induced increase in α-smooth muscle actin (α-SMA) and HG-induced decrease in E-cadherin. In addition, diosgenin antagonizes high glucose-induced epithelial-to-mesenchymal transition (EMT) signals partly by enhancing the catabolism of Snail in renal cells. Collectively, these data suggest that diosgenin has the potential to inhibit high glucose-induced renal tubular fibrosis possibly through EMT pathway.

Size- and support-dependent evolution of the oxidation state and structure by oxidation of subnanometer cobalt clusters.

Size-selected subnanometer cobalt clusters with 4, 7, and 27 cobalt atoms supported on amorphous alumina and ultrananocrystalline diamond (UNCD) surfaces were oxidized after exposure to ambient air. Grazing incidence X-ray absorption near-edge spectroscopy (GIXANES) and near-edge X-ray absorption fine structure (NEXAFS) were used to characterize the clusters revealed a strong dependency of the oxidation state and structure of the clusters on the surface. A dominant Co(2+) phase was identified in all samples. However, XANES analysis of cobalt clusters on UNCD showed that ∼10% fraction of a Co(0) phase was identified for all three cluster sizes and about 30 and 12% fraction of a Co(3+) phase in 4, 7, and 27 atom clusters, respectively. In the alumina-supported clusters, the dominating Co(2+) component was attributed to a cobalt aluminate, indicative of a very strong binding to the support. NEXAFS showed that in addition to strong binding of the clusters to alumina, their structure to a great extent follows the tetrahedral morphology of the support. All supported clusters were found to be resistant to agglomeration when exposed to reactive gases at elevated temperatures and atmospheric pressure.