Search Results (33)

Neuropilin-1 is henceforth a relevant target in cancer treatment; however, its way of action remains partly elusive, and the development of small inhibitory molecules is therefore required for its study. Here, we report that two small-sized neuropilin antagonists (NRPa-47 and NRPa-48), VEGF-A₁₆₅/NRP-1 binding inhibitors, are able to decrease VEGF-Rs phosphorylation and to modulate their downstream cascades in the triple-negative breast cancer cell line (MDA-MB-231). Nevertheless, NRPas exert a divergent pathway regulation of MAPK phosphorylation, such as JNK-1/-2/-3, ERK-1/-2, and p38β/γ/δ-kinases, as well as their respective downstream targets. However, NRPa-47 and NRPa-48 apply a common down-regulation of the p38α-kinase phosphorylation and their downstream targets, emphasising its central regulating role. More importantly, none of the 40 selected kinases, including SAPK2a/p38α, are affected in vitro by NRPas, strengthening their specificity. Taken together, NRPas induced cell death by the down-modulation of pro-apoptotic and anti-apoptotic proteins, cell death receptors and adaptors, heat shock proteins (HSP-27/-60/-70), cell cycle proteins (p21, p27, phospho-RAD17), and transcription factors (p53, HIF-1α). In conclusion, we showed for the first time how NRPas may alter tumour cell signalling and contribute to the down-modulation of the cancer therapeutic key factor p38α-kinase phosphorylation. Thus, the efficient association of NRPas and p38α-kinase inhibitor strengthened this hypothesis. Full article

Aromatic rice has gained significant attention due to its high economic and nutritional value. 2-Acetyl-1-pyrroline (2-AP), a key aroma compound in aromatic rice, plays a crucial role in elucidating the aroma characteristics of aromatic rice. However, there is no report on the effect of aromatic rice in rice–potato rotation on aroma characteristics. In order to study the influences of winter-planted potatoes on the yield, quality, and 2-AP biosynthesis of aromatic rice grains, the commonly cultivated aromatic rice variety Meixiangzhan-2 and the potato cultivar Huashu-5 were selected as experimental materials for a three-year consecutive field experiment with different tillage patterns consisting of rice–winter fallow as the control group (CK) and rice–potato rotation as the experimental group (RP). The results indicated that the RP treatment enhanced the soil nutrient content and decreased the bulk density. Compared with CK, RP treatment increased the effective panicle number by 10.88% and grain number per panicle by 8.82%, thereby increasing the yield by 11.99%. Meanwhile, RP treatment improved the brown rice rate by 2.61%, milled rice rate by 4.53%, head milled rice rate by 7.51%, and crude protein content by 6.98%. Regarding 2-AP biosynthesis in grains, in contrast to CK, the RP treatment raised the levels of related precursors (Δ1-pyrroline, Δ1-pyrrolidine-5-carboxylic acid, and proline increased by 8.95%, 18.14%, and 13.75%, respectively) and enzymes (proline dehydrogenase, ornithine transaminase, and diamine oxidase increased by 18.37%, 14.61%, and 11.36%, respectively) in its synthesis pathway, thereby facilitating the accumulation of 2-AP. Furthermore, we also observed a more stable yield and grain 2-AP content in aromatic rice under RP treatment. Overall, with regard to enhancing the aromatic rice yield and aroma, the rice–potato rotation system can be contemplated for vigorous promotion. Full article

Background: Boron is an essential micronutrient for plant growth and productivity, yet excessive boron leads to toxicity, posing significant challenges for agriculture. Fragrant rice is popular among consumers, but the impact of boron toxicity on qualitative traits of fragrant rice, especially aroma, remains largely unexplored. The individual potentials of melatonin and salicylic acid in reducing boron toxicity are less known, while their synergistic effects and mechanisms in fragrant rice remain unclear. Methods: Thus, this study investigates the combined application of melatonin and salicylic acid on fragrant rice affected by boron toxicity. One-week-old seedlings were subjected to boron (0 and 800 µM) and then treated with melatonin and salicylic acid (0 and 100 µM, for 3 weeks). Results: Boron toxicity significantly impaired photosynthetic pigments, plant growth, and chloroplast integrity while increasing oxidative stress markers such as hydrogen peroxide, malondialdehyde, methylglyoxal, and betaine aldehyde dehydrogenase. Likewise, boron toxicity abridged the precursors involved in the 2-acetyl-1-pyrroline (2-AP) biosynthesis pathway. However, individual as well as combined application of melatonin and salicylic acid ameliorated boron toxicity by strengthening the antioxidant defense mechanisms—including the enzymes involved during the ascorbate–glutathione (AsA–GSH) cycle and glyoxalase system—and substantially improved 2-AP precursors including proline, P5C, Δ1-pyrroline, and GABA levels, thereby restoring the 2-AP content and aroma. These findings deduce that melatonin and salicylic acid synergistically alleviate boron toxicity-induced disruptions on the 2-AP biosynthesis pathway by improving the 2-AP precursors and enzymatic activities, as well as modulating the physio-biochemical processes and antioxidant defense system of fragrant rice plants. Conclusions: The findings of this study have the potential to enhance rice productivity and stress tolerance, offering solutions to improve food security and sustainability in agricultural practices, particularly in regions affected by environmental stressors. Full article

Activating enhancer-binding protein 2 (AP-2) is a family of transcription factors (TFs) that play crucial roles in regulating embryonic and oncogenic development. In addition to splice isoforms, five major family members encoded by the TFAP2A/B/C/D/E genes have been identified in humans, i.e., AP-2α/β/γ/δ/ε. In general, the first three TFs have been studied more thoroughly than AP-2δ or AP-2ε. Currently, there is a relatively limited body of literature focusing on the AP-2 family in the context of gastroenterological research, and a comprehensive overview of the existing knowledge and recommendations for further research directions is lacking. Herein, we have collected available gastroenterological data on AP-2 TFs, discussed the latest medical applications of each family member, and proposed potential future directions. Research on AP-2 in gastrointestinal tumors has predominantly been focused on the two best-described family members, AP-2α and AP-2γ. Surprisingly, research in the past decade has highlighted the importance of AP-2ε in the drug resistance of gastric cancer (GC) and colorectal cancer (CRC). While numerous questions about gastroenterological disorders await elucidation, the available data undoubtedly open avenues for anti-cancer targeted therapy and overcoming chemotherapy resistance. In addition to gastrointestinal cancers, AP-2 family members (primarily AP-2β and marginally AP-2γ) have been associated with other health issues such as obesity, type 2 diabetes, liver dysfunction, and pseudo-obstruction. On the other hand, AP-2δ has been poorly investigated in gastroenterological disorders, necessitating further research to delineate its role. In conclusion, despite the limited attention given to AP-2 in gastroenterology research, pivotal functions of these transcription factors have started to emerge and warrant further exploration in the future. Full article

In this study, we confirmed that thrombin significantly increases the production of COX-2 and PGE₂ in human tracheal smooth muscle cells (HTSMCs), leading to inflammation in the airways and lungs. These molecules are well-known contributors to various inflammatory diseases. Here, we investigated in detail the involved signaling pathways using specific inhibitors and small interfering RNAs (siRNAs). Our results demonstrated that inhibitors targeting proteins such as protein kinase C (PKC)δ, proline-rich tyrosine kinase 2 (Pyk2), c-Src, epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), or activator protein-1 (AP-1) effectively reduced thrombin-induced COX-2 and PGE₂ production. Additionally, transfection with siRNAs against PKCδ, Pyk2, c-Src, EGFR, protein kinase B (Akt), or c-Jun mitigated these responses. Furthermore, our observations revealed that thrombin stimulated the phosphorylation of key components of the signaling cascade, including PKCδ, Pyk2, c-Src, EGFR, Akt, and c-Jun. Thrombin activated COX-2 promoter activity through AP-1 activation, a process that was disrupted by a point-mutated AP-1 site within the COX-2 promoter. Finally, resveratrol (one of the most researched natural polyphenols) was found to effectively inhibit thrombin-induced COX-2 expression and PGE₂ release in HTSMCs through blocking the activation of Pyk2, c-Src, EGFR, Akt, and c-Jun. In summary, our findings demonstrate that thrombin-induced COX-2 and PGE₂ generation involves a PKCδ/Pyk2/c-Src/EGFR/PI3K/Akt-dependent AP-1 activation pathway. This study also suggests the potential use of resveratrol as an intervention for managing airway inflammation. Full article

Osteoarthritis (OA) represents the foremost degenerative joint disease observed in a clinical context. The escalating issue of population aging significantly exacerbates the prevalence of OA, thereby imposing an immense annual economic burden on societies worldwide. The current therapeutic landscape falls short in offering reliable pharmaceutical interventions and efficient treatment methodologies to tackle this growing problem. However, the scientific community continues to dedicate significant efforts towards advancing OA treatment research. Contemporary studies have discovered that the progression of OA may be slowed through the strategic influence on peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated receptors within the nuclear hormone receptor family. The three distinctive subtypes—PPARα, PPARβ/δ, and PPARγ—find expression across a broad range of cellular terminals, thus managing a multitude of intracellular metabolic operations. The activation of PPARγ and PPARα has been shown to efficaciously modulate the NF-κB signaling pathway, AP-1, and other oxidative stress-responsive signaling conduits, leading to the inhibition of inflammatory responses. Furthermore, the activation of PPARγ and PPARα may confer protection to chondrocytes by exerting control over its autophagic behavior. In summation, both PPARγ and PPARα have emerged as promising potential targets for the development of effective OA treatments. Full article

Machaeriols and machaeridiols are unique hexahydrodibenzopyran-type aralkyl phytocannabinoids isolated from Machaerium Pers. Earlier studies of machaeriol A (1) and B (2) did not show any affinity for cannabinoid receptor 1 (CB1 or CNR1), although they are structural analogs of psychoactive hexahydrocannabinol. This study comprehensively reports on the affinities of isolated Machaerium Pers. compounds, namely machaeriol A–D (1–4) and machaeridiol A–C (5–7), against cannabinoid (CB1 and CB2) and opioid (κ, δ and µ) receptors. Among the isolated compounds, machaeriol D (4) and machaeridiol A–C (5–7) showed some selective binding affinity for the CB2 receptor, using a radioligand binding assay, with K_i values of >1.3, >1.77, >2.18 and >1.1 μM, respectively. On the other hand, none of the compounds showed any binding to the CB1 receptor. Due to recent reports on the anticancer potential of the endocannabinoid system, compounds 1–7 were tested against a battery of luciferase reporter gene vectors that assess the activity of many cancer-related signaling pathways, including Stat3, Smad2/3, AP-1, NF-κB, E2F, Myc, Ets, Notch, FoxO, Wnt, Hedgehog and pTK in HeLa and T98G glioblastoma cells. Complete dose–response curves have been determined for each compound in both of these cell lines, which revealed that machaeridiol 6 displayed activities (IC₅₀ in µM in HeLa and T98G cells) towards Stat3 (4.7, 1.4), Smad2/3 (1.2, 3.0), AP-1 (5.9, 4.2), NF-κB (0.5, 4.0), E2F (5.7, 0.7), Myc (5.3, 2.0), ETS (inactive, 5.9), Notch (5.3, 4.6), Wnt (4.2, inactive) and Hedgehog (inactive, 5.0). Furthermore, a combination study between machaeriol C (3) and machaeridiol B (6) displayed additive effects for E2F, ETS, Wnt and Hedgehog pathways, where these compounds individually were either minimally active or inactive. None of the compounds inhibited luciferase expression driven by the minimal thymidine kinase promoter (pTK), indicating the lack of general cytotoxicity for luciferase enzyme inhibition at the 50 µM concentration in both of these cell lines. The significance of the inhibition of these signaling pathways via machaeridiol 5–7 and their cross-talk potential has been discussed. Full article

Formerly hailed as “undruggable” proteins, transcription factors (TFs) are now under investigation for targeted therapy. In cancer, this may alter, inter alia, immune evasion or replicative immortality, which are implicated in genome organization, a process that accompanies multi-step tumorigenesis and which frequently develops in a non-random manner. Still, targeting-related research on some TFs is scarce, e.g., among AP-2 proteins, which are known for their altered functionality in cancer and prognostic importance. Using public repositories, bioinformatics tools, and RNA-seq data, the present study examined the ligandability of all AP-2 members, selecting the best one, which was investigated in terms of mutations, targets, co-activators, correlated genes, and impact on genome organization. AP-2 proteins were found to have the conserved “TF_AP-2” domain, but manifested different binding characteristics and evolution. Among them, AP-2δ has not only the highest number of post-translational modifications and extended strands but also contains a specific histidine-rich region and cleft that can receive a ligand. Uterine, colon, lung, and stomach tumors are most susceptible to AP-2δ mutations, which also co-depend with cancer hallmark genes and drug targets. Considering AP-2δ targets, some of them were located proximally in the spatial genome or served as co-factors of the genes regulated by AP-2δ. Correlation and functional analyses suggested that AP-2δ affects various processes, including genome organization, via its targets; this has been eventually verified in lung adenocarcinoma using expression and immunohistochemistry data of chromosomal conformation-related genes. In conclusion, AP-2δ affects chromosomal conformation and is the most appropriate target for cancer therapy focused on the AP-2 family. Full article

The need for new solutions for electrical insulation is growing due to the increased electrification in numerous industrial sectors, opening the door for innovation. Plasma spraying is a fast and efficient way to deposit various ceramics as electrical insulators, which are used in conditions where polymers are not suitable. Alumina (Al${}_2$O${}_3$) is among the most employed ceramics in the coating industry since it exhibits good dielectric properties, high hardness, and high melting point, while still being cost-effective. Various parameters (e.g., feedstock type, spray distance, plasma power) significantly influence the resulting coating in terms of microstructure, porosity, and metastable phase formation. Consequently, these parameters need to be investigated to estimate the impact on the dielectric properties of plasma-sprayed alumina coatings. In this work, alumina coatings with different spray distances have been prepared via atmospheric plasma spray (APS) on copper substrates. The microstructure, porosity, and corresponding phase formation have been analyzed with optical microscopy, X-ray diffraction (XRD), and scanning electron microscopy (SEM). Moreover, we present an in-depth analysis of the fundamental dielectric properties e.g., direct current (DC) resistance, breakdown strength, dielectric loss tangent, and permittivity. Our results show that decreasing spray distance reduces the resistivity from 6.31 × ${10}^9$$\mathsf{\Omega }$m (130 mm) to 6.33 × ${10}^8$$\mathsf{\Omega }$m (70 mm), while at the same time enhances the formation of the metastable $\mathsf{\delta }$-Al${}_2$O${}_3$ phase. Furthermore, space charge polarization is determined as the main polarization mechanism at low frequencies. Full article

Plant mineral nutrition substantially affects the growth, yield and quality of rice, whereas nitrogen (N) application contributes significantly in this regard. Undoubtedly, N application improves rice aroma biosynthesis; however, the molecular mechanism underlying the regulation of grain 2-acetyl-1-pyrroline (2-AP) biosynthesis in the presence of nitrogen application at the booting stage has remained largely unexplored. The present study examined the effects of three N levels, i.e., 0 g per pot (N0), 0.43 g per pot (N1) and 0.86 g per pot (N2) on intermediates, enzymes and genes involved in 2-AP biosynthesis, as well as on the yield of two fragrant rice cultivars viz, Meixiangzhan2 and Xiangyaxiangzhan. N was additionally applied at the booting stage. The results depicted that the levels of precursor, such as proline, and the activity of enzymes involved in 2-AP biosynthesis, such as Δ1-pyrroline-5-carboxylate synthetase (P5CS) and diamine oxidase (DAO), and P5CS1 gene expression were comparatively higher under N1 than N0 in both fragrant rice cultivars. Moreover, the N2 treatment increased the grain panicle⁻¹, filled grain percentage and grain yield of both rice cultivars, while the grain yield of Meixiangzhan2 and Xiangyaxiangzhan was increased by 15.87% and 12.09%, respectively, under N2 compared to N1 treatment. Hence, 0.43 g per pot of N showed positive performances in yield and aroma accumulation in fragrant rice and should be further employed in the practice and production for better cultivation in the rice market. Full article

A series of samples with the overall composition Gd_1-xSr_xCo_1-yFe_yO_3-δ (x = 0.8; 0.9 and 0.1 ≤ y ≤ 0.9), which are promising materials for catalytic and SOFC application, was prepared by a glycerol nitrate technique. X-ray diffraction analysis allowed to describe Gd_0.2Sr_0.8Co_1-yFe_yO_3-δ with 0.1 ≤ y ≤ 0.5 in a tetragonal 2a_p × 2a_p × 4a_p superstructure (SG I4/mmm), while oxides with 0.6 ≤ y ≤ 0.9 exhibit cubic disordered perovskite structure (SG Pm-3m). All Gd_0.1Sr_0.9Fe_1-yCo_yO_3-δ oxides within the composition range 0.1 ≤ y ≤ 0.9 possess the cubic perovskite structure (SG Pm-3m). The structural parameters were refined using the Rietveld full-profile method. The changes of oxygen content in Gd_1-xSr_xCo_1-yFe_yO_3-δ versus temperature were determined by thermogravimetric analysis. The introduction of iron into the cobalt sublattice leads to a gradual increase in the unit cell parameters and unit cell volume, accompanied with increasing oxygen content. The temperature dependency of conductivity for Gd_0.2Sr_0.8Co_0.3Fe_0.7O_3-δ exhibits a maximum (284 S/cm) at ≈600 K in air. The positive value of the Seebeck coefficient indicates predominant p-type conductivity in the Gd_0.2Sr_0.8Co_0.3Fe_0.7O_3-δ complex oxide. Full article

Ammonia (NH₃) volatilized from cropland significantly impacts the ecological environment and human health. The identification and quantification of atmospheric sources of NH₃ from cropland are therefore important for NH₃ emission reduction and air pollution control. Choosing appropriate nitrogen (N) fertilizer types is one of the key ways to reduce NH₃ emissions from agricultural systems due to different N fertilizers with different emission factors. The natural abundance isotope of N (δ¹⁵N) values can well identify the source of NH₃ volatilization, although there is rare research on δ¹⁵N-NH₃ values volatilized when applying different types of N fertilizers. Here, we conducted an incubation experiment to study the characteristics of δ¹⁵N-NH₃ values during the whole volatilization process after different N fertilizers were applied to the soil. The results show that the cumulative NH₃ volatilization from urea (U), urease inhibitor fertilizer (UI), compound fertilizer (CF) and ammonium nitrate phosphate fertilizer (AP) treatment was 5.25 ± 0.00, 3.11 ± 0.00, 3.22 ± 0.19 and 1.38 ± 0.12 kg N ha⁻¹ at the end of the 15-day incubation period, respectively. The average δ¹⁵N value of NH₃ volatilized from the U, UI, CF and AP treatments was −36.02 ± 4.95, −29.08 ± 9.70, −35.18 ± 4.98 and −29.42 ± 4.33‰, respectively. Generally, the δ¹⁵N-NH₃ values ranged from −41.33 to −6.30‰ during the NH₃ volatilization process. The δ¹⁵N-NH₃ value was lower in the U treatment than in the UI and AP treatments (p < 0.05), which suggests that N forms and the slow-release additions of different fertilizers, such as NO₃⁻-N and urease inhibitors, can delay or slow down NH₃ volatilization, resulting in relative isotopic enrichment. Therefore, the basic properties of different N fertilizers, the changes in soil NH₄⁺-N and cumulative NH₃ during the volatilization process significantly impacted the δ¹⁵N-NH₃ values. Full article

In this study, we used the stable water isotope record (δ¹⁸O) from an ice core drilled in Palmer Land, southern Antarctic Peninsula (AP). Utilizing δ¹⁸O we identified two climate regimes during the satellite era. During the 1979–1998 positive interdecadal Pacific oscillation (IPO) phase, a low-pressure system north of the Weddell Sea drove southeasterly winds that are associated with an increase in warm air mass intrusion onto the Larsen shelves, which melted and a decreased sea ice concentration in the Weddell Sea/increase in the Bellingshausen Sea. This climate setting is associated with anomaly low δ¹⁸O values (compared with the latter IPO period). There is significantly more melt along the northern AP ice shelf margins and on the Larsen D and southern Larsen C during the 1979–1998 IPO positive phase. The IPO positive climatic setting was coincidental with the Larsen A ice shelf collapse. In contrast, during the IPO negative phase (1999–2011), northerly winds caused a reduction in sea ice in the Bellingshausen Sea/Drake Passage region. Moreover, a Southern Ocean north of the Weddell Sea high-pressure system caused low-latitude warm humid air over the tip and east of the AP, a setting that is associated with increased northern AP snowfall, a high δ¹⁸O anomaly, and less prone to Larsen ice shelf melt. Full article

A novel energetic co-crystal composed of hydrazinium 3-nitro-1,2,4-triazol-5-one (HNTO) and ammonium nitrate (AN), as a composite solid propellant oxidizer, was recently developed to substitute either pure ammonium perchlorate (AP) or nitrate. Unfortunately, the thermodynamic properties of this co-crystal or even the pure HNTO are not available in the open literature. Therefore, in this work, the low-temperature heat capacities of HNTO and HNTO·AN co-crystal were measured in the temperature range from 213.15 K to 378.15 K using differential scanning calorimetry. By fitting the heat capacity data, the thermodynamic functions ΔH₂₉₈._15K, ΔG₂₉₈._15K, and ΔS₂₉₈._15K were derived. In addition, the standard molar energies of combustion Δ_cU° of HNTO and HNTO·AN co-crystal were determined, and from the combustion results, the standard molar enthalpies of combustion ${\Delta }_{\mathrm{c}}{H}_{\mathrm{m}}^{\mathrm{o}}$ and formation ${\Delta }_{\mathrm{f}}{H}_{\mathrm{m}}^{\mathrm{o}}$ of these energetic compounds were derived at T = 298.15 K. The set of thermochemical data has been proposed in this work for the first time and will be undoubtedly indispensable information for the development of energetic materials based on HNTO and HNTO·AN co-crystal. Full article

The most common medicinal claims for cannabis are relief from chronic pain, stimulation of appetite, and as an antiemetic. However, the mechanisms by which cannabis reduces pain and prevents nausea and vomiting are not fully understood. Among more than 450 constituents in cannabis, the most abundant cannabinoids are Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoids either directly or indirectly modulate ion channel function. Transient receptor potential vanilloid 1 (TRPV1) is an ion channel responsible for mediating several modalities of pain, and it is expressed in both the peripheral and the central pain pathways. Activation of TRPV1 in sensory neurons mediates nociception in the ascending pain pathway, while activation of TRPV1 in the central descending pain pathway, which involves the rostral ventral medulla (RVM) and the periaqueductal gray (PAG), mediates antinociception. TRPV1 channels are thought to be implicated in neuropathic/spontaneous pain perception in the setting of impaired descending antinociceptive control. Activation of TRPV1 also can cause the release of calcitonin gene-related peptide (CGRP) and other neuropeptides/neurotransmitters from the peripheral and central nerve terminals, including the vagal nerve terminal innervating the gut that forms central synapses at the nucleus tractus solitarius (NTS). One of the adverse effects of chronic cannabis use is the paradoxical cannabis-induced hyperemesis syndrome (HES), which is becoming more common, perhaps due to the wider availability of cannabis-containing products and the chronic use of products containing higher levels of cannabinoids. Although, the mechanism of HES is unknown, the effective treatment options include hot-water hydrotherapy and the topical application of capsaicin, both activate TRPV1 channels and may involve the vagal-NTS and area postrema (AP) nausea and vomiting pathway. In this review, we will delineate the activation of TRPV1 by cannabinoids and their role in the antinociceptive/nociceptive and antiemetic/emetic effects involving the peripheral, spinal, and supraspinal structures. Full article