Search Results (176)

In previous studies, we isolated a series of novel gentisides with nerve growth factor (NGF)-mimic activities from Gentiana rigescens Franch and conducted continuous structure–activity relationship (SAR) studies. Recently, a lead compound named TBG096 was discovered with significant NGF-mimic activity, low toxicity, and ability to pass through the blood–brain barrier (BBB). At the cell level, TBG096 exerts NGF-mimic activity by regulation of heat-shock cognate protein 70 (Hsc70) and downstream proteins. Subsequently, high-fat diet (HFD)-induced Alzheimer disease (AD) mouse models were used to evaluate the anti-AD efficacy of the compound. TBG096 significantly improved the memory dysfunction of AD mice at doses of 0.1, 5, and 20 mg/kg, respectively. In order to elucidate the mechanism of action of the compound against AD, the RNA-sequence analysis of transcriptomics, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence staining, and Western blot analysis were performed using animal samples. TBG096 significantly increased the expression of the Wnt gene family (Wnt10b, Wnt5a, and Wnt1) and the number of mature neurons and newborn neurons in the hippocampus and cerebral cortex of AD mice, respectively. At the same time, it reduced the activity of microglia, astrocyte cells, and expression of inducible nitric oxide synthase (INOS) in the brain. Moreover, this compound significantly increased phosphorylated-adenosine 5′-monophosphate-activated protein kinase (AMPK), Hsc70, and lysosomal-associated membrane protein 2a (LAMP2A) and decreased the expression of hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), amyloid precursor protein (APP), microtubule-associated protein tau (Tau), phosphoryl-Tau, and β-amyloid (Aβ) at the protein level. These results suggest that TBG096 produced the NGF-mimic activity and the anti-AD effect via promoting neurogenesis and modification of the Hsc70/HK2/PKM2/LAMP2A signaling pathway, proposing a potential novel approach to counteracting cognitive decline by developing small molecules that promote neurogenesis and the Hsc70 signaling pathway. Full article

There is relatively little research on cyclic amphiphilic block polymers, having both hydrophilic and hydrophobic segments placed in the ring and thus resulting in a higher degree of topological restriction, as drug vehicles. Cyclic amphiphilic binary block polymer is synthesized by the click coupling reaction of bimolecular homodifunctional precursors. The results indicate that cyclization between linear polymer precursors is successful if the trace linear by-products generated are ignored, which also suggests that the small molecule bifunctional terminating agent applied in traditional bimolecular homodifunctional ring-closure process can be extended to large molecule. Moreover, the study on the self-assembly behavior of polymers shows that, compared with linear counterparts, the stability and drug loading capacity of micelles based on the resultant cyclic polymer are not significantly improved due to the influence of topological structure and linear impurities. Nevertheless, drug loaded micelles formed by the obtained cyclic polymers still exhibit superior cellular uptake ability. It can be seen that topological effects do play an irreplaceable role in the application performance of polymers. Therefore, the construction and synthesis of cyclic and its derivative polymers with moderate topological confinement and high purity may be a key direction for future exploration of polymer drug delivery carriers. Full article

Brain-derived neurotropic factor (BDNF) is expressed by skeletal muscle as a myokine. Our previous work showed that the active precursor, proBDNF, is the predominant form of BDNF expressed in skeletal muscle, and that following skeletal muscle injury, proBDNF levels are significantly increased. However, the function of the muscle-derived proBDNF in injury-induced inflammation has yet to be fully understood. Using a model of tourniquet-induced ischemia–reperfusion (IR) injury of the hindlimb, this study presents, for the first time, strong and novel evidence that following IR injury, proBDNF is released from skeletal muscle into circulation as an endocrine signaling molecule. Further, this study shows that 1 day post-IR injury, the proBDNF receptor, p75^NTR, is upregulated 12-fold in splenic monocytes, which are known to be quickly mobilized to the injury site. We demonstrate that p75^NTR plays a role in the activation of splenic monocytes, and that treatment with a p75^NTR small-molecule modulator, LM11A-31, significantly reduced monocyte inflammatory responses upon lipopolysaccharide stimulation. Overall, the present study establishes proBDNF as a myokine that plays a significant role in skeletal muscle injury-induced inflammation through its receptor, p75^NTR, which may be modulated using LM11A-31 as potential translational therapeutic against injury and inflammation. Full article

Phase change fibers (PCFs) can effectively store and release heat, improve energy efficiency, and provide a basis for a wide range of energy applications. Improving energy storage density and preserving flexibility are the primary issues in the efficient manufacture and application development of PCFs. Herein, we have successfully fabricated a suite of flexible PCFs with high energy storage density, which use hollow carbon fibers (HCFs) encapsulated phase change materials (PCMs) to provide efficient heat storage and release, thereby enhancing energy efficiency and underpinning a broad range of energy applications. The flexible HCF/LA PCFs with high energy density were made by impregnating a small molecule LA solution, whereas the precursor of the PAN/ZIF-67 composite fibers was created by electrospinning. These PCFs have a high loading capacity for lauric acid (LA), demonstrating a 92% load percentage and a 153 J g⁻¹ phase change enthalpy value. The effects of doping quantity (ZIF-67), fiber orientation, pre-oxidation treatment, and particle size on the morphological and structural characteristics of HCFs, as well as the impact of HCFs’ pore structure on PCM encapsulation, were investigated. It was found that the oriented fiber structure serves to reduce the likelihood of fracture and breakage of precursor fibers after carbonization, whilst the gradient pre-oxidation can maintain the original fiber morphology of the fibers after carbonization. These findings establish a solid theoretical foundation for the design and production of high-performance flexible porous carbon nanofiber wiping phase change composites. Full article

Mitochondrial metabolism plays a pivotal role in regulating the synthesis of secondary metabolites, which are crucial for the survival and adaptation of organisms. These metabolites are synthesized during specific growth stages or in response to environmental stress, reflecting the organism’s ability to adapt to changing conditions. Mitochondria, while primarily known for their role in energy production, directly regulate secondary metabolite biosynthesis by providing essential precursor molecules, energy, and reducing equivalents necessary for metabolic reactions. Furthermore, they indirectly influence secondary metabolism through intricate signaling pathways, including reactive oxygen species (ROS), metabolites, and redox signaling, which modulate various metabolic processes. This review explores recent advances in understanding the molecular mechanisms governing mitochondrial metabolism and their regulatory roles in secondary metabolite biosynthesis, which highlights the involvement of transcription factors, small RNAs, and post-translational mitochondrial modifications in shaping these processes. By integrating current insights, it aims to inspire future research into mitochondrial regulatory mechanisms in Arabidopsis thaliana, Solanum tuberosum, Nicotiana tabacum, and others that may enhance their secondary metabolite production. A deeper understanding of the roles of mitochondria in secondary metabolism could contribute to the development of new approaches in biotechnology applications. Full article

Parkinson’s disease (PD) is a chronic, progressive neurological disorder affecting approximately 10 million people worldwide, with prevalence expected to rise as the global population ages. It is characterized by the degeneration of dopamine-producing neurons in the substantia nigra pars compacta, leading to motor symptoms such as tremor, rigidity, bradykinesia, postural instability, and gait disturbances, as well as non-motor symptoms including olfactory disturbances, sleep disorders, and depression. Currently, no cure exists for PD, and most available therapies focus on symptom alleviation. This dopamine deficiency impairs motor control, and since dopamine itself cannot cross the blood–brain barrier (BBB), the precursor L-Dopa is commonly used in treatment. L-Dopa is administered with enzyme inhibitors to prevent premature conversion outside the brain, allowing it to cross the BBB and convert to dopamine within the central nervous system. Although these therapies have improved symptom management, recent research has revealed additional molecular factors in PD pathology, such as α-synuclein aggregation, mitochondrial dysfunction, and lysosomal abnormalities, contributing to its complexity. These discoveries open up possibilities for neuroprotective therapies that could slow disease progression. In this review, we categorize PD therapeutic targets into two main groups: currently used therapies and targets under active research. We also introduce promising small-molecule compounds studied between 2019 and 2023, which may represent future treatment options. By examining both established and emerging targets, we aim to highlight effective strategies and potential directions for future drug development in Parkinson’s disease therapy. Full article

The heterobimetallic 15-MC-5 metallacrown of formula [CeCu₅(5mpzHA)₅(NO₃)(H₂O)₇]·2NO₃·7H₂O, designated MC-Ce, was synthesized using 5-methyl-2-pyrazinehydroxamic acid (5mpzHA) as a linker, reacting with Ce^III and Cu^II salts under mild conditions. Single-crystal X-ray diffraction analysis reveals a crown-like [Cu₅Ce(5mpzHA)₅] core, characteristic of a 15-MC-5 system, with five Cu^II atoms at the rim of the crown and the Ce^III ion occupying the dome of the crown, with water molecules, oxygen atoms and one nitrate anion filling the nine-coordination sphere around the Ce^III ion, which exhibits a distorted spherical tricapped trigonal prism geometry. The thermogravimetric analysis evidences successive mass losses due to the removal of water molecules and decomposition of the structure after 217 °C, whereas the PXRD analysis of the thermal decomposition residue reveals the presence of copper and copper/cerium oxide particles. These nanocomposite materials were also synthesized using the metallacrown MC-Ce under a hydrothermal method in the presence of multi-walled carbon nanotubes (MWCNTs), affording insights that this metallacrown can act as a source precursor for the synthesis of these mixed cerium/copper oxide nanomaterials. The experimental χMT value in MC-Ce at room temperature is 3.175 cm³ mol⁻¹ K, which is higher than the calculated one for one magnetically isolated Ce^III plus five Cu^II ions, probably due to the antiferromagnetic interactions among Cu^II ions within the metallacrown hoop plus the thermal depopulation of JZ sublevels of Ce^III ground state (5/2), which exhibit a small splitting under the anisotropic ligand field effects. The χMT decreases continuously until it reaches the value of 0.80 cm³ mol⁻¹ K at 10 K, reinforcing the presence of intramolecular antiferromagnetic interactions. Full article

This article explores the important, and yet often overlooked, solid-state structures of selected bioaromatic compounds commonly found in lignin hydrogenolysis oil, a renewable bio-oil that holds great promise to substitute fossil-based aromatic molecules in a wide range of chemical and material industrial applications. At first, single-crystal X-ray diffraction (SCXRD) was applied to the lignin model compounds, dihydroconiferyl alcohol, propyl guaiacol, and eugenol dimers, in order to elucidate the fundamental molecular interactions present in such small lignin-derived polyols. Then, considering the potential use of these lignin-derived molecules as building blocks for polymer applications, structural analysis was also performed for two chemically modified model compounds, i.e., the methylene-bridging propyl-guaiacol dimer and propyl guaiacol and eugenol glycidyl ethers, which can be used as precursors in phenolic and epoxy resins, respectively, thus providing additional information on how the molecular packing is altered following chemical modifications. In addition to the expected H-bonding interactions, other interactions such as π–π stacking and C–H∙∙∙π were observed. This resulted in unexpected trends in the tendencies towards the crystallization of lignin compounds. This was further explored with the aid of DSC analysis and CLP intermolecular energy calculations, where the relationship between the major interactions observed in all the SCXRD solid-state structures and their physico-chemical properties were evaluated alongside other non-crystallizable lignin model compounds. Beyond lignin model compounds, our findings could also provide important insights into the solid-state structure and the molecular organization of more complex lignin fragments, paving the way to the more efficient design of lignin-based materials with improved properties for industrial applications or improving downstream processing of lignin oils in biorefining processes, such as in enhancing the separation and isolation of specific bioaromatic compounds). Full article

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. While there have been many potential factors implicated for ALS development, such as oxidative stress and mitochondrial dysfunction, no exact mechanism has been determined at this time. Nicotinamide adenine dinucleotide (NAD⁺) is one of the most abundant metabolites in mammalian cells and is crucial for a broad range of cellular functions from DNA repair to energy homeostasis. NAD⁺ can be synthesized from three different intracellular pathways, but it is the NAD⁺ salvage pathway that generates the largest proportion of NAD⁺. Impaired NAD⁺ homeostasis has been connected to aging and neurodegenerative disease-related dysfunctions. In ALS mice, NAD⁺ homeostasis is potentially disrupted prior to the appearance of physical symptoms and is significantly reduced in the nervous system at the end stage. Treatments targeting NAD⁺ metabolism, either by administering NAD⁺ precursor metabolites or small molecules that alter NAD⁺-dependent enzyme activity, have shown strong beneficial effects in ALS disease models. Here, we review the therapeutic interventions targeting NAD⁺ metabolism for ALS and their effects on the most prominent pathological aspects of ALS in animal and cell models. Full article

Background: Small molecules play a crucial role in the exploration of physiological pathways and in drug development by targeting deoxyribonucleic acid (DNA). DNA is a central focus for both endogenous and exogenous ligands, which interact directly or indirectly to regulate transcription and replication processes, thus controlling genetic expression in specific cells. Among these molecules, indole derivatives like tryptophan, serotonin, and melatonin are notable for their widespread presence in nature and significant biological effects. Tryptophan, an essential amino acid, serves as a vital structural element in proteins and a precursor for bioactive compounds like serotonin and melatonin, which impact various physiological functions. Methods: Experimental studies have been conducted to reveal the interaction mechanisms of these endogenous indole derivatives with calf thymus DNA (ct-DNA). These investigations involve viscosity measurements and analysis of double-stranded DNA behavior in the presence of indole molecules, using spectrophotometric UV absorption techniques to assess their impact on DNA stability. Additionally, the influence of calcium and magnesium ions on the resulting complexes of these indole derivatives with ct-DNA has been evaluated. Molecular docking validated our findings, offering additional insights into potential DNA–ligand interactions. Utilizing a crystallographic oligomer with an intercalation gap improved docking accuracy, distinguishing intercalation from groove recognition and enhancing assessment precision. Results: Our study offers detailed insights into the interaction patterns of the indole derivatives with DNA and is highly supported by molecular docking analyses: the indole derivatives were predominantly localized between C and G, interacting via π-π interactions and hydrogen bonds and aligning with known data on conventional intercalators. These findings underscore the importance of small compounds’ planar structure and appropriate size, facilitating tight insertion between adjacent base pairs and disrupting regular DNA stacking. Conclusions: Indoles’ physiological roles and potential as drug candidates targeting specific pathways are highlighted, emphasizing their significance as ubiquitous molecules with the ability to modulate biological effects on DNA structure. Full article

One-stage synthesis technology for preparing carbon adsorbents with tailored porosity from agricultural waste is worthwhile due to their extensive application value. Thermal gravimetric analysis, low-temperature N₂ adsorption, X-ray diffraction (XRD), small-angle X-ray scattering (SAXS), and Raman spectroscopy were used to record the structure transformations of carbon materials, namely pore development, proceeding in the course of the step-wise pyrolysis of renewable and low-cost raw materials such as walnut shells (WNSs), which was carried out within a temperature range of 240–950 °C in a CO₂ flow. The minimum threshold carbonization temperature for preparing nanoporous carbon materials from WNSs, determined by the examination of the N₂ adsorption data, was 500 °C. The maximum specific micropore volume and BET surface achieved in the process without holding a material at a specified temperature were only 0.19 cm³/g and 440 m²/g, respectively. The pyrolysis at 400–600 °C produced amorphous sp² carbon. At a temperature as high as 750 °C, an increase in the X-ray reflection intensity indicated the ordering of graphite-like crystallites. At high burn-off degrees, the size of coherently scattering domains becomes smaller, and an increased background in X-ray patterns indicates the destruction of cellulose nanofibrils, the disordering of graphene stacks, and an increase in the amount of disordered carbon. At this stage, pores develop in the crystallites. They are tentatively assigned to crystallites with sizes of 15–20 nm and to micropores. According to the Raman spectra combined with the XRD and SAXS data, the structure of all the pyrolysis products is influenced by the complex structure of the walnut shell precursor, which comprises cellulose nanofibrils embedded in lignin. This structure was preserved in the initial stage of pyrolysis, and the graphitization of cellulose fibrils and lignin proceeds at different rates. Most of the pores accessible for gas molecules in the resulting carbon materials are associated with former cellulose fibrils. Full article

Sulforaphane is considered the bioactive metabolite of glucoraphanin after dietary consumption of broccoli sprouts. Although both molecules pass through the gut lumen to the large intestine in stable form, their biological impact on the first intestinal tract is poorly described. In celiac patients, the function of the small intestine is affected by celiac disease (CD), whose severe outcomes are controlled by gluten-free dietary protocols. Nevertheless, pathological signs of inflammation and oxidative stress may persist. The aim of this study was to compare the biological activity of sulforaphane with its precursor glucoraphanin in a cellular model of gliadin-induced inflammation. Human intestinal epithelial cells (CaCo-2) were stimulated with a pro-inflammatory combination of cytokines (IFN-γ, IL-1β) and in-vitro-digested gliadin, while oxidative stress was induced by H₂O₂. LC-MS/MS analysis confirmed that sulforaphane from broccoli sprouts was stable after simulated gastrointestinal digestion. It inhibited the release of all chemokines selected as inflammatory read-outs, with a more potent effect against MCP-1 (IC₅₀ = 7.81 µM). On the contrary, glucoraphanin (50 µM) was inactive. The molecules were unable to counteract the oxidative damage to DNA (γ-H2AX) and catalase levels; however, the activity of NF-κB and Nrf-2 was modulated by both molecules. The impact on epithelial permeability (TEER) was also evaluated in a Transwell^® model. In the context of a pro-inflammatory combination including gliadin, TEER values were recovered by neither sulforaphane nor glucoraphanin. Conversely, in the context of co-culture with activated macrophages (THP-1), sulforaphane inhibited the release of MCP-1 (IC₅₀ = 20.60 µM) and IL-1β (IC₅₀ = 1.50 µM) only, but both molecules restored epithelial integrity at 50 µM. Our work suggests that glucoraphanin should not merely be considered as just an inert precursor at the small intestine level, thus suggesting a potential interest in the framework of CD. Its biological activity might imply, at least in part, molecular mechanisms different from sulforaphane. Full article

Area selective deposition (ASD) is a promising IC fabrication technique to address misalignment issues arising in a top–down litho-etch patterning approach. ASD can enable resist tone inversion and bottom–up metallization, such as via prefill. It is achieved by promoting selective growth in the growth area (GA) while passivating the non-growth area (NGA). Nevertheless, preventing undesired particles and defect growth on the NGA is still a hurdle. This work shows the selectivity of Ru films by passivating the Si oxide NGA with self-assembled monolayers (SAMs) and small molecule inhibitors (SMIs). Ru films are deposited on the TiN GA using a metal-organic precursor tricarbonyl (trimethylenemethane) ruthenium (Ru TMM(CO)₃) and O₂ as a co-reactant by atomic layer deposition (ALD). This produces smooth Ru films (<0.1 nm RMS roughness) with a growth per cycle (GPC) of 1.6 Å/cycle. Minimizing the oxygen co-reactant dose is necessary to improve the ASD process selectivity due to the limited stability of the organic molecule and high reactivity of the ALD precursor, still allowing a Ru GPC of 0.95 Å/cycle. This work sheds light on Ru defect generation mechanisms on passivated areas from the detailed analysis of particle growth, coverage, and density as a function of ALD cycles. Finally, an optimized ASD of Ru is demonstrated on TiN/SiO₂ 3D patterned structures using dimethyl amino trimethyl silane (DMA-TMS) as SMI. Full article

In the realm of plant biology, small RNAs (sRNAs) are imperative in the orchestration of gene expression, playing pivotal roles across a spectrum of developmental sequences and responses to environmental stressors. The biosynthetic cascade of sRNAs is characterized by an elaborate network of enzymatic pathways that meticulously process double-stranded RNA (dsRNA) precursors into sRNA molecules, typically 20 to 30 nucleotides in length. These sRNAs, chiefly microRNAs (miRNAs) and small interfering RNAs (siRNAs), are integral in guiding the RNA-induced silencing complex (RISC) to selectively target messenger RNAs (mRNAs) for post-transcriptional modulation. This regulation is achieved either through the targeted cleavage or the suppression of translational efficiency of the mRNAs. In plant development, sRNAs are integral to the modulation of key pathways that govern growth patterns, organ differentiation, and developmental timing. The biogenesis of sRNA itself is a fine-tuned process, beginning with transcription and proceeding through a series of processing steps involving Dicer-like enzymes and RNA-binding proteins. Recent advances in the field have illuminated the complex processes underlying the generation and function of small RNAs (sRNAs), including the identification of new sRNA categories and the clarification of their involvement in the intercommunication among diverse regulatory pathways. This review endeavors to evaluate the contemporary comprehension of sRNA biosynthesis and to underscore the pivotal role these molecules play in directing the intricate performance of plant developmental processes. Full article

Bridgehead alkenes are polycyclic molecules bearing at least one C=C bond that includes a bridgehead carbon atom. For small bicyclic systems, these bonds are highly strained due to geometric constraints placed on the sp² hybridized carbon atoms. These small, strained molecules have been termed “anti-Bredt” alkenes. β-halo carbanions have served as convenient precursors to bridgehead alkenes in experimental studies. We observed that upon attempted computational geometric optimizations (ωB97X-D/aug-cc-pVDZ) of the precursors, spontaneous elimination of the halide occurs along with formation of the anti-Bredt alkene in many cases. Such computational eliminations were shown to faithfully mimic experimentally obtained results. Computational elimination was not observed for [1.1.1] or [2.1.1] frameworks, in agreement with predictions that these bridgehead alkenes are too strained to be formed. However, computational elimination from the [2.2.1] framework was observed to form 1-norbornene, a compound suggested in experimental work to be a reactive intermediate. Similarly, [3.1.1] frameworks and higher led to eliminations upon computational geometric optimization, in agreement with experimental findings. Natural bond order (NBO) calculations of the starting geometries proved to be excellent predictors as to whether elimination would take place. Those precursor compounds exhibiting delocalization energies in the order of 10 kcal/mol between the lone-pair electrons of the carbon atom and σ*_C-Br were generally found to undergo elimination. Thus, computational optimization of β-halo substituted bicyclic precursor anions can be used to predict whether strained anti-Bredt alkenes are likely to be formed, thereby saving valuable time and costs in the experimental lab. Full article