Novel CCR3-targeted cyclic peptides as potential therapeutic agents for age-related macular degeneration via inhibiting angiogenesis and reducing retinal photoreceptor damage.

The prolonged intravitreal administration of anti-vascular endothelial growth factor (VEGF) drugs is prone to inducing aberrant retinal vascular development and causing damage to retinal neurons. Hence, we have taken an alternative approach by designing and synthesizing a series of cyclic peptides targeting CC motif chemokine receptor 3 (CCR3). Based on the binding mode of the N-terminal region in CCR3 protein to CCL11, we used computer-aided identification of key amino acid sequence, conformational restriction through different cyclization methods, designed and synthesized a series of target cyclic peptides, and screened the preferred compound IB-2 through affinity. IB-2 exhibits excellent anti-angiogenic activity in HRECs. The apoptosis level of 661W cells demonstrated a significant decrease with the escalating concentration of IB-2. This suggests that IB-2 may have a protective effect on photoreceptor cells. In vivo experiments have shown that IB-2 significantly reduces retinal vascular leakage and choroidal neovascularization (CNV) area in a laser-induced mouse model of CNV. These findings indicate the potential of IB-2 as a safe and effective therapeutic agent for AMD, warranting further development.

AI-driven design of customized 3D-printed multi-layer capsules with controlled drug release profiles for personalized medicine.

Personalized medicine aims to effectively and efficiently provide customized drugs that cater to diverse populations, which is a significant yet challenging task. Recently, the integration of artificial intelligence (AI) and three-dimensional (3D) printing technology has transformed the medical field, and was expected to facilitate the efficient design and development of customized drugs through the synergy of their respective advantages. In this study, we present an innovative method that combines AI and 3D printing technology to design and fabricate customized capsules. Initially, we discretized and encoded the geometry of the capsule, simulated the dissolution process of the capsule with classical drug dissolution model, and verified it by experiments. Subsequently, we employed a genetic algorithm to explore the capsule geometric structure space and generate a complex multi-layer structure that satisfies the target drug release profiles, including stepwise release and zero-order release. Finally, Two model drugs, isoniazid and acetaminophen, were selected and fused deposition modeling (FDM) 3D printing technology was utilized to precisely print the AI-designed capsule. The reliability of the method was verified by comparing the in vitro release curve of the printed capsules with the target curve, and the f2 value was more than 50. Notably, accurate and autonomous design of the drug release curve was achieved mainly by changing the geometry of the capsule. This approach is expected to be applied to different drug needs and facilitate the development of customized oral dosage forms.

Site-specific metal-support interaction to switch the activity of Ir single atoms for oxygen evolution reaction.

The metal-support interactions (MSI) could greatly determine the electronic properties of single-atom catalysts, thus affecting the catalytic performance. However, the typical approach to regulating MSI usually suffers from interference of the variation of supports or sacrificing the stability of catalysts. Here, we effectively regulate the site-specific MSI of Ir single atoms anchored on Ni layered double hydroxide through an electrochemical deposition strategy. Cathodic deposition drives Ir atoms to locate at three-fold facial center cubic hollow sites with strong MSI, while anodic deposition drives Ir atoms to deposit onto oxygen vacancy sites with weak MSI. The mass activity and intrinsic activity of Ir single-atom catalysts with strong MSI towards oxygen evolution reaction are 19.5 and 5.2 times that with weak MSI, respectively. Mechanism study reveals that the strong MSI between Ir atoms and the support stimulates the activity of Ir sites by inducing the switch of active sites from Ni sites to Ir sites and optimizes the adsorption strength of intermediates, thereby enhancing the activity.

OsWRKY97, an Abiotic Stress-Induced Gene of Rice, Plays a Key Role in Drought Tolerance.

Drought stress is one of the major causes of crop losses. The WRKY families play important roles in the regulation of many plant processes, including drought stress response. However, the function of individual WRKY genes in plants is still under investigation. Here, we identified a new member of the WRKY families, OsWRKY97, and analyzed its role in stress resistance by using a series of transgenic plant lines. OsWRKY97 positively regulates drought tolerance in rice. OsWRKY97 was expressed in all examined tissues and could be induced by various abiotic stresses and abscisic acid (ABA). OsWRKY97-GFP was localized to the nucleus. Various abiotic stress-related cis-acting elements were observed in the promoters of OsWRKY97. The results of OsWRKY97-overexpressing plant analyses revealed that OsWRKY97 plays a positive role in drought stress tolerance. In addition, physiological analyses revealed that OsWRKY97 improves drought stress tolerance by improving the osmotic adjustment ability, oxidative stress tolerance, and water retention capacity of the plant. Furthermore, OsWRKY97-overexpressing plants also showed higher sensitivity to exogenous ABA compared with that of wild-type rice (WT). Overexpression of OsWRKY97 also affected the transcript levels of ABA-responsive genes and the accumulation of ABA. These results indicate that OsWRKY97 plays a crucial role in the response to drought stress and may possess high potential value in improving drought tolerance in rice.

Overexpression of OsHAD3, a Member of HAD Superfamily, Decreases Drought Tolerance of Rice.

Haloacid dehalogenase-like hydrolase (HAD) superfamily have been shown to get involved in plant growth and abiotic stress response. Although the various functions and regulatory mechanism of HAD superfamily have been well demonstrated, we know little about the function of this family in conferring abiotic stress tolerance to rice. Here, we report OsHAD3, a HAD superfamily member, could affect drought tolerance of rice. Under drought stress, overexpression of OsHAD3 increases the accumulation of reactive oxygen species and malondialdehyde than wild type. OsHAD3-overexpression lines decreased but antisense-expression lines increased the roots length under drought stress and the transcription levels of many well-known stress-related genes were also changed in plants with different genotypes. Furthermore, overexpression of OsHAD3 also decreases the oxidative tolerance. Our results suggest that overexpression of OsHAD3 could decrease the drought tolerance of rice and provide a new strategy for improving drought tolerance in rice.

Overexpression of Rice Histone H1 Gene Reduces Tolerance to Cold and Heat Stress.

Temperature stresses, including low- and high-temperature stresses, are the main abiotic stresses affecting rice yield. Due to global climate change, the impact of temperature pressure on rice yield is gradually increasing, which is also a major concern for researchers. In this study, an H1 histone in Oryza sativa (OsHis1.1, LOC_Os04g18090) was cloned, and its role in rice's response to temperature stresses was functionally characterized. The GUS staining analysis of OsHis1.1 promoter-GUS transgenic rice showed that OsHis1.1 was widely expressed in various rice tissues. Transient expression demonstrated that OsHis1.1 was localized in the nucleus. The overexpression of OsHis1.1 reduces the tolerance to temperature stress in rice by inhibiting the expression of genes that are responsive to heat and cold stress. Under stress conditions, the POD activity and chlorophyll and proline contents of OsHis1.1-overexpression rice lines were significantly lower than those of the wild type, while the malondialdehyde content was higher than that of the wild type. Compared with Nip, OsHis1.1-overexpression rice suffered more serious oxidative stress and cell damage under temperature stress. Furthermore, OsHis1.1-overexpression rice showed changes in agronomic traits.

OsMLP423 Is a Positive Regulator of Tolerance to Drought and Salt Stresses in Rice.

Rice (Oryza sativa L.) is one of the main food crops for human survival, and its yield is often restricted by abiotic stresses. Drought and soil salinity are among the most damaging abiotic stresses affecting today's agriculture. Given the importance of abscisic acid (ABA) in plant growth and abiotic stress responses, it is very important to identify new genes involved in ABA signal transduction. We screened a drought-inducing gene containing about 158 amino acid residues from the transcriptome library of rice exposed to drought treatment, and we found ABA-related cis-acting elements and multiple drought-stress-related cis-acting elements in its promoter sequence. The results of real-time PCR showed that OsMLP423 was strongly induced by drought and salt stresses. The physiological and biochemical phenotype analysis of transgenic plants confirmed that overexpression of OsMLP423 enhanced the tolerance to drought and salt stresses in rice. The expression of OsMLP423-GFP fusion protein indicated that OsMLP423 was located in both the cell membrane system and nucleus. Compared with the wild type, the overexpressed OsMLP423 showed enhanced sensitivity to ABA. Physiological analyses showed that the overexpression of OsMLP423 may regulate the water loss efficiency and ABA-responsive gene expression of rice plants under drought and salt stresses, and it reduces membrane damage and the accumulation of reactive oxygen species. These results indicate that OsMLP423 is a positive regulator of drought and salinity tolerance in rice, governing the tolerance of rice to abiotic stresses through an ABA-dependent pathway. Therefore, this study provides a new insight into the physiological and molecular mechanisms of OsMLP423-mediated ABA signal transduction participating in drought and salt stresses.

OsSCL30 overexpression reduces the tolerance of rice seedlings to low temperature, drought and salt.

Rice is one of the main food crops for the world population. Various abiotic stresses, such as low temperature, drought, and high salinity, affect rice during the entire growth period, determining its yield and quality, and even leading to plant death. In this study, by constructing overexpression vectors D-163 + 1300:OsSCL30 and D-163 + 1300-AcGFP:OsSCL30-GFP, the mechanism of action of OsSCL30 in various abiotic stresses was explored. Bioinformatics analysis showed that OsSCL30 was located on the chromosome 12 of rice Nipponbare, belonging to the plant-specific SCL subfamily of the SR protein family. The 1500 bp section upstream of the open reading frame start site contains stress-related cis-acting elements such as ABRE, MYC, and MYB. Under normal conditions, the expression of OsSCL30 was higher in leaves and leaf sheaths. The results of reverse transcription polymerase chain reaction showed that the expression of OsSCL30 decreased after low temperature, drought and salt treatment. In root cells OsSCL30 was localized in the nuclei. The results of the rice seedling tolerance and recovery tests showed that overexpression of OsSCL30 diminished the resistance to low temperature, drought and salt stresses in transgenic rice and resulted in larger accumulation of reactive oxygen species. This study is of great significance for exploring the response mechanisms of SR proteins under abiotic stresses.

Melatonin regulates Aß production/clearance balance and Aß neurotoxicity: A potential therapeutic molecule for Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease with multiple predisposing factors and complicated pathogenesis. Aß peptide is one of the most important pathogenic factors in the etiology of AD. Accumulating evidence indicates that the imbalance of Aß production and Aß clearance in the brain of AD patients leads to Aß deposition and neurotoxic Aß oligomer formation. Melatonin shows a potent neuroprotective effect and can prevent or slow down the progression of AD, supporting the view that melatonin is a potential therapeutic molecule for AD. Melatonin modulates the regulatory network of secretase expression and affects the function of secretase, thereby inhibiting amyloidogenic APP processing and Aß production. Additionally, melatonin ameliorates Aß-induced neurotoxicity and probably promotes Aß clearance through glymphatic-lymphatic drainage, BBB transportation and degradation pathways. In this review, we summarize and discuss the role of melatonin against Aß-dependent AD pathogenesis. We explore the potential cellular and molecular mechanisms of melatonin on Aß production and assembly, Aß clearance, Aß neurotoxicity and circadian cycle disruption. We summarize multiple clinical trials of melatonin treatment in AD patients, showing that melatonin has a promising effect on improving sleep quality and cognitive function. This review aims to stimulate further research on melatonin as a potential therapeutic agent for AD.

Lactate: A Novel Signaling Molecule in Synaptic Plasticity and Drug Addiction.

l-Lactate is emerging as a crucial regulatory nexus for energy metabolism in the brain and signaling transduction in synaptic plasticity, memory processes, and drug addiction instead of being merely a waste by-product of anaerobic glycolysis. In this review, the role of lactate in various memory processes, synapse plasticity and drug addiction on the basis of recent studies is summarized and discussed. To this end, three main parts are presented: first, lactate as an energy substrate in energy metabolism of the brain is described; second, lactate as a novel signaling molecule in synaptic plasticity, neural circuits, memory, and drug addiction is described; and third, in light of the above descriptions, it is plausible to speculate that lactate is predominantly a signaling molecule in specific memory processes and partly acts as an energy substrate. The future perspective in lactate signaling involving microglia and associated precise signaling pathways in the brain is highlighted.

Chronic alcohol exposure induced gut microbiota dysbiosis and its correlations with neuropsychic behaviors and brain BDNF/Gabra1 changes in mice.

Alcohol addiction can cause brain dysfunction and many other diseases. Recently, increasing evidences have suggested that gut microbiota plays a vital role in regulating alcohol addiction. However, the exact mechanism has not yet been elucidated. Here, our study focused on the intestinal bacteria alternations and their correlations with alcohol-induced neuropsychic behaviors. When consuming alcohol over 3-week period, animals gradually displayed anxiety/depression-like behaviors. Moreover, 16S rRNA sequencing showed significant intestinal microflora dysbiosis and distinct community composition. Actinobacteria and Cyanobacteria were both increased at the phylum level. At the genus level, Adlercreutzia spp., Allobaculum spp., and Turicibacter spp. were increased whereas Helicobacter spp. was decreased. We also found that the distances in inner zone measured by open field test and 4% (v/v) alcohol preference percentages were significantly correlated with Adlercreutzia spp. The possible mechanisms were explored and we found the expression of brain-derived neurotrophic factor (BDNF) and α1 subunit of γ-aminobutyric acid A receptor (Gabra1) were both decreased in prefrontal cortex (PFC). Especially, further correlation analyses demonstrated that decreased Adlercreutzia spp. was positively correlated with alcohol preference and negatively correlated with anxiety-like behavior and BDNF/Gabra1 changes in PFC. Similar relationships were observed between Allobaculum spp. and alcohol preference and BDNF changes. Helicobacter spp. and Turicibacter spp. were also correlated with PFC BDNF and hippocampus Gabra1 level. Taken together, our study showed that gut microbiota dysbiosis during chronic alcohol exposure was closely correlated with alcohol-induced neuropsychic behaviors and BDNF/Gabra1 expression, which provides a new perspective for understanding underlying mechanisms in alcohol addiction. © 2018 BioFactors, 45(2):187-199, 2019.