Discovery of Novel Hybrids of Edaravone and 6-Phenyl-4,5-dihydropyridazin-3(2H)-one with Antiplatelet Aggregation and Neuroprotection for Ischemic Stroke Treatment.

Drugs with anti-platelet aggregation and neuroprotection are of great significance for the treatment of ischemic stroke. A series of edaravone and 6-phenyl-4,5-dihydropyridazin-3(2H)-one hybrids were designed and synthesized. Among them, 6g showed the most effective cytoprotective effect against oxygen-glucose deprivation/reoxygenation-induced damage in BV2 cells and an excellent inhibitory effect on platelet aggregation induced by adenosine diphosphate and arachidonic acid. Additionally, 6g could prevent thrombosis caused by ferric chloride in rats and pose a lower risk of causing bleeding compared with aspirin. It provides better protection against ischemia/reperfusion injury in rats compared with edaravone and alleviates the oxidative stress related to cerebral ischemia/reperfusion by increasing the GSH and SOD levels and decreasing the MDA concentration. Finally, molecular docking results showed that 6g probably acts on PDE3 A and plays an anti-platelet aggregation effect. Overall, 6g could be a potential candidate compound for the treatment of ischemic stroke.

Novel 1,3,4-oxadiazole hybrids of 3-n-butylphthalide derivatives as potential anti-ischemic stroke agents.

In continuation of our program to search for novel potential anti-ischemic stroke agents, a series of 1,3,4-oxadiazole and sulfoxide hybrids of phthalide derivatives was designed and synthesized in this study to evaluate their anti-ischemic stroke activity. Among them, compounds 5b, 5d, 5 l, and 5 m exhibited excellent inhibitory effects on platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid (AA). In particular, compound 5b possessed considerable antithrombotic activity in animal models, as demonstrated by the effective alleviation of carrageenan-induced and FeCl3-induced thrombosis in tail and carotid arteries, respectively. Notably, intraperitoneal administration of compound 5b could better protect the brain from injury caused by ischemia/reperfusion in rats compared with precursor 3-n-butylphthalide. Further pharmacokinetics, liver microsomal stability, and PAMPA-BBB assays also indicated that compound 5b had relatively high bioavailability, metabolic stability, and BBB permeability. Moreover, compound 5b showed a safety profile that was superior to the clinical drugs clopidogrel, aspirin, and 3-n-butylphthalide in the mouse-tail bleeding assay. Finally, molecular docking predicted that the potential target of the antiplatelet aggregation activity of compound 5b was P2Y12 receptor. This research provides a novel candidate compound for the treatment of ischemic stroke.

X3DFast model for classifying dairy cow behaviors based on a two-pathway architecture.

Behavior is one of the important factors reflecting the health status of dairy cows, and when dairy cows encounter health problems, they exhibit different behavioral characteristics. Therefore, identifying dairy cow behavior not only helps in assessing their physiological health and disease treatment but also improves cow welfare, which is very important for the development of animal husbandry. The method of relying on human eyes to observe the behavior of dairy cows has problems such as high labor costs, high labor intensity, and high fatigue rates. Therefore, it is necessary to explore more effective technical means to identify cow behaviors more quickly and accurately and improve the intelligence level of dairy cow farming. Automatic recognition of dairy cow behavior has become a key technology for diagnosing dairy cow diseases, improving farm economic benefits and reducing animal elimination rates. Recently, deep learning for automated dairy cow behavior identification has become a research focus. However, in complex farming environments, dairy cow behaviors are characterized by multiscale features due to large scenes and long data collection distances. Traditional behavior recognition models cannot accurately recognize similar behavior features of dairy cows, such as those with similar visual characteristics, i.e., standing and walking. The behavior recognition method based on 3D convolution solves the problem of small visual feature differences in behavior recognition. However, due to the large number of model parameters, long inference time, and simple data background, it cannot meet the demand for real-time recognition of dairy cow behaviors in complex breeding environments. To address this, we developed an effective yet lightweight model for fast and accurate dairy cow behavior feature learning from video data. We focused on four common behaviors: standing, walking, lying, and mounting. We recorded videos of dairy cow behaviors at a dairy farm containing over one hundred cows using surveillance cameras. A robust model was built using a complex background dataset. We proposed a two-pathway X3DFast model based on spatiotemporal behavior features. The X3D and fast pathways were laterally connected to integrate spatial and temporal features. The X3D pathway extracted spatial features. The fast pathway with R(2 + 1)D convolution decomposed spatiotemporal features and transferred effective spatial features to the X3D pathway. An action model further enhanced X3D spatial modeling. Experiments showed that X3DFast achieved 98.49% top-1 accuracy, outperforming similar methods in identifying the four behaviors. The method we proposed can effectively identify similar dairy cow behaviors while improving inference speed, providing technical support for subsequent dairy cow behavior recognition and daily behavior statistics.

The causal relationship between gut microbiota and inflammatory dermatoses: a Mendelian randomization study.

Background: Observational studies have shown that gut microbiota is closely associated with inflammatory dermatoses such as psoriasis, rosacea, and atopic dermatitis (AD). However, the causal relationship between gut microbiota and inflammatory dermatosis remains unclear. Methods: Based on Maximum Likelihood (ML), MR-Egger regression, Inverse Variance Weighted (IVW), MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), Weighted Mode, and Weighted Median Estimator (WME) methods, we performed a bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationship between gut microbiota and inflammatory dermatosis. The genome-wide association study (GWAS) summary data of gut microbiota came from the MiBioGen consortium, while the GWAS summary data of inflammatory dermatosis (including psoriasis, AD, rosacea, vitiligo, acne, and eczema) came from the FinnGen consortium and IEU Open GWAS project. Cochran's IVW Q test tested the heterogeneity among instrumental variables (IVs). The horizontal pleiotropy was tested by MR-Egger regression intercept analysis and MR-PRESSO analysis. Results: Eventually, the results indicated that 5, 16, 17, 11, 15, and 12 gut microbiota had significant causal effects on psoriasis, rosacea, AD, vitiligo, acne, and eczema, respectively, including 42 protective and 34 risk causal relationships. Especially, Lactobacilli and Bifidobacteria at the Family and Genus Level, as common probiotics, were identified as protective factors for the corresponding inflammatory dermatoses. The results of reverse MR analysis suggested a bidirectional causal effect between AD and genus Eubacterium brachy group, vitiligo and genus Ruminococcaceae UCG004. The causal relationship between gut microbiota and psoriasis, rosacea, acne, and eczema is unidirectional. There was no significant heterogeneity among these IVs. In conclusion, this bidirectional two-sample MR study identified 76 causal relationships between the gut microbiome and six inflammatory dermatoses, which may be helpful for the clinical prevention and treatment of inflammatory dermatoses.

The role of circadian clock genes in colorectal carcinoma: Novel insights into regulatory mechanism and implications in clinical therapy.

Colorectal cancer (CRC) is a lethal malignancy with limited treatment strategies. Accumulating evidence indicates that CRC tumorigenesis, progression and metastasis are intimately associated with circadian clock, an inherent 24-h cycle oscillation of biochemical, physiological functions in almost every eukaryote. In the present review, we summarize the altered expression level of circadian genes in CRC and the prognosis associated with gene abundance switch. We illustrate the function and potential mechanisms of circadian genes in CRC pathogenesis and progression. Moreover, circadian based-therapeutic strategies including chronotherapy, therapeutics targeting potential circadian components, and melatonin treatment in CRC are also highlighted.

Synthesis of Novel 3-Butylphthalide Derivatives Containing Isopentenylphenol Moiety as Potential Antiplatelet Agents for the Treatment of Ischemic Stroke.

In order to find novel antiplatelet drugs for the treatment of ischemic stroke, a series of 3-butylphthalide derivatives containing isopentenylphenol moiety were designed, synthesized and characterized with spectroscopic analyses. The in vitro antiplatelet activity results indicated that compound 3 better inhibited the arachidonic acid (AA) induced platelet aggregation than aspirin (ASP) and 3-butylphthalide (NBP). Additionally, compared with precursor NBP, compound 3 possessed outstanding antithrombotic activity in the animal experiment model, which could effectively alleviate the formation of tail thrombus and carotid artery thrombus in mice. More importantly, intraperitoneal administration of compound 3 can well protected the rats against ischemia/reperfusion-induced brain injury. Further pharmacokinetic (PK) assay indicated that compound 3 had good absorption characteristics and metabolic stability in vivo. Overall, the present research provides a new candidate compound for the treatment of ischemic stroke caused by platelet aggregation.

Specificity Protein 1: A Protein With a Two-Sided Role in Ischemic Stroke.

Stroke is one of the leading causes of death and disability worldwide. However, there is a lack of effective medications to speed up the recovery process. Ischemic stroke, as the result of cerebral infarction or cerebral artery narrowing, is accompanied by hemiplegia or impaired consciousness. There are many transcription factors involved in the development of this condition, whose alterations can influence or signal the prognostic outcomes of ischemic stroke. Among them, the augmented expression of specificity protein 1 (SP1) can participate in the progression of the disease by binding DNA to regulate the transcriptions of many genes. Different studies have provided different answers as to whether SP1 plays a positive or a negative role in ischemic stroke. On the one hand, SP1 can play a cytoprotective role as both an antioxidant and anti-apoptotic agent for neurons and glial cells. On the other hand, it can also damage neuronal cells by promoting inflammation and exacerbating brain edema. In this review, we highlight the roles of SP1 in ischemic stroke and shed light on the underlying mechanism.

The CBL-CIPK network mediates different signaling pathways in plants.

The calcineurin B-like protein-CBL-interacting protein kinase (CBL-CIPK) signaling pathway in plants is a Ca²âº-related pathway that responds strongly to both abiotic and biotic environmental stimuli. The CBL-CIPK system shows variety, specificity, and complexity in response to different stresses, and the CBL-CIPK signaling pathway is regulated by complex mechanisms in plant cells. As a plant-specific Ca²âº sensor relaying pathway, the CBL-CIPK pathway has some crosstalk with other signaling pathways. In addition, research has shown that there is crosstalk between the CBL-CIPK pathway and the low-K⁺ response pathway, the ABA signaling pathway, the nitrate sensing and signaling pathway, and others. In this paper, we summarize and review research discoveries on the CBL-CIPK network. We focus on the different modification and regulation mechanisms (phosphorylation and dephosphorylation, dual lipid modification) of the CBL-CIPK network, the expression patterns and functions of CBL-CIPK network genes, the responses of this network to abiotic stresses, and its crosstalk with other signaling pathways. We also discuss the technical research methods used to analyze the CBL-CIPK network and some of its newly discovered functions in plants.