Regulation of cerebral blood flow boosts precise brain targeting of vinpocetine-derived ionizable-lipidoid nanoparticles.

Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid nanoparticles efficiently breach the blood-brain barrier; (ii) they have high gene-loading capacity, facilitating endosomal escape and intracellular transport; (iii) their administration is safe with minimal immunogenicity even with prolonged use; and (iv) they have potent pharmacologic brain-protective activity and may synergize with treatments for brain disorders as demonstrated in male APP/PS1 mice.

Reactive Oxygen Species Activate a Ferritin-Linked TRPV4 Channel under a Static Magnetic Field.

Magnetogenetics has shown great potential for cell function and neuromodulation using heat or force effects under different magnetic fields; however, there is still a contradiction between experimental effects and underlying mechanisms by theoretical computation. In this study, we aimed to investigate the role of reactive oxygen species (ROS) in mechanical force-dependent regulation from a physicochemical perspective. The transient receptor potential vanilloid 4 (TRPV4) cation channels fused to ferritin (T4F) were overexpressed in HEK293T cells and exposed to static magnetic fields (sMF, 1.4-5.0 mT; gradient: 1.62 mT/cm). An elevation of ROS levels was found under sMF in T4F-overexpressing cells, which could lead to lipid oxidation. Compared with the overexpression of TRPV4, ferritin in T4F promoted the generation of ROS under the stimulation of sMF, probably related to the release of iron ions from ferritin. Then, the resulting ROS regulated the opening of the TRPV4 channel, which was attenuated by the direct addition of ROS inhibitors or an iron ion chelator, highlighting a close relationship among iron release, ROS production, and TRPV4 channel activation. Taken together, these findings indicate that the produced ROS under sMF act on the TRPV4 channel, regulating the influx of calcium ions. The study would provide a scientific basis for the application of magnetic regulation in cellular or neural regulation and disease treatment and contribute to the development of the more sensitive regulatory technology.

Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 3: Alleviation of hypoxia, muscle-wasting, and modulation of redox functions in amyotrophic lateral sclerosis.

OBJECTIVE: The aim of this clinical study is to obtain evidence for the clinical efficacy of Bu-Shen-Jian-Pi formula (BSJP), a traditional Chinese medicine, used for the treatment of amyotrophic lateral sclerosis, a relatively rare, progressive and usually fatal disease possibly associated with alterations in tissue redox status, hypoxia, and muscular injury. BACKGROUND: The active agents in BSJP formula† causing apoptosis, modulation of redox changes, and alterations in the immune status have been studied previously by us using cell cultures. The findings from these investigations have been incorporated into pharmacology databases employed in our analysis of BSJP using network pharmacology analysis/artifical intelligence. This information has been used here in the design of the investigation and to optimize evaluation of the clinical efficacy and usefulness of this herbal medicine, as far as possible using evidence-based medicine criteria. MATERIALS AND METHODS: The design of the study was a randomized multi-center, controlled clinical trial in 127 patients with confirmed diagnoses of amyotrophic lateral sclerosis. Patients and investigator were double-blinded. Clinical efficacy was determined using the Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatment Scale (ALS-SSIT) and the Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R), together with tests of limb muscle strength using the manual muscle test (MMT), forced vital capacity (FVC), and clinical chemistry laboratory tests over a 20-week observation period. RESULTS: The scores of ALS-SSIT in the BSJP group increased significantly (22%) after treatment. The ALSFRS-R score in the BSJP group decreased significantly after treatment (19%). The rate of decrease in muscle function (MMT score) in most BSJP patients was lower than that in the control group, where the differences in the scores for the trapezius and triceps brachii were statistically significant compared to the control group. The fall in FVC in the BJSP group was significantly slower than in the control group. There were no marked differences observed in the frequency of side effects. Serum vitamin D3 levels in the BSJP group showed greater increases compared to the control group. CONCLUSION: BSJP treatment reduced the rate of progression of amyotrophic lateral sclerosis according to the ALS-SSITS and ALSFRS scores and significantly reduced the rate of deterioration in muscle function in the limbs of amyotrophic lateral sclerosis patients. The modes of action of BSJP in treating amyotrophic lateral sclerosis are probably diverse and multi targeted, some of which may involve regulation of serum vitamin D3 and alleviation of the impairments in liver and kidney function.

Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 2: Modulation of hypoxia, redox status, and mitochondrial protection in a neuroblastoma cell line, SH-SY5Y.

OBJECTIVE: To examine the mitochondrial protective effects of icariin, naringenin, kaempferol, and formononetin, potentially active agents in Bu-Shen-Jian-Pi formula (BSJP) identified using network pharmacology analysis. MATERIALS AND METHODS: Mitochondrial protection activity was determined using a hypoxia-reoxygenation in vitro model based on the neuroblastoma cell line SH-SY5Y and measurements of anti-ferroptotic activity. RESULTS: Icariin, naringenin, kaempferol, and formononetin showed mitochondrial protective activity involving diverse signaling pathways. The cytoprotective effects of formononetin depended on the inhibition of ferroptosis. Hypoxia-reoxygenation stimulation induced ferroptosis in SH-SY5Y cells. DISCUSSION: Ferroptosis is a key mechanism in nervous system diseases and is associated with hypoxia-reoxygenation injury. Naringenin and kaempferol were devoid of anti-ferroptotic activity. CONCLUSION: Evidence has been obtained showing that the core components: icariin, naringenin, kaempferol, and formononetin in BSJP formula have anti-hypoxic and mitochondrial protective activity of potential clinical importance in the treatment of amyotrophic lateral sclerosis and patients with symptoms of hypoxia.

Synthesis and in†vitro Anti-Inflammatory Activity of Novel Dendrobine Amide/Sulfonamide Derivatives.

A traditional Chinese medicine ingredient, dendrobine, has been demonstrated to have anti-inflammatory properties. However, due to its poor anti-inflammatory properties, its clinical use is limited. Consequently, we have designed and synthesized 32 new amide/sulfonamide dendrobine derivatives and screened their anti-inflammatory activities in vitro. Experiments showed that nitric oxide (NO) generation in lipopolysaccharide (LPS)-induced RAW264.7 cells was strongly reduced by derivative 14, with an IC50 of 2.96 µM. Western blot research revealed that 14 decreased the concentration-dependent expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (INOS). Molecular docking was used to predict the binding of the inflammation-associated proteins COX-2 and INOS to compound 14.

Tanshinone analog inhibits castration-resistant prostate cancer cell growth by inhibiting glycolysis in an AR-dependent manner.

Androgen receptor (AR) is one of the key targets for the treatment of castration-resistant prostate cancer (CRPC). Current endocrine therapy can greatly improve patients with CRPC. However, with the change of pathogenic mechanism, acquired resistance often leads to the failure of treatment. Studies have shown that tanshinone IIA (TS-IIA) and its derivatives have significant antitumor activity, and have certain AR-targeting effects, but the mechanism is unknown. In this study, the TS-IIA analog TB3 was found to significantly inhibit the growth of CRPC in vitro and in vivo. Molecular docking, cellular thermal shift assay, and cycloheximide experiments confirmed that AR was the target of TB3 and promoted the degradation of AR. Furthermore, TB3 can significantly inhibit glycolysis metabolism by targeting the AR/PKM2 axis. The addition of pyruvic acid could significantly alleviate the inhibitory effect of TB3 on CRPC cells. Besides, the knockdown of AR or PKM2 also could reverse the effect of TB3 on CRPC cells. Taken together, our study suggests that TS-IIA derivative TB3 inhibits glycolysis to prevent the CRPC process by targeting the AR/PKM2 axis.

Applying image features of proximal paracancerous tissues in predicting prognosis of patients with hepatocellular carcinoma.

BACKGROUND: Most of the methods using digital pathological image for predicting Hepatocellular carcinoma (HCC) prognosis have not considered paracancerous tissue microenvironment (PTME), which are potentially important for tumour initiation and metastasis. This study aimed to identify roles of image features of PTME in predicting prognosis and tumour recurrence of HCC patients. METHODS: We collected whole slide images (WSIs) of 146 HCC patients from Sun Yat-sen Memorial Hospital (SYSM dataset). For each WSI, five types of regions of interests (ROIs) in PTME and tumours were manually annotated. These ROIs were used to construct a Lasso Cox survival model for predicting the prognosis of HCC patients. To make the model broadly useful, we established a deep learning method to automatically segment WSIs, and further used it to construct a prognosis prediction model. This model was tested by the samples of 225 HCC patients from the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC). RESULTS: In predicting prognosis of the HCC patients, using the image features of manually annotated ROIs in PTME achieved C-index 0.668 in the SYSM testing dataset, which is higher than the C-index 0.648 reached by the model only using image features of tumours. Integrating ROIs of PTME and tumours achieved C-index 0.693 in the SYSM testing dataset. The model using automatically segmented ROIs of PTME and tumours achieved C-index of 0.665 (95% CI: 0.556-0.774) in the TCGA-LIHC samples, which is better than the widely used methods, WSISA (0.567), DeepGraphSurv (0.593), and SeTranSurv (0.642). Finally, we found the Texture SumAverage Skew HV on immune cell infiltration and Texture related features on desmoplastic reaction are the most important features of PTME in predicting HCC prognosis. We additionally used the model in prediction HCC recurrence for patients from SYSM-training, SYSM-testing, and TCGA-LIHC datasets, indicating the important roles of PTME in the prediction. CONCLUSIONS: Our results indicate image features of PTME is critical for improving the prognosis prediction of HCC. Moreover, the image features related with immune cell infiltration and desmoplastic reaction of PTME are the most important factors associated with prognosis of HCC.

Structurally Diverse Coumarins from Peucedanum praeruptorum and their Anti-Inflammatory Activities via NF-κB Signaling Pathway.

The phytochemical study of Peucedanum praeruptorum led to the isolation of twenty-five coumarins (1-25). Of which, (±) praeruptol A (±1), one pair of previous undescribed seco-coumarin enantiomers were obtained. Their structures were established according to HR-ESI-MS, NMR, X-ray single crystal diffraction analysis, as well as ECD calculation. All compounds were tested for anti-inflammatory activity in the RAW264.7 macrophage model, and eight compounds (7-10, and 13-16) exhibited significant inhibitory effects with IC50 values ranging from 9.48 to 34.66 µM. Among them, compound 7 showed the strongest inhibitory effect, which significantly suppressed the production of IL-6, IL-1ß, and TNF-α, as well as iNOS and COX-2 in a concentration-dependent manner. Further investigated results showed that compound 7 exerted an anti-inflammatory effect via the NF-κB signaling pathway.

New clerodane diterpenoids from Callicarpa pseudorubella and their antitumor proliferative activity.

Six previously undescribed clerodane diterpenes, cardorubellas A-F (1-6), along with seven known ones (7-13), were isolated from the aerial parts of Callicarpa pseudorubella. Their chemical structures were established by analysis of 1D and 2D NMR, HR-ESI-MS, X-ray diffraction, and electronic circular dichroism (ECD) data. Notably, cardorubella B (2) represented the first examples of naturally occurring succinic anhydride-containing clerodane diterpenes derivatives. The anti-proliferative activities of these compounds were assessed. Remarkably, compound 2 exhibited comparable inhibitory activity against HEL cell lines, surpassing the positive control with an IC50 value of 14.01 ± 0.77 µM, compared to 17.02 ± 4.70 µM for 5-fluorouracil.

Detection of chlorophyll content based on optical properties of maize leaves.

The chlorophyll content reflects plants' photosynthetic capacity, growth stage, and nitrogen status. Maize is one of the three widely planted gain crops in the world. In order to offer useful information for the development of chlorophyll content detectors of maize leaves, a single integrating sphere system was used to measure the transmittance and reflectance spectra of maize leaves over the wavelength range of 500-950 nm. The linear relationships of transmittance and reflectance with chlorophyll content were investigated. The feature wavelengths (FWs) sensitive to chlorophyll content were extracted from the full transmittance and reflectance spectra using the successive projections algorithm (SPA). The partial least squares regression (PLSR) models for predicting the chlorophyll content were established using the full spectra and extracted FWs. The results showed that there were obvious linear relationships between transmittance and reflectance with chlorophyll content of maize leaves and the best linear relationships were found at 709 nm and 714 nm, respectively, with the linear correlation coefficients of 0.801 and 0.696, and the root-mean-squares error (RMSEP) of 0.321 mg·g-1 and 0.405 mg·g-1, respectively. Eight and 6 FWs were extracted from the transmittance and reflectance spectra, respectively. The PLSR model established using the selected FWs from transmittance spectra had better prediction performance with RMSEP of 0.208 mg·g-1 than using full transmittance spectra. The built PLSR models using the full reflectance spectra and extracted FWs had poor robustness. This research offers some theoretical basis for developing a maize leaf chlorophyll content detector based on transmittance or reflectance.

Short sleep duration is associated with worse quality of life in Parkinson's disease: A multicenter cross-sectional study.

OBJECTIVE: To characterize sleep duration and investigate its association with quality of life among Parkinson's Disease (PD) patients. METHODS: In this multicenter cross-sectional study, 970 PD patients were divided into five groups based on self-reported sleep duration: <5, ≥5 to <6, ≥6 to <7, ≥7 to ≤8, and >8 h. The quality of life was evaluated using the 39-Item Parkinson's Disease Questionnaire (PDQ-39). Multivariable linear regression analysis, subgroup analysis, and mediation analysis were conducted to examine the association between sleep duration and quality of life. RESULTS: In multivariable linear regression model, patients with sleep duration (<5 h) had significantly higher PDQ-39 scores (ß = 8.132, 95 % CI: 3.99 to 12.266), especially in mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort (p < 0.05). The association between sleep duration (<5 h) and worse quality of life was more pronounced in patients with higher HY stage, longer disease duration, and sleep disorders. Moreover, a significant indirect effect of sleep duration (<5 h) on quality of life was observed, with UPDRS I, UPDRS II, and UPDRS IV scores acting as mediators. CONCLUSIONS: Short sleep duration (<5 h) is associated with worse quality of life among PD patients. This association was stronger among patients with advanced PD and sleep disorders, while non-motor symptoms and motor complications were identified as significant mediators in this association. These findings highlight the significance of adequate sleep duration and suitable interventions for sleep may help improve quality of life.

Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 1: Biogenic components and identification of targets and signaling pathways in amyotrophic lateral sclerosis patients.

BACKGROUND: There is evidence that Bu-Shen-Jian-Pi (BSJP), a traditional Chinese medicine, has curative effects in patients suffering from amyotrophic lateral sclerosis (ALS), a progressive and potentially fatal hypoxic condition. OBJECTIVE: To identify biogenic components in BSJP extracts having potential pharmacological efficacy in ALS. MATERIALS AND METHODS: Biogenic components in BSJP and their potential pharmacological targets and signaling pathways in ALS were identified and assessed using network pharmacology/hub node analysis. RESULTS: Network pharmacology analysis identified icariin, naringenin, kaempferol, quercetin, and formononetin as core components in BSJP with potential activity involving mitochondrial protection in patients with ALS. CONCLUSION: Network pharmacology analysis proved to be a successful screening tool for obtaining information from scientific databases on the pharmacology of biogenic components in BSJP showing potential therapeutic activity in ALS.

Discovery of tricyclic PARP7 inhibitors with high potency, selectivity, and oral bioavailability.

PARP7 has been recently identified as an effective drug target due to its specific role in tumor generation and immune function recovery. Herin, we report the discovery of compound 8, which contained a tricyclic fused ring, as a highly selective PARP7 inhibitor against other PARPs. In particular, compound 8 strongly inhibits PARP7 with an IC50 of 0.11 nM, and suppresses the proliferation of NCI-H1373 lung cancer cells with an IC50 of 2.5 nM. Compound 8 exhibits a favorable pharmacokinetic profile with a bioavailability of 104 % in mice, and 78 % in dogs. Importantly, daily treatment of 30 mg/kg of 8 induced 81.6 % tumor suppression in NCI-H1373 lung xenograft mice tumor models, which is significantly better than the clinical candidate, RBN-2397. These intriguing features highlight the promising advantages of 8 as an antitumor agent.

Radiomics-based machine learning and deep learning to predict serosal involvement in gallbladder cancer.

OBJECTIVE: Our study aimed to determine whether radiomics models based on contrast-enhanced computed tomography (CECT) have considerable ability to predict serosal involvement in gallbladder cancer (GBC) patients. MATERIALS AND METHODS: A total of 152 patients diagnosed with GBC were retrospectively enrolled and divided into the serosal involvement group and no serosal involvement group according to paraffin pathology results. The regions of interest (ROIs) in the lesion on all CT images were drawn by two radiologists using ITK-SNAP software (version 3.8.0). A total of 412 features were extracted from the CT images of each patient. The Mann‒Whitney U test was applied to identify features with significant differences between groups. Seven machine learning algorithms and a deep learning model based on fully connected neural networks (f-CNNs) were used for radiomics model construction. The prediction efficacy of the models was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: Through the Mann‒Whitney U test, 75 of the 412 features extracted from the CT images of patients were significantly different between groups (P < 0.05). Among all the algorithms, logistic regression achieved the highest performance with an area under the curve (AUC) of 0.944 (sensitivity 0.889, specificity 0.8); the f-CNN deep learning model had an AUC of 0.916, and the model showed high predictive power for serosal involvement, with a sensitivity of 0.733 and a specificity of 0.801. CONCLUSION: Radiomics models based on features derived from CECT showed convincing performances in predicting serosal involvement in GBC.

A novel L-shaped ortho-quinone analog as PLK1 inhibitor blocks prostate cancer cells in G2 phase.

Prostate cancer is the most common malignant tumor among men worldwide. Currently, the main treatments are radical prostatectomy, radiotherapy, chemotherapy, and endocrine therapy. However, most of them are poorly effective and induce side effects. Polo-like kinase 1 (PLK1) regulates cell cycle and mitosis. Its inhibitor BI2536 promotes the therapeutic effect of nilotinib in chronic myeloid leukemia, enhances the sensitivity of neural tube cell tumors to radiation therapy and PLK1 silencing enhances the sensitivity of squamous cell carcinoma to cisplatin. Therefore, the aim of this study was to evaluate the effect of the PLK1 inhibitor L-shaped ortho-quinone analog TE6 on prostate cancer. In vitro on prostate cancer cells showed that TE6 inhibited PLK1 protein expression and consequently cell proliferation by blocking the cell cycle at G2 phase. In vivo on a subcutaneous tumor model in nude mice confirmed that TE6 effectively inhibited tumor growth in nude mice, inhibited PLK1 expression and regulated the expression of cell cycle proteins such as p21, p53, CDK1, Cdc25C, and cyclinB1. Thus, PLK1 was identified as the target protein of TE6, these results reveal the critical role of PLK1 in the growth and survival of prostate cancer and point out the ability of TE6 on targeting PLK1, being a potential drug for prostate cancer therapy.

Limonoids from the Branches and Leaves of Aglaia lawii and Their Cytotoxic Activities.

Three undescribed limonoids (1-3), named aglaians G-I, and one new natural product azedaralide (4), together with nine known analogues (5-13) were isolated from the branches and leaves of Aglaia lawii by RP C18 column, silica gel column, Sephadex LH-20 column chromatography and preparative HPLC. The structures of the new compounds were elucidated by IR, HRESIMS, 1D, 2D NMR, electronic circular dichroism (ECD) calculations and X-ray crystallography diffraction analysis. The results of bioassay showed that the compound 12 exhibited potential inhibitory activity against six human tumor cell lines (MDA-MB-231, MCF-7, Ln-cap, A549, HeLa and HepG-2) with IC50 values as 8.0-18.6 µM.

Codonopsis pilosula polysaccharide alleviates rotenone-induced murine brain organoids death through downregulation of gene body DNA methylation modification in the ZIC4/PGM5/CAMTA1 axis.

Here, the protective mechanism of Codonopsis pilosula polysaccharide (CpP) against mouse brain organoids (mBO) damage was analyzed, and the rotenone affected the genomic epigenetic modifications and physiological activity of mouse brain organoids was examined. Pathological experiments have shown that rotenone significantly damaged the subcellular organelles of mouse brain organoids. According to RRBS-Seq, rotenone significantly promoted gene body hypermethylation modifications in mouse brain organoids. Molecular biology experiments have confirmed that rotenone significantly promoted the hypermethylation modification of Zic4, Pgm5, and Camta1 gene bodies in mouse brain organoids, and their expression levels were significantly lower than those of the control group. Bioinformatic analysis suggested that multiple binding motif of transcription factors ZIC4 (Zinc finger protein of the cerebellum 4) were present at the promoters of both the Pgm5 (Phosphoglucomutase 5) and Camta1 (Calmodulin binding transcription activator 1) genes. When the expression of Zic4 was silenced, the proliferation of mouse brain organoids was significantly reduced and the expression level of PGM5 was also significantly decreased. In addition, Codonopsis pilosula polysaccharide treatment of mouse brain organoids significantly reduced the cytotoxicity of rotenone, promoted cell cycle progression, increased intracellular glutathione activity, significantly induced the demethylation modification of the Zic4, Pgm5, and Camta1 gene bodies, and promoted the high expression of ZIC4 and PGM5. Therefore, the study confirmed that Codonopsis pilosula polysaccharide alleviated rotenone-induced mouse brain organoids death by downregulating DNA gene bodies methylation modification of the Zic4/Pgm5/Camta1 axis.

Copper-Catalyzed Oxygenative Skeletal Rearrangement of Tetrahydro-ß-carbolines Using H2 O and O2 as Oxygen Sources.

Herein, we report an unprecedented skeletal rearrangement reaction of tetrahydro-ß-carbolines enabled by copper-catalyzed single-electron oxidative oxygenation, in which H2 O and O2 act as oxygen sources to generate a unique 2-hydroxyl-3-peroxide indoline intermediate. The synthetic reactivity of 2-hydroxyl-3-peroxide indoline species was demonstrated by a unique multi-step bond cleavage and formation cascade. Using a readily available copper catalyst under open-air conditions, highly important yet synthetically difficult spiro[pyrrolidone-(3,1-benzoxazine)] products were obtained in a single operation. The synthetic utility of this methodology is demonstrated by the efficient synthesis of the natural products donaxanine and chimonamidine, as well as the 3-hydroxyl-pyrroloindoline scaffold, in just one or two steps.

Red Room-Temperature Phosphorescence Supramolecular Assemblies Based on Cucurbit[7]uril: Reversible Temperature Stimulation Response and Cell-Specific Silver Ion Imaging.

Solid-state materials with efficient room-temperature phosphorescence (RTP) emission have been widely used in materials science, and organic RTP-emitting systems with heavy-metal doping in aqueous solutions have attracted much attention in recent years. A novel supramolecular interaction was induced by host-guest assembly using cucurbit[7]uril (Q[7]) as the host and brominated naphthalimide phosphor as the guest. This interaction was further enhanced through synergistic chelation stimulated by analytical silver ion complexation. This approach facilitated the system's structural rigidity, intersystem crossing, and oxygen shielding. We achieved deep red phosphorescence emission in aqueous solution and ambient conditions along with quantitative determination of silver ions. The new complex exhibited good reversible thermoresponsive behavior and was successfully applied for the first time to target phosphorescence imaging of silver ions in the mitochondria of A549 cancer cells. These results are beneficial for constructing novel RTP systems with stimulus-responsive luminescence in aqueous solution, contributing to future research in bioimaging, detection, optical sensors, and thermometry materials.