Elucidating the mechanism of action of Isobavachalcone induced autophagy and apoptosis in non-small cell lung cancer by network pharmacology and experimental validation methods.

BACKGROUND: Lung cancer is the leading cause of cancer deaths, and non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer-related mortality. In recent years, there have been numerous treatments for non-small cell lung cancer, but the cure and survival rates are still extremely low. Isobavachalcone (IBC) belongs to the chalcone component of the traditional Chinese medicine Psoralea corylifolia L., and is a unique Protein kinase B (AKT) pathway inhibitor with significant anticancer effects. Previous studies have shown that IBC possess a variety of biological properties, including anti-cancer, anti-inflammatory, and antioxidant properties. This study focused on the use of network pharmacology analysis, molecular docking technology and experimental validation to elucidate the potential mechanisms of IBC for the treatment of NSCLC. METHODS: Screening key genes and pathways of IBC action in NSCLC using network pharmacology. The IBC target genes were from The Encyclopedia of Traditional Chinese Medicine (ETCM) and BATMAN-TCM databases, the NSCLC target genes were from GeneCards, Online Mendelian Inheritance in Man (OMIM) and The Therapeutic Target database (TTD) databases, both of which were taken as intersecting genes for protein-protein interaction network analysis and enrichment analysis, and the binding energies of the compounds to the core targets were further verified by molecular docking. Cell lines in vitro experiments were then performed to further unravel the mechanism of IBC for NSCLC. RESULTS: A total of 279 potential targets were retrieved by searching the intersection of IBC and NSCLC targets. Protein-protein interaction (PPI) network analysis indicated that 6 targets, including AKT1, RXRA, NCOA1, RXRB, RARA, PPARG were hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that IBC treatment of NSCLC mainly involves steroid binding, transcription factor activity, Pathways in cancer, cAMP signaling pathway, Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. Among them, the AMPK signaling pathway, which contained the largest number of enriched genes, may play a greater role in the treatment of NSCLC. Then, the results of in vitro experiment indicated that IBC could inhibit proliferation of NSCLC cells and induce cell autophagy and apoptosis. The results also showed that IBC could increase the protein expression of AMPK and decrease the protein expression of AKT and mammalian target of rapamycin (mTOR), suggesting that IBC can treat NSCLC by inducing cellular autophagy and apoptosis as well as modulating AMPK and AKT signaling pathways. CONCLUSIONS: In summary, this study provided a new insight into the protective mechanism of IBC against NSCLC through network pharmacology and experimental validation.

Effect of lace-up ankle brace on the tibiotalar and subtalar joint during the landing.

Objective: Ankle braces can affect the kinematics of the ankle joint during landing tasks. Previous studies were primarily relied on traditional marker-based motion capture systems, which pose limitations in non-invasively capturing the motion of the talus bone. The effect of ankle braces on the in vivo kinematics of the tibiotalar and subtalar joints during landing remains unknown. This study used a high-speed dual fluoroscopic imaging system (DFIS) and magnetic resonance imaging (MRI) to investigate effect of ankle braces on the in vivo kinematics of the tibiotalar and subtalar joints during landing. Methods: Fourteen healthy participants were recruited for this study. During the experiment, static three-dimensional MRI data were collected for each participant, and 3D ankle joint models for the calcaneus, talus, and tibia were constructed. The DFIS was used to capture the images of each participant performing a single-leg landing-jump task at a height of 40 cm. The images were captured once with and without a brace in the fatigue condition, which was induced by running. The six-degree-of-freedom (6DOF) kinematic data were obtained by 2D-3D registration. Results: The flexion-extension range of motion (ROM) (42.73 ± 4.76° vs. 38.74 ± 5.43°, p = 0.049) and anterior-posterior translation ROM (16.86 ± 1.74 mm vs. 15.03 ± 1.73 mm, p = 0.009) of the tibiotalar joint were decreased. The maximum inversion angle (-3.71 ± 2.25° vs. 2.11 ± 1.83°, p = 0.047) of the subtalar joint was decreased. Conclusion: The ankle brace limited the flexion-extension ROM of the tibiotalar joints and the inversion angle of the subtalar joint during landing.

Effects of fatigue on the in vivo kinematics and kinetics of talocrural and subtalar joint during landing.

Objective: Fatigue can affect the ankle kinematic characteristics of landing movements. Traditional marker-based motion capture techniques have difficulty in accurately obtaining the kinematics of the talocrural and subtalar joints. This study aimed to investigate the effects of fatigue on the talocrural and subtalar joints during the landing using dual fluoroscopic imaging system (DFIS). Methods: This study included fourteen healthy participants. The foot of each participant was scanned using magnetic resonance imaging to create 3D models. High-speed DFIS was used to capture images of the ankle joint during participants performing a single-leg landing jump from a height of 40 cm. Fatigue was induced by running and fluoroscopic images were captured before and after fatigue. Kinematic data were obtained by 3D/2D registration in virtual environment software. The joint kinematics in six degrees of freedom and range of motion (ROM) were compared between the unfatigued and fatigued conditions. Results: During landing, after the initial contact with the ground, the main movement of the talocrural joint is extension and abduction, while the subtalar joint mainly performs extension, eversion, and abduction. Compared to unfatigued, during fatigue the maximum medial translation (1.35 ± 0.45 mm vs. 1.86 ± 0.69 mm, p = 0.032) and medial-lateral ROM (3.19 ± 0.60 mm vs. 3.89 ± 0.96 mm, p = 0.029) of the talocrural joint significantly increased, the maximum flexion angle (0.83 ± 1.24° vs. 2.11 ± 1.80°, p = 0.037) of the subtalar joint significantly increased, and the flexion-extension ROM (6.17 ± 2.21° vs. 7.97 ± 2.52°, p = 0.043) of the subtalar joint significantly increased. Conclusion: This study contributes to the quantitative understanding of the normal function of the talocrural and subtalar joints during high-demand activities. During landing, the main movement of the talocrural joint is extension and abduction, while the subtalar joint mainly performs extension, eversion, and abduction. Under fatigue conditions, the partial ROM of the talocrural and subtalar joints increases.

Poly (ADP-ribose) polymerase 1 and neurodegenerative diseases: Past, present, and future.

Poly (ADP-ribose) polymerase 1 (PARP1) is a first responder that recognizes DNA damage and facilitates its repair. Neurodegenerative diseases, characterized by progressive neuron loss driven by various risk factors, including DNA damage, have increasingly shed light on the pivotal involvement of PARP1. During the early phases of neurodegenerative diseases, PARP1 experiences controlled activation to swiftly address mild DNA damage, thereby contributing to maintain brain homeostasis. However, in late stages, exacerbated PARP1 activation precipitated by severe DNA damage exacerbates the disease condition. Consequently, inhibition of PARP1 overactivation emerges as a promising therapeutic approach for neurodegenerative diseases. In this review, we comprehensively synthesize and explore the multifaceted role of PARP1 in neurodegenerative diseases, with a particular emphasis on its over-activation in the aggregation of misfolded proteins, dysfunction of the autophagy-lysosome pathway, mitochondrial dysfunction, neuroinflammation, and blood-brain barrier (BBB) injury. Additionally, we encapsulate the therapeutic applications and limitations intrinsic of PARP1 inhibitors, mainly including limited specificity, intricate pathway dynamics, constrained clinical translation, and the heterogeneity of patient cohorts. We also explore and discuss the potential synergistic implementation of these inhibitors alongside other agents targeting DNA damage cascades within neurodegenerative diseases. Simultaneously, we propose several recommendations for the utilization of PARP1 inhibitors within the realm of neurodegenerative disorders, encompassing factors like the disease-specific roles of PARP1, combinatorial therapeutic strategies, and personalized medical interventions. Lastly, the encompassing review presents a forward-looking perspective along with strategic recommendations that could guide future research endeavors in this field.

Targeting autophagy to discover the Piper wallichii petroleum ether fraction exhibiting antiaging and anti-Alzheimer's disease effects in Caenorhabditis elegans.

BACKGROUND: With population aging, the incidence of aging-related Alzheimer's disease (AD) is increasing, accompanied by decreased autophagy activity. At present, Caenorhabditis elegans (C. elegans) is widely employed to evaluate autophagy and in research on aging and aging-related diseases in vivo. To discover autophagy activators from natural medicines and investigate their therapeutic potential in antiaging and anti-AD effects, multiple C. elegans models related to autophagy, aging, and AD were used. METHOD: In this study, we employed the DA2123 and BC12921 strains to discover potential autophagy inducers using a self-established natural medicine library. The antiaging effect was evaluated by determining the lifespan, motor ability, pumping rate, lipofuscin accumulation of worms, and resistance ability of worms under various stresses. In addition, the anti-AD effect was examined by detecting the paralysis rate, food-sensing behavior, and amyloid-ß and Tau pathology in C. elegans. Moreover, RNAi technology was used to knock down the genes related to autophagy induction. RESULTS: We discovered that Piper wallichii extract (PE) and the petroleum ether fraction (PPF) activated autophagy in C. elegans, as evidenced by increased GFP-tagged LGG-1 foci and decreased GFP-p62 expression. In addition, PPF extended the lifespan and enhanced the healthspan of worms by increasing body bends and pumping rates, decreasing lipofuscin accumulation, and increasing resistance to oxidative, heat, and pathogenic stress. Moreover, PPF exhibited an anti-AD effect by decreasing the paralysis rate, improving the pumping rate and slowing rate, and alleviating Aß and Tau pathology in AD worms. However, the feeding of RNAi bacteria targeting unc-51, bec-1, lgg-1, and vps-34 abolished the antiaging and anti-AD effects of PPF. CONCLUSION: Piper wallichii may be a promising drug for antiaging and anti-AD. More future studies are also needed to identify autophagy inducers in Piper wallichii and clarify their molecular mechanisms.

Therapeutic potential of Polygala saponins in neurological diseases.

BACKGROUND: There are many types of neurological diseases with complex etiologies. At present, most clinical drugs can only relieve symptoms but cannot cure these diseases. Radix Polygalae, a famous traditional Chinese medicine from the root of plants of the genus Polygala, has the traditional effect of treating insomnia, forgetfulness, and palpitation and improving intelligence and other symptoms of neurological diseases. Saponins are important bioactive components of plants of the genus Polygala and exhibit neuroprotective effects. PURPOSE: This review aimed to summarize the traditional use of Polygala species and discuss the latest phytochemical, pharmacological, and toxicological findings, mainly with regard to Polygala saponins in the treatment of neurological disorders. METHODS: Literature was searched and collected using databases, including PubMed, Science Direct, CNKI, and Google Scholar. The search terms used included "Polygala", "saponins", "neurological diseases", "Alzheimer's disease", "toxicity", etc., and combinations of these keywords. A total of 1202 papers were retrieved until August 2022, and we included 135 of these papers on traditional uses, phytochemistry, pharmacology, toxicology and other fields. RESULTS: This literature review mainly reports on the traditional use of the Polygala genus and prescriptions containing Radix Polygalae in neurological diseases. Phytochemical studies have shown that plants of the genus Polygala mainly include saponins, flavonoids, oligosaccharide esters, alkaloids, coumarins, lignans, flavonoids, etc. Among them, saponins are the majority. Modern pharmacological studies have shown that Polygala saponins have neuroprotective effects on a variety of neurological diseases. Its mechanism of action involves autophagic degradation of misfolded proteins, anti-inflammatory, anti-apoptotic, antioxidative stress and so on. Toxicological studies have shown that Polygala saponins trigger gastrointestinal toxicity, and honey processing and glycosyl disruption of Polygala saponins can effectively ameliorate its gastrointestinal side effect. CONCLUSION: Polygala saponins are the major bioactive components in plants of the genus Polygala that exhibit therapeutic potential in various neurological diseases. This review provides directions for the future study of Polygala saponins and references for the clinical use of prescriptions containing Radix Polygalae for the treatment of neurological diseases.