Activating Lobule VI PCTH+-Med Pathway in Cerebellum Blocks the Acquisition of Methamphetamine Conditioned Place Preference in Mice.

Cerebellum has been implicated in drug addiction; however, its underlying cellular populations and neuronal circuitry remain largely unknown. In the current study, we identified a neural pathway from tyrosine hydroxylase (TH)-positive Purkinje cells (PCTH+) in cerebellar lobule VI to calcium/calmodulin-dependent protein kinase II (CaMKII)-positive glutamatergic neurons in the medial cerebellar nucleus (MedCaMKII), forming the lobule VI PCTH+-MedCaMKII pathway in male mice. In naive male mice, inhibition of PCTH+ neurons activated Med neurons. During conditioned place preference (CPP) training, exposure to methamphetamine (METH) inhibited lobule VI PCTH+ neurons while excited MedCaMKII neurons in mice. Silencing MedCaMKII using a tetanus toxin light chain (tettox) suppressed the acquisition of METH CPP in mice but resulted in motor coordination deficits in naive mice. In contrast, activating lobule VI PCTH+ terminals within Med inhibited the activity of Med neurons and subsequently blocked the acquisition of METH CPP in mice without affecting motor coordination, locomotor activity, and sucrose reinforcements in naive mice. Our findings identified a novel lobule VI PCTH+-MedCaMKII pathway within the cerebellum and explored its role in mediating the acquisition of METH-preferred behaviors.

Pathological polarizations from microglia to astrocyte contributes to spatial memory deficit in methamphetamine abstinence mice.

Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.

Network pharmacology and experimental verification study on the mechanism of Hedyotis diffusa Willd in treating colorectal cancer.

This study aimed to evaluate the pharmacological mechanism of Hedyotis diffusa Willd against CRC (colorectal cancer) using network pharmacological analysis combined with experimental validation. The active components and potential targets of Hedyotis diffusa Willd were screened from the tax compliance management program public database using network pharmacology. The core anti-CRC targets were screened using a protein-protein interaction (PPI) network. The mRNA and protein expression of core target genes in normal colon and CRC tissues and their relationship with overall CRC survival were evaluated using The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Functional and pathway enrichment analyses of the potential targets were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The first six core targets with stable binding were molecular-docked with the active components quercetin and ß-sitosterol. Finally, the results of network pharmacology were verified using in vitro experiments. In total, 149 potential targets were identified by searching for seven types of active components and the intersection of all potential and CRC targets. PPI network analysis showed that ten target genes, including tumor protein p53 (TP53) and recombinant cyclin D1 (CCND1), were pivotal genes. GO enrichment analysis involved 2043 biological processes, 52 cellular components, and 191 molecular functions. KEGG enrichment analysis indicated that the anticancer effects of H. alba were mediated by tumor necrosis factor, interleukin-17, and nuclear factor-κB (NF-κB) signaling pathways. Validation of key targets showed that the validation results for most core genes were consistent with those in this study. Molecular docking revealed that the ten core target proteins could be well combined with quercetin and ß-sitosterol and the structure remained stable after binding. The results of the in vitro experiment showed that ß-sitosterol inhibited proliferation and induced apoptosis in SW620 cells. This study identified a potential target plant for CRC through network pharmacology and in vitro validation.

Value of prognostic nutritional index and controlling nutritional status score for advanced non-small cell lung cancer patients receiving PD-1 inhibitors.

OBJECTIVE: To explore the value of preoperative prognostic nutritional index (PNI) and controlling nutritional status (CONUT) score in predicting response and prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving programmed cell death protein 1 (PD-1) inhibitors. METHODS: A retrospective study was conducted in patients who received PD-1 inhibitors for advanced NSCLC. Patients were assigned by immunotherapy effects into response (partial and complete response, pCR) group (n=52) and non-response (non-pCR) group (n=132). The pathological and clinical data were collected for statistical analysis of factors influencing the immunotherapeutic response. The diagnostic value of PNI and CONUT score for response was assessed. The overall survival (OS) was observed over a 3-year follow-up. COX regression analysis was performed to identify risk factors affecting the survival. The effects of different PNI and CONUT scores on the survival were observed. RESULTS: Multivariate regression analysis showed that, the tumor-node-metastasis (TNM) stage (P=0.001), PNI (P<0.001), and CONUT score (P<0.001) were associated with response. The non-pCR group had a higher 3-year mortality rate and a shorter 3-year OS than the pCR group (P<0.001). COX regression analysis showed that low PNI and high CONUT score were risk factors for poor prognosis. Further analysis showed that patients with low PNI and high CONUT score had lower 3-year survival rates (P=0.005, P<0.001). CONCLUSION: High TNM stage, PNI<50, and CONUT score ≥5 are risk factors for poor response in patients with advanced NSCLC receiving PD-1 inhibitors, and low PNI and high CONUT score suggest poor prognosis.

The top 100 most cited papers in insomnia: A bibliometric analysis.

Objective: The number of citations to a paper represents the weight of that work in a particular area of interest. Several highly cited papers are listed in the bibliometric analysis. This study aimed to identify and analyze the 100 most cited papers in insomnia research that might appeal to researchers and clinicians. Methods: We reviewed the Web of Science (WOS) Core Collection database to identify articles from 1985 to 24 March 2022. The R bibliometric package was used to further analyze citation counts, authors, year of publication, source journal, geographical origin, subject, article type, and level of evidence. Word co-occurrence in 100 articles was visualized using VOS viewer software. Results: A total of 44,654 manuscripts were searched on the Web of Science. Between 2001 and 2021, the top 100 influential manuscripts were published, with a total citation frequency of 38,463. The top countries and institutions contributing to the field were the U.S. and Duke University. Morin C.M. was the most productive author, ranking first in citations. Sleep had the highest number of manuscripts published in the top 100 (n = 31), followed by Sleep Medicine Reviews (n = 9). The most cited manuscript (Bastien et al., Sleep Medicine, 2001; 3,384 citations) reported clinical validation of the Insomnia Severity Index (ISI) as a brief screening indicator for insomnia and as an outcome indicator for treatment studies. Co-occurrence analyses suggest that psychiatric disorders combined with insomnia and cognitive behavioral therapy remain future research trends. Conclusion: This study provides a detailed list of the most cited articles on insomnia. The analysis provides researchers and clinicians with a detailed overview of the most cited papers on insomnia over the past two decades. Notably, COVID-19, anxiety, depression, CBT, and sleep microstructure are potential areas of focus for future research.