Uncovering the ferroptosis related mechanism of laduviglusib in the cell-type-specific targets of the striatum in Huntington's disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder featured by abnormal movements, arising from the extensive neuronal loss and glial dysfunction in the striatum. Although the causes and pathogenetic mechanisms of HD are well established, the development of disease-modifying pharmacological therapies for HD remains a formidable challenge. Laduviglusib has demonstrated neuroprotective effects through the enhancement of mitochondrial function in the striatum of HD animal models. Ferroptosis is a nonapoptotic form of cell death that occurs as a consequence of lethal iron-dependent lipid peroxidation and mitochondrial dysfunction. However, the ferroptosis-related mechanisms underlying the neuroprotective effects of laduviglusib in the striatum of HD patients remain largely uncharted. In this study, we leveraged single-nucleus RNA sequencing data obtained from the striatum of HD patients in stages 2-4 to identify differentially expressed genes within distinct cell-type. We subsequently integrated these differentially expressed genes of HD, laduviglusib target genes and ferroptosis-related genes to predict the ferroptosis-related mechanisms underpinning the neuroprotective effects of laduviglusib in HD patients. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses unveiled that the effects of laduviglusib on direct pathway striatal projection neurons (dSPNs) is mainly associated with Th17 cell differentiation pathways. Conversely, its impact on indirect pathway striatal projection neurons (iSPNs) extends to the Neurotrophin signaling pathway, FoxO signaling pathway, and reactive oxygen species pathway. In microglia, laduviglusib appears to contribute to HD pathology via mechanisms related to Th17 cell differentiation and the FoxO signaling pathway. Further, molecular docking results indicated favorable binding of laduviglusib with PARP1 (associated with dSPNs and iSPNs), SCD (associated with astrocytes), ALOX5 (associated with microglia), and HIF1A (associated with dSPNs, iSPNs, and microglia). In addition, the KEGG results suggest that laduviglusib may enhance mitochondrial function and protect against neuronal loss by targeting ferroptosis-related signaling pathways, particularly mediated by ALOX5 in microglia. These findings provide valuable insights into the potential mechanisms through which laduviglusib exerts its effects on distinct cell-types within the HD striatum.

Circulating tumor DNA methylation: a promising clinical tool for cancer diagnosis and management.

Cancer continues to pose significant challenges to the medical community. Early detection, accurate molecular profiling, and adequate assessment of treatment response are critical factors in improving the quality of life and survival of cancer patients. Accumulating evidence shows that circulating tumor DNA (ctDNA) shed by tumors into the peripheral blood preserves the genetic and epigenetic information of primary tumors. Notably, DNA methylation, an essential and stable epigenetic modification, exhibits both cancer- and tissue-specific patterns. As a result, ctDNA methylation has emerged as a promising molecular marker for noninvasive testing in cancer clinics. In this review, we summarize the existing techniques for ctDNA methylation detection, describe the current research status of ctDNA methylation, and present the potential applications of ctDNA-based assays in the clinic. The insights presented in this article could serve as a roadmap for future research and clinical applications of ctDNA methylation.

Salvia miltiorrhiza inhibited lung cancer through aerobic glycolysis suppression.

Lung cancer causes the most cancer deaths and needs new treatment strategies urgently. Salvia miltiorrhiza is a classical Chinese herb and a strong candidate for tumor treatment. The study found that the aqueous extract of Salvia miltiorrhiza (DSAE), ethanol extract of Salvia miltiorrhiza (DSEE), and its active components danshensu (DSS) and dihydrotanshinone I (DHI), exhibited antineoplastic effects in vivo and in vitro. Meanwhile, DSAE, DSEE, DSS, and DHI reduced glycolysis metabolites (ATP, lactate, and pyruvate contents) production, decreased aerobic glycolysis enzymes, and inhibited Seahorse indexes (OCR and ECAR) in Lewis lung cancer cells (LLC). Data suggests that aerobic glycolysis could be inhibited by Salvia miltiorrhiza and its components. The administration of DSS and DHI further reduced the level of HKII in lung cancer cell lines that had been inhibited with HK-II antagonists (2-deoxyglucose, 2-DG; 3-bromo-pyruvate, 3-BP) or knocked down with siRNA, thereby exerting an anti-lung cancer effect. Although DSS and DHI decreased the level of HKII in HKII-Knock-In lung cancer cell line, their anti-lung cancer efficacy remained limited due to the persistent overexpression of HKII in these cells. Reiterating the main points, we have discovered that the anti-lung cancer effects of Salvia miltiorrhiza may be attributed to its ability to regulate HKII expression levels, thereby inhibiting aerobic glycolysis. This study not only provides a new research paradigm for the treatment of cancer by Salvia miltiorrhiza, but also highlights the important link between glucose metabolism and the effect of Salvia Miltiorrhiza.

Neural Circuit Mechanisms of Sinisan formula for the Treatment of adolescent Depression: prefrontal cortex to dorsal raphe nucleus.

ETHNOPHARMACOLOGICAL RELEVANCE: Sinisan formula (SNSF), documented in the classic books Shanghan Lun, is known for its ability to regulate liver-qi and treat depression. However, its underlying mechanism, particularly its effects on dynamic real-time neuron activity and circuits remains to be fully elucidated. AIM OF THE STUDY: This study aimed to investigate the antidepressant effect of SNSF and its central nervous system mechanism on depression-like behaviors, focusing on the prefrontal cortex (PFC) to dorsal raphe nucleus (DRN) neural circuit in a stress-induced adolescent animal model. MATERIALS AND METHODS: SNSF comprised four herbs, the root of Bupleurum chinense DC., the root of Paeonia lactiflora Pall., the fruit of Citrus aurantium L., the rhizome of Glycyrrhiza uralensis Fisch., in equal propotions. The adolescent depression animal model was induced by maternal separation (MS) and chronic restraint stress (CRS). In-vivo multichannel physiological electrodes were implanted into the PFC on PND 28 and animals were recorded 5 times during PND 35-46. From PND 47, the behavioral tests were performed to evaluate the antidepressant efficacy of SNSF. Subsequently, brain tissue was collected for Western blot and immunofluorescence staining analysis. Retro virus was injected into the DRN to explore sources of projections received by serotonergic (5-HTergic) neurons. And the PFC-to-DRN circuit was activated or inhibited through chemogenetic techniques to investigate the effects of SNSF on depression-like behaviors. RESULTS: Administration of SNSF for 18 days effectively alleviated depression-like behaviors in MS&CRS adolescent mice. The PFC emerged as the primary glutamatergic projection source of the DRN5-HT neurons. Following SNSF administration for 13/15/18 days, there was an increase in the firing rate of excitatory neurons and excitatory/inhibitory (E/I) ratio in the PFC. MS&CRS stress let to a reduction in the density of 5-HT+ and CaMKII + neurons in the DRN, accompanied by an increase in the density of GAD + neurons in the DRN, while SNSF administration reversed the alterations. Chemogenetic activation of the PFC-to-DRN circuit rescued the depression-like behaviors induced by MS&CRS, whereas suppression of this circuit attenuated the antidepressant effect of SNSF. CONCLUSIONS: SNSF significantly mitigated depression-like behaviors in MS&CRS mice. SNSF exerts its antidepressant effects by increasing the E/I ratio in the PFC and enhancing glutamatergic projections from the PFC to the DRN.