This paper summarized the clinical experience in treating ischemic stroke with jiao （角） medicine （triple-medicinal combinations）. Clinically， the combination of Roucongrong （Cistanche deserticola）-Shanyurou （Cornus officinalis）-Guijia （Testudinis Carapax et Plastrum） is used to nourish the kidneys and liver for disease mechanism of liver-kidney depletion， and foundation deficiency due to insufficient essence and blood； the combination of Xixiancao （Sigesbeckia orientalis）-Tianma （Gastrodia elata）-Gouteng （Uncaria rhynchophylla） is used to extinguish wind and eliminate dampness for treating numbness and swelling of limbs caused by ischemic stroke； the combination of Shichangpu （Acorus Tatarinowii）-Yuanzhi （Polygala tenuifolia）-Yujin （Curcumae Radix） is used to improve intelligence， refresh the brain， and clear the mind for treating cognitive impairment， memory loss， or speech difficulties caused by ischemic stroke； the combination of Banxia （Pinellia ternata）-Baizhu （Atractylodes macrocephala）- Tianma （Gastrodiae rhizoma） is used to dissolve phlegm and extinguish wind， unblock meridians and relieve dizziness for treating dizziness or headache caused by ischemic stroke； the combination of Danggui （Angelica sinensis radix）- Chuanxiong （Ligusticum chuanxiong）-Guijianyu （Euonymus alatus） is used to nourish and activate blood circulation， remove blood stasis and unblock meridians for treating weak limbs and activiry difficulty caused by ischemic stroke； the combination of Chaihu （Bupleurum chinense）-Zhiziz （Gardenia jasminoides）-Guanye Jinsitao （Hypericum perforatum） is used to soothe the liver and resolve constraint， cool the blood and calm the mind for treating emotional complications.

Xiang thinking is a cognitive approach that reflects the relationships between phenomena and their underlying principles by analyzing their external manifestations through methods such as analogy， reasoning， deduction， and symbolism. This article applied xiang thinking to analyze the etiology and pathogenesis of "wind， fire， phlegm， and blood stasis" in stroke， thereby exploring its impact on the principles of syndrome differentiation and treatment of this condition. Meanwhile， the article traced the construction process of xiang thinking， and interpreted the concept of "toxin pathogen" in traditional Chinese medicine from four perspectives， state， attribute， origin， and law. Furthermore， the relationship between the process of constructing xiang thinking and the origin of etiology， identification methods， pathogenesis evolution， and treatment strategies for stroke with syndrome of combined blood stasis and toxin was explored， so as to provide insights into research on the etiology and pathogenesis of stroke， as well as clinical diagnosis and treatment approaches.

BACKGROUND: Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens. METHODS: Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ. RESULTS: This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 ( COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival. CONCLUSION P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.
Temozolomide ; Humans ; Glioblastoma/drug therapy* ; Animals ; Mice ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; YAP-Signaling Proteins ; Hydroxylation ; Dacarbazine/pharmacology* ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Collagen/biosynthesis* ; Collagen Type I/metabolism* ; Prolyl Hydroxylases/metabolism* ; Antineoplastic Agents, Alkylating/therapeutic use*

Xiang thinking is the key way of thinking to construct the life model of human body in traditional Chinese medicine （TCM）， and the theory of ascending and descending of qi movement is an important manifestation of xiang thinking in the theory of TCM. Based on the theory of qi movement， this paper interpreted the mechanism of ischemic stroke through the perspective of xiang thinking "earth weakness - wood constraint - fire hyperactivity"， as "earth weakness in the central and dampness accumulated to phlegm" "wood constraint and stirring wind led to blood stasis" and "fire hyperactivity and fire toxin showed flaming upward" due to disorder of qi movement. Combined with the "xiang of medicinal properties and therapy methods" to discuss the treatment and prescriptions of ischaemic stroke， applying wind medicinals to elevate ji-earth （己土） and yi-wood （乙木）， so that phlegm and stasis can be eliminated， and cold medicinals to descend jia-wood （甲木） and wu-earth （戊土） so that fire toxin can be cleared， with a view to restore ascending and descending of qi movement for ischaemic stroke.

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Objective To compare the application of main concept analysis(MCA)and story narration as-sessment(SNA)in aphasia discourse assessment,and study their clinical applicability.Methods A total of 8 apha-sic and 22 healthy control subjects were recruited.Local sequential picture materials were used to elicit language samples.The differences between groups in the assessment results of the MCA and the SNA were compared,the consistency of the assessment results of the two methods were also analyzed.The inter-rater and the intra-rater reli-ability of the two methods was discussed.Results The results of the MCA showed that the number of accurate and complete(AC)main concepts(P＜0.01),the number of accurate and complete main concepts per minute(AC/min)(P＜0.05)and main concept scores(MC scores)(P＜0.05)of the aphasia group were significantly lower than those of the healthy group.The number of absent(AB)main concepts(P＜0.05)were significantly higher than those of the control group.As for the result of SNA,the score of the content of sub picture description(P＜0.05),the total score of sub picture description(P＜0.05)and the total score of overall description(P＜0.05)in the aphasia group were significantly less than those in the control group(P＜0.05).No significant difference be-tween the standardized scores of the two methods were observed,and inter-rater and the intra-rater reliability were both in a good range.Conclusion The clinical applicability of the two methods is excellent and the evaluation results are conststent.The MCA has outstanding advantages in evaluating the quality and quantity of information,while SNA examines the syntax and content organization,which can reflect the overall discourse performance.

Objective:To investigate mRNA and N6-methyladenosine (m6A) changes in retinal pigment epithelium (RPE) cells treated with recombinant human methyl-CpG binding protein 2 (MeCP2) and the mechanisms.Methods:The passaged ARPE-19 cells were divided into normal control and MeCP2 groups after adhesion culture.Cells in the normal control group were continuously cultured in normal culture medium, and the cells in the MeCP2 group were cultured in culture medium containing a final concentration of 20 ng/ml of recombinant human MeCP2 protein for 72 hours.Transcriptomic sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq) were used to extract and analyze total RNA.Differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were screened using the edgeR software package based on P<0.05.The biological function of differential genes was determined by gene ontology (GO) enrichment analysis, and the pathway enrichment analysis was performed by Kyoto Encyclopedia of Genes and Genomes (KEGG).Intersection of genes between DEGs and DMGs were screened, and real-time fluorescence quantitative PCR was used to determine the mRNA expression levels of differential genes. Results:A total of 100 DEGs and 7 441 DMGs genes were screened.According to enrichment analysis, the DEGs were enriched to extracellular matrix (ECM)-receptor interaction, cell division, phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway and so on.The DMGs were associated with microtubule cytoskeleton, angiogenesis, epidermal growth factor receptor (ErbB) signaling pathway, advanced glycation end-products (AGEs) -glycation end-products receptor (RAGE) signaling pathway, mammalian target of rapamycin (mTOR) signaling pathway, Notch signaling pathway and transforming growth factors-β (TGF-β) signaling pathway and so on.There were 24 up-regulated and 76 down-regulated DEGs.Five DMGs had hypermethylation peaks, and 7 439 DMGs had hypomethylation peaks.After annotation of peaks, 7 626 genes in the normal control group and 8 006 genes in the MeCP2 group had m6A methylation, with 7 360 intersecting genes between the two groups.The m6A methylation in the normal control group and MeCP2 group was concentrated in the CDS, intron and 3'-untranslated region (3'UTR) regions of the transcript, with the methylation ratio of 23.62%/22.27%, 48.53%/48.35% and 23.66%/25.28%, respectively.Joint analysis showed that CSPG5 and RBP1 genes related to the epithelial-mesenchymal transition (EMT) had lower amount of mRNA and m6A.Fluorescence quantitative PCR results showed that the relative mRNA expression levels of GSPG5, RBP1 and ZNF484 in MeCP2 group were significantly lower than those in normal control group ( t=7.885, 7.613, 7.345; all at P<0.01). Conclusions:The regulatory mechanism of MeCP2 on EMT in RPE cells is related to m6A methylation modification. CSPG5 and RBP1 genes may be the target genes of m6A methylation and participate in the EMT regulated by MeCP2.

Objective To investigate the correlation between red blood cell distribution width(RDW),systemic immune-inflammation index(SII)and major depressive disorder(MDD).Methods The clinical data of 176 MDD patients hospitalized in the clinical psychology department of our hospital from 2020 to 2022 and 209 non-MDD comparators who were routinely examined in Hebei General Hospital were retrospectively analyzed.Blood analysis was conducted to obtain values of RDW,SII,and red blood cell distribution width/platelet ratio(RPR).The data was used to plot the receiver operator characteristic(ROC)curve to determine the optimal threshold and the area under the curve(AUC)for RDW to discriminate between patients and controls.Result Patients in the MDD group had significantly higher RDW[median and quartiles:13.20(12.70,13.98)vs.12.80(12.40,13.35)],and SII levels[median and quartiles 510.87(350.95,878.12)vs.405.33(313.74,539.92)]compared with those in non-MDD group(P<0.05).There was no significant difference in RPR between the two groups(P>0.05).Multifactorial logistic regression analysis showed that RDW was positively correlated with MDD after adjusting for confounders(OR=3.086,95% CI:1.926-4.944).ROC curve showed that the optimal threshold for RDW to differentiate the risk of developing MDD was 12.85,with an AUC of 0.647(95% CI:0.592-0.702;P<0.001).Conclusion Present study shows that high RDW is a risk factor for the occurrence of MDD and an important parameter for the risk of developing depression.

Background: s/Aims: Transmembrane 6 superfamily member 2 (TM6SF2) E167K variant is closely associated with the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the role and mechanism of TM6SF2 E167K variant during MASLD progression are not yet fully understood. Methods: The Tm6sf2167K knock-in (KI) mice were subjected to high-fat diet (HFD). Hepatic lipid levels of Tm6sf2167K KI mice were detected by lipidomics analysis. Thin-layer chromatography (TLC) was used to measure the newly synthesized triglyceride (TG) and phosphatidylcholine (PC). Results: The TM6SF2 E167K variant significantly aggravated hepatic steatosis and injury in HFD-induced mice. Decreased polyunsaturated PC level and increased polyunsaturated TG level were found in liver tissue of HFDinduced Tm6sf2167K KI mice. Mechanistic studies demonstrated that the TM6SF2 E167K variant increased the interaction between TM6SF2 and PNPLA3, and impaired PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from TG to PC. The TM6SF2 E167K variant increased the level of fatty acid-induced malondialdehyde and reactive oxygen species, and decreased fatty acid-downregulated cell membrane fluidity. Additionally, the TM6SF2 E167K variant decreased the level of hepatic PC containing C18:3, and dietary supplementation of PC containing C18:3 significantly attenuated the TM6SF2 E167K-induced hepatic steatosis and injury in HFD-fed mice. Conclusions The TM6SF2 E167K variant could promote its interaction with PNPLA3 and inhibit PNPLA3-mediated transfer of PUFAs from TG to PC, resulting in the hepatic steatosis and injury during MASLD progression. PC containing C18:3 could act as a potential therapeutic supplement for MASLD patients carrying the TM6SF2 E167K variant.

ObjectiveTo investigate the comprehensive spoken communication performance of children with disabilities, and explore the related individual and environmental factors. MethodsFrom August to November, 2022, questionnaires of Communication Function Scale for Children based on ICF-CY were distributed online to parents of healthy children and children with disabilities aged two years to five years and eleven months in Shanghai, Nanjing and other areas. ResultsA total of 500 copies were sent out, and 407 valid questionnaires were returned, including 84 healthy children, 85 with hearing impairment, 119 with mental retardation, 35 with cerebral palsy and 84 with autism. There were significant differences in the comprehensive spoken communication function performance among the children with different impairment types (F = 127.618, P < 0.001). The comprehensive spoken communication ability was significantly poorer in the children with disabilities than in the healthy children (P < 0.05), and the ability was better in hearing-impaired children than in the children with other disabilities (P < 0.05). The higher the education of mother (r = -0.311, P < 0.001) and father (r = -0.280, P < 0.001), and family annual income (r = -0.228, P < 0.001), the better the children's comprehensive spoken communication performance; the children's comprehensive spoken communication performance was better when the family used Putonghua as unified communication language (r = 0.210, P < 0.001). ConclusionThe comprehensive spoken communication performance for children with disabilities is heterogeneous among different impairment types, and is affected by parents' education, family annual income, and family communication language.