Aberrant Resting-State Functional Connectivity in MDD and the Antidepressant Treatment Effect-A 6-Month Follow-Up Study.

BACKGROUND: The mechanism by which antidepressants normalizing aberrant resting-state functional connectivity (rsFC) in patients with major depressive disorder (MDD) is still a matter of debate. The current study aimed to investigate aberrant rsFC and whether antidepressants would restore the aberrant rsFC in patients with MDD. METHODS: A total of 196 patients with MDD and 143 healthy controls (HCs) received the resting-state functional magnetic resonance imaging and clinical assessments at baseline. Patients with MDD received antidepressant treatment after baseline assessment and were re-scanned at the 6-month follow-up. Network-based statistics were employed to identify aberrant rsFC and rsFC changes in patients with MDD and to compare the rsFC differences between remitters and non-remitters. RESULTS: We identified a significantly decreased sub-network and a significantly increased sub-network in MDD at baseline. Approximately half of the aberrant rsFC remained significantly different from HCs after 6-month treatment. Significant overlaps were found between baseline reduced sub-network and follow-up increased sub-network, and between baseline increased sub-network and follow-up decreased sub-network. Besides, rsFC at baseline and rsFC changes between baseline and follow-up in remitters were not different from non-remitters. CONCLUSIONS: Most aberrant rsFC in patients with MDD showed state-independence. Although antidepressants may modulate aberrant rsFC, they may not specifically target these aberrations to achieve therapeutic effects, with only a few having been directly linked to treatment efficacy.

Si-Ni-San reduces lipid droplet deposition associated with decreased YAP1 in metabolic dysfunction-associated fatty liver disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide. However, its complex pathogenesis and lack of effective drugs for treating it present significant challenges. Si-Ni-San (SNS) is one of the representative formulas for treating patients with MAFLD in traditional Chinese medicine (TCM) clinics. According to our previous work, SNS reduces lipid droplet (LD) deposition in livers of mice with MAFLD. AIM OF THE STUDY: To elucidate the mechanism of SNS in reducing LD deposition in MAFLD. MATERIALS AND METHODS: First, LD areas were detected with Oil red O staining in HepG2 cells induced by oleic acid (OA). Cell Counting Kit-8 (CCK-8) assay was used to test cell viability after treatment with different concentrations of SNS serum. The expression of Yes-associated protein 1 (YAP1) was monitored by Western blot. Second, C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks and gavaged with SNS decoction during the 11th and 12th weeks. Then, the weight of the body and the liver was examined. LD numbers and their locations in the liver were detected by triglyceride (TG) assay and hematoxylin and eosin staining (H&E). The expression levels of YAP1 and perilipin2 (PLIN2) were detected using Western blot and immunohistochemistry (IHC) in liver tissues. Finally, active ingredients of SNS decoction and SNS serum were identified by liquid chromatography-mass spectrometry (LC-MS). Finally, molecular docking was performed between the compounds in SNS and YAP1 to analyze their active interaction. RESULTS: Cellular experiments showed that SNS serum reduced LD vacuoles and YAP1 expression in OA-induced HepG2 cells. Animal experiments confirmed that LD vacuoles, PLIN2 expression (3.16-fold), and YAP1 expression (2.50-fold) were increased in the HFD group compared with the normal diet (ND) group. SNS reduced LD vacuoles, TG content (0.84-fold), PLIN2 expression (0.33-fold), and YAP1 expression (0.27-fold) compared with the normal saline (NS) group in Yap1Flox mice with MAFLD. In SNS, baicalein-6-glucuronide, desoxylimonin, galangin-7-glucoside, glycyrrhizic-acid, licoricesaponin-K2, and nobiletin showed a high binding effect with YAP1. Knockout of hepatocyte YAP1 reduced LD vacuoles, TG content (0.40-fold), and PLIN2 expression (0.62-fold) in mice. Meanwhile, SNS reduced LD vacuoles, TG content (0.70-fold), and PLIN2 expression (0.19-fold) in Yap1LKO mice with MAFLD. The effect of SNS in reducing TG and PLIN2 was diminished in Yap1LKO mice compared with Yap1Flox mice. CONCLUSION: SNS reduced LD deposition and YAP1 expression in MAFLD liver cells both in vivo and in vitro. YAP1 was highly expressed in livers with MAFLD, and knockout of hepatocellular YAP1 reduced LD deposition in mice. SNS reduced LD deposition associated with decreased YAP1 in MAFLD liver cells.

YAP1 suppression inhibits autophagy and improves the efficacy of anti-PD-1 immunotherapy in hepatocellular carcinoma.

Anti-PD-1 immunotherapy is a promising treatment for hepatocellular carcinoma (HCC), but some patients with HCC do not experience clinical benefits. Autophagy promotes tumor progression and participates in drug resistance. Previous studies have revealed that suppressing the expression level of Yes-associated protein 1 (YAP1) improves anti-PD-1 therapy efficacy. Therefore, the relationship between YAP1 expression and autophagy activity during anti-PD-1 treatment was investigated in this study. A positive correlation was found between the expression level of YAP1 and LC3B by analyzing The Cancer Genome Atlas (TCGA), UALCAN databases, and HCC tissue microarray. Meanwhile, YAP1 expression and autophagy constituted positive feedback, in which YAP1 inhibition decreased the autophagy activity in liver tumor cells by hepatocyte-specific Yap1 knockout mice. Further, anti-PD-1 treatment increased autophagy and YAP1 expression levels in the cancer tissues from DEN/TCPOBOP-induced liver cancer mice. Finally, Yap1 knockout suppressed autophagy and improved anti-PD-1 therapy efficacy in hepatocyte-specific Yap1 knockout mice with liver tumors. These results suggested that YAP1 suppression was sensitized to anti-PD-1 treatment and inhibited autophagy activity in liver tumor cells. YAP1 is a promising target for improving the efficacy of anti-PD-1 immunotherapy in HCC.

Integrated analysis of transcriptomics and metabolomics in human hepatocellular carcinoma HepG2215 cells after YAP1 knockdown.

Yes-associated protein 1 (YAP1) plays a critical role in hepatocellular carcinoma (HCC). Inhibition of YAP1 expression suppresses HCC progression, but the underlying mechanism is still unclear. In this study, we studied the effects and molecular mechanisms of YAP1 knockdown on the growth and metabolism in human HCC HepG2215 cells. Inhibition of YAP1 expression inhibits the proliferation and metastasis in HepG2215 cells, and differentially expressed genes (DEGs) and metabolites were identified in shYAP1-HepG2215 cells. Further, 805 DEGs, mainly associated with metabolism and particularly lipid metabolism, were identified by transcriptome sequencing analyses in shYAP1-HepG2215 cells. YAP1 knockdown increased albumin (ALB) levels by Protein-protein interaction (PPI) network analyses in HepG2215 cells. Metabolomic profiling identified 37 metabolites with significant differences in the shYAP1 group, and amino acid metabolism generally decreased in the shYAP1 group. Comprehensive analysis of transcriptomics and metabolomics revealed that the ATP-binding cassette (ABC) transporters play a central role after YAP1 knockdown in HepG2215 cells. Therefore, YAP1 knockdown inhibited HCC growth, which affected the metabolism of lipids and amino acids by regulating the expression of ALB and ABC transporters in HepG2215 cells.

Wolfberry enhanced the abundance of Akkermansia muciniphila by YAP1 in mice with acetaminophen-induced liver injury.

Drug-induced liver injury (DILI) by acetaminophen (APAP) was one of the most challenging liver diseases. Wolfberry (Lycium barbarum L.), a traditional Chinese medicinal material and food supplement, has a potential effect on increasing the abundance of Akkermansia muciniphila (A. muciniphila) in mice colons. However, the effect and mechanism of wolfberry remain unclear in APAP-induced DILI. In this study, wolfberry promoted the proliferation of activated-A. muciniphila in vitro and in vivo. For the first time, we detected that the activated-A. muciniphila but not the killed-A. muciniphila increased the expression level of Yes-associated protein 1 (YAP1) in the liver and alleviated liver injury in APAP-induced DILI mice. Mechanically, A. muciniphila improved the intestinal mucosal barrier and reduced lipopolysaccharide (LPS) content in the liver, leading to the increased expression level of YAP1. Furthermore, wolfberry increased the A. muciniphila abundance in the colon and YAP1 expression in the liver from APAP-induced DILI mice, which promoted the recovery of APAP-induced liver injury. Meanwhile, wolfberry combination with A. muciniphila synergistically increased AKK abundance and YAP1 expression in the liver. Our research provides an innovative strategy to improve DILI.

Dihydroartemisinin reduced lipid droplet deposition by YAP1 to promote the anti-PD-1 effect in hepatocellular carcinoma.

BACKGROUND: Anti-PD-1 was used to treat for many cancers, but the overall response rate of monoclonal antibodies blocking the inhibitory PD-1/PD-L1 was less than 20%. Lipid droplet (LD) deposition reduced chemotherapy efficacy, but whether LD deposition affects anti-PD-1 treatment and its mechanism remains unclear. Dihydroartemisinin (DHA) was FDA proved antimalarial medicine, but its working mechanism on LD deposition has not been clarified. PURPOSE: This study aimed to elucidate the mechanism of DHA reducing LDs deposition and improving the efficacy of anti-PD-1. METHODS: LD numbers and area were separately detected by electron microscopy and oil Red O staining. The expression of YAP1 and PLIN2 was detected by immunohistochemical staining in liver cancer tissues. Transcription and protein expression levels of YAP1 and PLIN2 in cells were detected by qRT-PCR and Western blot after DHA treated HepG2215 cells and Yap1LKO mice. RESULTS: LD accumulation was found in the liver tumor cells of DEN/TOPBCOP-induced liver tumor mice with anti-PD-1 treatment. But DHA treatment or YAP1 knockdown reduced LD deposition and PLIN2 expression in HepG2215 cells. Furthermore, DHA reduced the LD deposition, PLIN2 expression and triglycerides (TG) content in the liver tumor cells of Yap1LKO mice with liver tumor. CONCLUSION: Anti-PD-1 promoted LD deposition, while YAP1 knockdown/out reduced LD deposition in HCC. DHA reduced LD deposition by inhibiting YAP1, enhancing the effect of anti-PD-1 therapy.

A joint model of household time use and task assignment for elderly couples with multiple constraints.

Household time-use patterns are expected to reflect each household member's daily activity participation and duration with intra-household interactions constrained by multiple budgets. Among various activities, the allocated activity derived from undertaking a household task is studied relatively less in the literature. Who will take an allocated activity is a discrete choice problem of household task assignment, and once a household member is assigned with one household task, other members will have more time to do other activities. To better understand household time-use patterns affected by household task assignment, this paper proposed a joint household-level multiple discrete-continuous extreme value-multinomial logit (MDCEV-MNL) model with multiple constraints. The Karush-Kuhn-Tucker (KKT) method combined with the simulation-based maximum likelihood estimation method is proposed to estimate the proposed model. Based on the household activity-travel data from Beijing of China, the proposed model is customized to explore elderly couples' time-use patterns with intra-household interactions affected by household task assignment. Following the findings, policy implications are suggested to build an age-friendly society.

A constrained multinomial Probit route choice model in the metro network: Formulation, estimation and application.

Considering that metro network expansion brings us with more alternative routes, it is attractive to integrate the impacts of routes set and the interdependency among alternative routes on route choice probability into route choice modeling. Therefore, the formulation, estimation and application of a constrained multinomial probit (CMNP) route choice model in the metro network are carried out in this paper. The utility function is formulated as three components: the compensatory component is a function of influencing factors; the non-compensatory component measures the impacts of routes set on utility; following a multivariate normal distribution, the covariance of error component is structured into three parts, representing the correlation among routes, the transfer variance of route, and the unobserved variance respectively. Considering multidimensional integrals of the multivariate normal probability density function, the CMNP model is rewritten as Hierarchical Bayes formula and M-H sampling algorithm based Monte Carlo Markov Chain approach is constructed to estimate all parameters. Based on Guangzhou Metro data, reliable estimation results are gained. Furthermore, the proposed CMNP model also shows a good forecasting performance for the route choice probabilities calculation and a good application performance for transfer flow volume prediction.