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Abstract Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.

Accelerated by technological advancements, while online platforms equipped with recommendation algorithms offer convenience to obtain information, it also brought algorithm bias, shaping the norms and behaviors of their users. The filter bubble, conceived as a negative consequence of algorithm bias, means the reduction of the diversity of users’ information consumption, garnering extensive attention. Previous research on filter bubbles typically used users’ self-reported or behavioral data independently. However, existing studies have disputed whether filter bubbles exist on the platform, possibly owing to variations in measurement methods. In our study, we took content category diversity to measure the filter bubbles and innovatively used a combination of participants’ self-reported and website behavioral data, examining filter bubbles on a single online video platform (Bilibili). We conducted a questionnaire survey among 337 college students and collected 3,22,324 browsing records with their informed authorization, constituting the dataset for research analysis. The existence of filter bubbles on Bilibli is found, such that diversity will decrease when viewing Game videos increases. Furthermore, we considered the factors that influence filter bubbles from the perspective of demographics and user behavior. In demographics, female and non-member users are more likely to be trapped in filter bubbles. In user behavior, results of feature importance analysis indicate that the diversity of information consumption of heavy users is higher than others, and both activity and fragmentation have an impact on the formation of filter bubbles, but in different directions. Finally, we discuss the reasons for these results and a theoretical explanation that the filter bubbles effect may be lower than we thought for both heavy and normal users on online platforms. Our conclusions provide valuable insights for understanding filter bubbles and platform management.

Senescence of activated hepatic stellate cells (aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression. Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). But little is known about how alanine-serine-cysteine transporter type-2 (ASCT2), a high affinity glutamine transporter, affects HSC senescence and SASP during liver fibrosis. Here, we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers. We first discovered ASCT2 inhibition induced HSCs to senescence in vitro and in vivo. The proinflammatory SASP were restricted by ASCT2 inhibition at senescence initiation to prevent paracrine migration. Mechanically, ASCT2 was a direct target of glutaminolysis-dependent proinflammatory SASP, interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82. From a translational perspective, atractylenolide III is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2. The presence of –OH group in atractylenolide III is suggested to be favorable for the inhibition of ASCT2. Importantly, atractylenolide III could be utilized to treat liver fibrosis mice. Taken together, ASCT2 controlled HSC senescence while modifying the proinflammatory SASP. Targeting ASCT2 by atractylenolide III could be a therapeutic candidate for liver fibrosis.

Both the liver and bone are important secretory organs in the endocrine system. By secreting organ factors (hepatokines), the liver regulates the activity of other organs. Similarly, bone-derived factors, osteokines, are created during bone metabolism and act in an endocrine manner. Generally, the dysregulation of hepatokines is frequently accompanied by changes in bone mass, and osteokines can also disrupt liver metabolism. The crosstalk between the liver and bone, particularly the function and mechanism of hepatokines and osteokines, has increasingly gained notoriety as a topic of interest in recent years. Here, based on preclinical and clinical evidence, we summarize the potential roles of hepatokines and osteokines in liver-bone interaction, discuss the current shortcomings and contradictions, and make recommendations for future research.

BackgroundCyberchondria has been brought into sharp focus during the COVID-19 health emergency; it refers to individuals who obsessively and compulsively search for health information online, resulting in excessive health concerns. Recent scholarship focuses on its obsessive and compulsive aspect, following a biopsychosocial approach as opposed to a pathology of health anxiety. It lacks interpretation of the socio-psychological dynamics between the dimensions.ObjectiveThis review aims to propose a holistic view toward understanding cyberchondria as an obsessive–compulsive syndrome and considers possible interventions. It specifically seeks to explain cyberchondria from diversified mediator variables and to pinpoint connections between each perspective.MethodologyComprehensive searches of databases such as PubMed and Springer were conducted to identify English articles relating to cyberchondria from 2001 to 2022. Based on a systematic filtering process, 27 articles were finally reviewed.FindingsThe authors compare and confirm three forecasts to predict cyberchondria, associating it with individual metacognition, uncertainty of unverified information, and algorithm-driven, biased information environments.ValueTheoretically, a holistic framework is proposed to explain the obsessive and compulsive features of cyberchondria. Clinically, the research calls for more professional psychoeducation and chain screening of cyberchondria and other psychological disorders. Socially, it promotes support for risk-sensitive, information-deficient groups during pandemics like COVID-19. It also stresses more careful use of algorithm-driven search engine technology for platforms delivering medical information. Future research may explore areas such as the association between cyberchondria and other social-related disorders, as well as correlations among cyberchondria, obsessive and compulsive disorders, medical trust, and algorithm-driven search results.

Liver fibrosis is a repair process of chronic liver injuries induced by toxic substances, pathogens, and inflammation, which exhibits a feature such as deposition of the extracellular matrix. The initiation and progression of liver fibrosis heavily relies on excessive activation of hepatic stellate cells (HSCs). The activated HSCs express different kinds of chemokine receptors to further promote matrix remodulation. The long-term progression of liver fibrosis will contribute to dysfunction of the liver and ultimately cause hepatocellular carcinoma. The liver also has abundant innate immune cells, including DCs, NK cells, NKT cells, neutrophils, and Kupffer cells, which conduct complicated functions to activation and expansion of HSCs and liver fibrosis. Autophagy is one specific type of cell death, by which the aberrantly expressed protein and damaged organelles are transferred to lysosomes for further degradation, playing a crucial role in cellular homeostasis. Autophagy is also important to innate immune cells in various aspects. The previous studies have shown that dysfunction of autophagy in hepatic immune cells can result in the initiation and progression of inflammation in the liver, directly or indirectly causing activation of HSCs, which ultimately accelerate liver fibrosis. Given the crosstalk between innate immune cells, autophagy, and fibrosis progression is complicated, and the therapeutic options for liver fibrosis are quite limited, the exploration is essential. Herein, we review the previous studies about the influence of autophagy and innate immunity on liver fibrosis and the molecular mechanism to provide novel insight into the prevention and treatment of liver fibrosis.

Liver fibrosis is a repair response process after chronic liver injury. During this process, activated hepatic stellate cells (HSCs) will migrate to the injury site and secrete extracellular matrix (ECM) to produce fibrous scars. Clearing activated HSCs may be a major strategy for the treatment of liver fibrosis. Curcumol isolated from plants of the genus Curcuma can effectively induce apoptosis of many cancer cells, but whether it can clear activated HSCs remains to be clarified. In the present study, we found that the effect of curcumol in treating liver fibrosis was to clear activated HSCs by inducing necroptosis of HSCs. Receptor-interacting protein kinase 3 (RIP3) silencing could impair necroptosis induced by curcumol. Interestingly, endoplasmic reticulum (ER) stress-induced cellular dysfunction was associated with curcumol-induced cell death. The ER stress inhibitor 4-PBA prevented curcumol-induced ER stress and necroptosis. We proved that ER stress regulated curcumol-induced necroptosis in HSCs via Sirtuin-1(Sirt1)/Notch signaling pathway. Sirt1-mediated deacetylation of the intracellular domain of Notch (NICD) led to degradation of NICD, thereby inhibiting Notch signalling pathway to alleviate liver fibrosis. Specific knockdown of Sirt1 by HSCs in male ICR mice further exacerbated CCl4-induced liver fibrosis. Overall, our study elucidates the anti-fibrotic effect of curcumol and reveals the underlying mechanism between ER stress and necroptosis.

Background: Under the uncertainty led by the decentralized information on social media, people seek homogeneity in either opinions or affection to establish group identity to better understand the information. This also means they are easily polarized, not only ideologically but also in their actions. Affective polarization is the emotional tendency for people to show animosity toward opposing partisans while seeking homogeneity from fellow partisans. Much research into online affective polarization has focused on quantifying anxiety at an individual level while neglecting that on a collective basis. Therefore, this paper examined the polarization of collective anxiety in topic-based communities on Weibo.Methods: We aim to interpret correlations between collective anxiety online and topic characteristics, user competence, as well as the proportion of influencers of Weibo topic-based communities. Our neural networks model and statistical analysis were based on 200 communities with 403,380 personal accounts and 1,012,830 messages.Results: Collective anxiety levels are correlated to (1) the extent to which a topic captures public interest, (2) how community members articulate topics on social network platforms, and (3) the ratio of influencers in the community. Specifically, people’s conflicting perceptions and articulations of topics might increase collective anxiety, while the extent to which a topic is of the public interest and the number of influencers engaged in a topic account for any decline in its ranking. Furthermore, familiarity with a topic does not help predict collective anxiety levels. There are no significant links between community size or interactivity dynamics and the level of collective anxiety in the topic-based community. Our computational model has 85.00% precision and 87.00% recall.Conclusion: This study found the collective anxiety augment due to topic proximities to public interest and members’ lack of declarative knowledge on topics, while to decline with an increasing portion of online influencers. These findings indicate that collective anxiety is induced due to a lack of credibility. Also, the amount of conflicting information shared by different people places them in a state of flux. Therefore, a community with more influencers may be more likely to experience anxiety polarization, bringing forth the issue of layered information and inequality.

Acute-on-chronic liver failure (ACLF) is described as a characteristic of acute jaundice and coagulation dysfunction. Effective treatments for ACLF are unavailable and hence are urgently required. We aimed to define the effect of Yi-Qi-Jian-Pi Formula (YQJPF) on liver injury and further examine the molecular mechanisms. In this study, we established CCl4-, LPS-, and d-galactosamine (D-Gal)-induced ACLF rat models in vivo and LPS- and D-Gal-induced hepatocyte injury models in vitro. We found that YQJPF significantly ameliorates liver injury in vivo and in vitro that is associated with the regulation of hepatocyte necroptosis. Specifically, YQJPF decreased expression of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and pseudokinase mixed lineage kinase domain-like (MLKL) to inhibit the migration of RIPK1 and RIPK3 into necrosome. YQJPF also reduces the expression of inflammatory cytokines IL-6, IL-8, IL-1β, and TNF-α, which were regulated by RIPK3 mediates cell death. RIPK1 depletion was found to enhance the protective effect of YQJPF. Furthermore, we showed that YQJPF significantly downregulates the mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization, with ROS scavenger, 4-hydroxy-TEMPO treatment recovering impaired RIPK1-mediated necroptosis and reducing the expression of IL-6, IL-8, IL-1β, and TNF-α. In summary, our study revealed the molecular mechanism of protective effect of YQJPF on hepatocyte necroptosis, targeting RIPK1/RIPK3-complex-dependent necroptosis via ROS signaling. Overall, our results provided a novel perspective to indicate the positive role of YQJPF in ACLF.