Ginkgolic acid inhibits the expression of SAE1 and induces ferroptosis to exert an anti-hepatic fibrosis effect.

BACKGROUND: Finding a drug for early intervention in the hepatic fibrosis process has important clinical significance. Previous studies have suggested SUMOylation as a potential target for intervention in hepatic fibrosis. However, the role of SAE1, a marker of SUMOylation, in hepatic fibrosis is unknown. Additionally, whether ginkgolic acid (GA), a SUMOylation inhibitor, inhibits hepatic fibrosis by inhibiting SUMO1-activating enzyme subunit 1 (SAE1) should be further investigated. METHODS: Liver tissues of patients with hepatic cirrhosis and a rat model of hepatic fibrosis constructed with CCl4 (400 mg/kg, twice weekly) or TAA (200 mg/kg, twice weekly) were selected, and the degree of hepatic fibrosis was then evaluated using H&E, Sirius red, and Masson's trichrome staining. After knockdown or overexpression of SAE1 in hepatic stellate cells, the expression levels of ferroptosis and hepatic fibrosis markers were measured in vitro. After intervention with a ferroptosis inhibitor, the expression levels were again measured in vivo and in vitro. RESULTS: We first demonstrated that SAE1 increased in patients with hepatic cirrhosis. Subsequently, testing of the rat hepatic fibrosis model confirmed that GA reduced the expression of SAE1 and improved hepatic fibrosis in rats. Then, we used hepatic stellate cell lines to confirm in vitro that GA inhibited SAE1 expression and induced ferroptosis, and that overexpression of SAE1 or inhibition of ferroptosis reversed this process. Finally, we confirmed in vivo that GA induced ferroptosis and alleviated the progression of hepatic fibrosis, while inhibiting ferroptosis also reversed the progression of hepatic fibrosis in rats. CONCLUSION: SAE1 is a potential anti-fibrotic target protein, and GA induces ferroptosis of hepatic stellate cells by targeting SAE1 to exert an anti-hepatic fibrosis effect, which lays an experimental foundation for the future clinical application of its anti-hepatic fibrosis effect.

A feasibility study on low-dose mindfulness-based stress reduction intervention among prediabetes and diabetes patients.

OBJECTIVES: To investigate the feasibility of delivering a low-dose mindfulness-based stress reduction (MBSR) intervention among prediabetes/diabetes patients in a clinical setting. DESIGN AND SETTING: This was a single-arm, mixed methods, feasibility study among prediabetes/diabetes patients at a healthcare center in United States. INTERVENTION: The low-dose MBSR intervention was delivered in group format over 4 waves and each wave comprised 8-10 h of 8 sessions over 6-8 weeks. MAIN OUTCOME MEASURES: We evaluated recruitment, adherence, and attrition rates, participants' satisfaction, motivation and barriers of low-dose MBSR. Psychological, behavioral, and physical measures were compared between pre- and post-intervention. RESULTS: We enrolled 19 participants of 34 eligible individuals with a recruitment rate of 55.9%. Among 19 enrolled participants, 4 dropped out after baseline data collection and did not attend any session and 1 attended one session but did not finish post-intervention data collection, resulting in an attrition rate of 26.3%. Among 15 participants attending at least one session, 46.7% attended all sessions and 80.0% attended at least 5 sessions. Qualitative analysis among 11 participants indicated that 90.9% had positive overall experience with the intervention. Compared to pre-intervention, there was a significant reduction in depression score (mean reduction = 5.04, SD = 7.66, p = 0.02), a higher proportion of engaging in flexibility exercises (42.86% vs. 85.71%, p = 0.01) and a lower level of glycosylated hemoglobin (HbA1c) (mean reduction = 1.43%, SD = 2.54%, p = 0.03) at post-intervention. CONCLUSIONS: Delivering a low-dose MBSR intervention to prediabetes/diabetes patients in a primary care setting is feasible. Future studies with randomized controlled design and larger sample are warranted.

Ventromedial Thalamus-Projecting DCN Neurons Modulate Associative Sensorimotor Responses in Mice / 神经科学通报·英文版

The deep cerebellar nuclei (DCN) integrate various inputs to the cerebellum and form the final cerebellar outputs critical for associative sensorimotor learning. However, the functional relevance of distinct neuronal subpopulations within the DCN remains poorly understood. Here, we examined a subpopulation of mouse DCN neurons whose axons specifically project to the ventromedial (Vm) thalamus (DCNVm neurons), and found that these neurons represent a specific subset of DCN units whose activity varies with trace eyeblink conditioning (tEBC), a classical associative sensorimotor learning task. Upon conditioning, the activity of DCNVm neurons signaled the performance of conditioned eyeblink responses (CRs). Optogenetic activation and inhibition of the DCNVm neurons in well-trained mice amplified and diminished the CRs, respectively. Chemogenetic manipulation of the DCNVm neurons had no effects on non-associative motor coordination. Furthermore, optogenetic activation of the DCNVm neurons caused rapid elevated firing activity in the cingulate cortex, a brain area critical for bridging the time gap between sensory stimuli and motor execution during tEBC. Together, our data highlights DCNVm neurons' function and delineates their kinematic parameters that modulate the strength of associative sensorimotor responses.

Unmet needs as indicator of improving chronic care delivery system in China.

In 2009, China strengthened its public health service system. Since then, the country has made remarkable achievements in community-based chronic disease prevention and control; however, certain groups still have unmet needs. During 2019 to 2029, China will consolidate the top-level design of its medical health system. During this period, the coordination of department policies, improvement of service delivery mechanisms, building an integrated health service system, and other issues will be highlighted. This study will provide a basis for designing China's chronic disease prevention and control system during the next stage of development. We will consider the unmet needs of patients with chronic diseases as an indicator for remodeling the prediction system in combination with the elements and structural theories of complex health systems. In this article, we first introduce the definition and measurement methods of unmet needs. Second, we identify the existing unmet needs found among patients with chronic diseases with reference to the chronic disease prevention and control policies of China as well as current service items. Finally, we propose the design of community chronic disease service package for the next development stage based on unmet needs of patients with chronic diseases. We also provide suggestions for how to improve China's chronic care delivery system.