The biphasic role of Hspb1 on ferroptotic cell death in Parkinson's disease.

Rationale: Ferroptosis-driven loss of dopaminergic neurons plays a pivotal role in the pathogenesis of Parkinson's disease (PD). In PD patients, Hspb1 is commonly observed at abnormally high levels in the substantia nigra. The precise consequences of Hspb1 overexpression in PD, however, have yet to be fully elucidated. Methods: We used human iPSC-derived dopaminergic neurons and Coniferaldehyde (CFA)-an Nrf2 agonist known for its ability to cross the blood-brain barrier-to investigate the role of Hspb1 in PD. We examined the correlation between Hspb1 overexpression and Nrf2 activation and explored the transcriptional regulation of Hspb1 by Nrf2. Gene deletion techniques were employed to determine the necessity of Nrf2 and Hspb1 for CFA's neuroprotective effects. Results: Our research demonstrated that Nrf2 can upregulate the transcription of Hspb1 by directly binding to its promoter. Deletion of either Nrf2 or Hspb1 gene abolished the neuroprotective effects of CFA. The Nrf2-Hspb1 pathway, newly identified as a defense mechanism against ferroptosis, was shown to be essential for preventing neurodegeneration progression. Additionally, we discovered that prolonged overexpression of Hspb1 leads to neuronal death and that Hspb1 released from ruptured cells can trigger secondary cell death in neighboring cells, exacerbating neuroinflammatory responses. Conclusions: These findings highlight a biphasic role of Hspb1 in PD, where it initially provides neuroprotection through the Nrf2-Hspb1 pathway but ultimately contributes to neurodegeneration and inflammation when overexpressed. Understanding this dual role is crucial for developing therapeutic strategies targeting Hspb1 and Nrf2 in PD.

Variation in worldwide incidence of Guillain-Barré syndrome: a population-based study in urban China and existing global evidence.

Background and objectives: Geographical variation existed in the incidences of Guillain-Barré syndrome (GBS), but no national population-based study has evaluated the incidences of GBS in China. This study aimed to estimate the incidence of GBS in urban China and evaluate the worldwide variation in the incidence of GBS. Methods: Firstly, we did a population-based study to calculate the incidence of GBS in urban China based on the National Urban Medical Insurance database from 2013 to 2017. To identify GBS cases, natural language processing was used first for handling the lengthy and unstructured diagnostic information and then checked by prestigious neurologists. Secondly, a systematic review and meta-analysis were performed to analyze the incidence of GBS worldwide. Up to July 4, 2022, Medline, Embase, and Web of Science were retrieved to identify the population-based studies regarding the incidence of GBS. The basic information and the statistics regarding incidence were extracted. Quality assessment considered sample representativeness, condition assessment, and statistical methods. Results: A total of 1.44 billion person-years in insurance data was covered, with 3,534 GBS cases identified. The annual incidences of GBS in urban China between 2013 and 2017 ranged from 0.41 (95% CI: 0.27 to 0.58) to 0.58 (95% CI: 0.38 to 0.82) per 100,000 person-years. The incidence was the highest in Northwest China and the lowest in Northeast China. The meta-analysis included 122 articles. The quality assessment showed that the quality scores of 43.3% of studies were ≥ 0.75 (the total score is 1). The global incidence of GBS was 1.12 (95% CI: 0.98 to 1.27) per 100,000 person-years. The incidences in West Europe, South Asia, and North Europe were higher, while the incidences in Australia and New Zealand, Southeast Asia, and North Africa were lower. The incidence of enteric infections was positively associated with the incidence of GBS (coefficient=0.0000185, P=0.007). The incidence in Europe, Australia, and America rose significantly from 1960 to 2020 (coefficient=0.01, t=2.52, P=0.015). Discussion: There is a clear regional variation of the GBS incidence at both national and global levels. Careful control of enteric infections should be conducted to reduce the disease burden.

The role of ferroptosis and its mechanism in ischemic stroke.

Ischemic stroke is an acute cerebrovascular disease with a high morbidity, mortality, and disability rate. Persistent ischemia of brain tissue can cause irreversible damage to neurons, leading to neurological dysfunction and seriously affecting patients' quality of life. However, current clinical therapies are limited and have not achieved satisfactory outcome, due to the incomplete understanding of the mechanism of neuronal damage during ischemic stroke. Recent studies have found that ferroptosis is implicated in the pathophysiology of ischemic stroke. Ferroptosis is an iron-dependent regulated cell death driven by lipid peroxidation. Under normal physiological conditions, GSH/GPX4, FSP1/CoQ10, GCH/BH4 and other anti-ferroptosis pathways can function effectively to suppress the occurrence of ferroptosis. After ischemic stroke, two typical ferroptosis characteristics, lipid peroxidation and iron accumulation, are observed, accompanied by changes in the expression of ferroptosis related genes such as GPX4, ACSL4, and SLC7A11, suggesting that ferroptosis plays a key role in ischemic stroke, which provides a new idea for the clinical treatment of ischemic stroke. This article reviewed the pathological mechanisms of ferroptosis in the occurrence and development of ischemic stroke, as well as the related progress of ferroptosis targeted therapy.

Heme biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.

With age, people tend to accumulate body fat and reduce energy expenditure 1 . Brown (BAT) and beige adipose tissue dissipate heat and increase energy expenditure via the activity of the uncoupling protein UCP1 and other thermogenic futile cycles 2,3 . The activity of brown and beige depots inversely correlates with BMI and age 4-11 , suggesting that promoting thermogenesis may be an effective approach for combating age-related metabolic disease 12-15 . Heme is an enzyme cofactor and signaling molecule that we recently showed to regulate BAT function 16 . Here, we show that heme biosynthesis is the primary contributor to intracellular heme levels in brown adipocytes. Inhibition of heme biosynthesis leads to mitochondrial dysfunction and reduction in UCP1. Although supplementing heme can restore mitochondrial function in heme-synthesis-deficient cells, the downregulation of UCP1 persists due to the accumulation of the heme precursors, particularly propionyl-CoA, which is a product of branched-chain amino acids (BCAA) catabolism. Cold exposure promotes BCAA uptake in BAT, and defects in BCAA catabolism in this tissue hinder thermogenesis 17 . However, BCAAs' contribution to the TCA cycle in BAT and WAT never exceeds 2% of total TCA flux 18 . Our work offers a way to integrate current literature by describing heme biosynthesis as an important metabolic sink for BCAAs.

Ecological impact assessment of green virtual water flow in inter-provincial crop commutation within China.

Green water is crucial for to regional ecological sustainability. Currently, there is a lack of research on the impact of crop green water communication on the regional ecology in China. The ecological impact index (EII) and integrated ecological water supply (IES) were proposed to comprehensively evaluate the regional ecological impact of the green virtual water flow (GVWF) of crops. Based on the principle of trade cost minimization, this study simulated the inter-provincial crop commutation within China during 2010-2019 by assigning weights to production, demand, and transportation costs, and analyzed the impact of crop communication on regional ecology. The results showed that multi-year average GVWF among provinces was 216.45 Gm3, accounting for 33.7 % of the total green water footprint of crops. The ecological impact of GVWF varies among provinces and years. The EII values in Beijing, Shanghai, and Jiangsu were all >100, whereas it was <1 in Yunnan and Xizang. Regional management policies for water resources, ecology, and economic development should be formulated taking into account the IES and EII jointly. It is recommended to increase the export of green virtual water of crops and expand the ecological area while ensuring the utilization rate of green water in regions with higher EII values, such as Guangxi and Yunnan. In the future, it is important for district managers to prioritize the quality of ecological development and protect ecological areas from erosion while pursuing urban development. This study innovatively evaluated the ecological impact of crop communication in different regions, which has guiding significance for the trade management in the ecologically water-deficient areas.

DELE1 is protective for mitochondrial cardiomyopathy.

Mitochondrial dysfunction in heart triggers an integrated stress response (ISR) through phosphorylation of eIF2α and subsequent ATF4 activation. DAP3 Binding Cell Death Enhancer 1 (DELE1) is a mitochondrial protein recently found to be critical for mediating mitochondrial stress-triggered ISR (MSR)-induced eIF2α-ATF4 pathway activation. However, the specific role of DELE1 in heart at baseline or in response to mitochondrial stress remains largely unknown. In this study, we report that DELE1 is dispensable for cardiac development and function under baseline conditions. Conversely, DELE1 is essential for mediating an adaptive response to mitochondrial dysfunction-triggered stress in the heart, playing a protective role in mitochondrial cardiomyopathy.

IP3R-mediated Ca2+ signaling controls B cell proliferation through metabolic reprogramming.

Emerging evidence shows that metabolic regulation may be a critical mechanism in B cell activation and function. As targets of several most widely used immunosuppressants, Ca2+ signaling and calcineurin may play an important role in regulating B cell metabolism. Here, we demonstrate that IP3R-mediated Ca2+ signaling and calcineurin regulate B cell proliferation and survival by activating metabolic reprogramming in response to B cell receptor (BCR) stimulation. Both IP3R-triple-knockout (IP3R-TKO) and calcineurin inhibition dramatically suppress the metabolic switch in oxidative phosphorylation and glycolysis of stimulated B cells through regulation of glucose uptake, glycolytic enzyme expression, and mitochondrial remodeling, leading to impaired cell-cycle entry and survival. In addition, IP3R-Ca2+ acts as a master regulator of the calcineurin-MEF2C-Myc pathway in driving B cell metabolic adaptations. As genetic defects of IP3Rs were recently identified as a new class of inborn errors of immunity, these results have important implications for understanding the pathogenesis of such diseases.

Barth Syndrome Cardiomyopathy: An Update.

Barth syndrome (BTHS) is an X-linked mitochondrial lipid disorder caused by mutations in the TAFAZZIN (TAZ) gene, which encodes a mitochondrial acyltransferase/transacylase required for cardiolipin (CL) biosynthesis. Cardiomyopathy is a major clinical feature of BTHS. During the past four decades, we have witnessed many landmark discoveries that have led to a greater understanding of clinical features of BTHS cardiomyopathy and their molecular basis, as well as the therapeutic targets for this disease. Recently published Taz knockout mouse models provide useful experimental models for studying BTHS cardiomyopathy and testing potential therapeutic approaches. This review aims to summarize key findings of the clinical features, molecular mechanisms, and potential therapeutic approaches for BTHS cardiomyopathy, with particular emphasis on the most recent studies.