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High‐altitude cardiac injury (HACI) is one of the common tissue injuries caused by high‐altitude hypoxia that may be life threatening. Notoginsenoside R1 (NG‐R1), a major saponin of Panax notoginseng, exerts anti‐oxidative, anti‐inflammatory, and anti‐apoptosis effects, protecting the myocardium from hypoxic injury. This study aimed to investigate the protective effect and molecular mechanism of NG‐R1 against HACI. We simulated a 6000 m environment for 48 h in a hypobaric chamber to create a HACI rat model. Rats were pretreated with NG‐R1 (50, 100 mg/kg) or dexamethasone (4 mg/kg) for 3 days and then placed in the chamber for 48 h. The effect of NG‐R1 was evaluated by changes in Electrocardiogram parameters, histopathology, cardiac biomarkers, oxidative stress and inflammatory indicators, key protein expression, and immunofluorescence. U0126 was used to verify whether the anti‐apoptotic effect of NG‐R1 was related to the activation of ERK pathway. Pretreatment with NG‐R1 can improve abnormal cardiac electrical conduction and alleviate high‐altitude‐induced tachycardia. Similar to dexamethasone, NG‐R1 can improve pathological damage, reduce the levels of cardiac injury biomarkers, oxidative stress, and inflammatory indicators, and down‐regulate the expression of hypoxia‐related proteins HIF‐1α and VEGF. In addition, NG‐R1 reduced cardiomyocyte apoptosis by down‐regulating the expression of apoptotic proteins Bax, cleaved caspase 3, cleaved caspase 9, and cleaved PARP1 and up‐regulating the expression of anti‐apoptotic protein Bcl‐2 through activating the ERK1/2‐P90RSK‐Bad pathway. In conclusion, NG‐R1 prevented HACI and suppressed apoptosis via activation of the ERK1/2‐P90RSK‐Bad pathway, indicating that NG‐R1 has therapeutic potential to treat HACI. [ABSTRACT FROM AUTHOR]

Since human neurons are postmitotic and long-lived, the regulation of their genomic content is crucial. Normal neuronal function is uniquely dependent on gene dosage, with diverse genome copy number alterations (CNA) associated with neurodevelopmental and neuropsychiatric conditions 1-3 . In this study, we evaluated the landscape of CNA arising in normal human brains, focusing on prenatal and perinatal ages. We surveyed ∼5,897 CNA in >1,200 single neurons from human postmortem brain of individuals without a neurological diagnosis, ranging in age from gestational week (GW) 14 to 90 years old. Using Tn5-based single-cell whole-genome amplification (scWGA) and informatic advances to validate CNAs in single neurons, we determined that a striking proportion of neurons (up to 45%) in human prenatal cortex showed aberrant genomes, characterized by large-scale CNAs in multiple chromosomes, which reduces significantly during the perinatal period (p<0.1). Furthermore, we identified micronuclei in the developing cortex, reflecting genetic instability reminiscent of that described in early embryonic development 4-6 . The scale of CNA appeared to alter the trajectory of neuronal elimination, as subchromosomal CNAs were more slowly eliminated, over the course of a lifetime. CNAs were depleted for dosage-sensitive genes and genes involved in neurodevelopmental disorders (p<.05), and thus represent genomic quality control mechanisms that eliminate selectively those neurons with CNA involving critical genes. Perinatal elimination of defective neuronal genomes may in turn reflect a developmental landmark essential for normal cognitive function.

Ethnopharmacological Relevance: Ginseng has historically been utilized as a conventional herbal remedy and dietary supplement to enhance physical stamina and alleviate fatigue. The primary active component of Ginseng, Ginsenoside Rg3 (GS-Rg3), possesses diverse pharmacological properties including immune modulation and anti-inflammatory effects. Furthermore, GS-Rg3 has demonstrated efficacy in mitigating tissue and organ damage associated with metabolic disorders such as hypertension, hyperglycemia, and hyperlipidemia. Nevertheless, its potential impact on high-altitude cardiac injury (HACI) remains insufficiently explored., Aim of the Study: The aim of this study was to examine the potential cardioprotective effects of Ginsenoside Rg3, and to investigate how Ginsenoside Rg3 preconditioning can enhance high-altitude cardiac injury by inhibiting the RhoA/ROCK pathway and ferroptosis in cardiac tissue. The findings of this study may contribute to the development of novel therapeutic strategies using traditional Chinese medicine for high-altitude cardiac injury, based on experimental evidence., Materials and Methods: A hypobaric hypoxia chamber was employed to simulate hypobaric hypoxia conditions equivalent to an altitude of 6000 m. Through a randomization process, groups of six male mice were assigned to receive either saline, Ginsenoside Rg3 at doses of 15 mg/kg or 30 mg/kg, or lysophosphatidic acid (LPA) at 1 mg/kg. The impact of Ginsenoside Rg3 on high altitude-induced arrhythmias was evaluated using electrocardiography. Cardiac pathology sections stained with hematoxylin and eosin were evaluated for damage, with the extent of cardiomyocyte damage observed via transmission electron microscopy. The impact of Ginsenoside Rg3 on high-altitude cardiac injury was investigated through analysis of serum biomarkers for cardiac injury (CK-MB, BNP), inflammatory cytokines (TNF, IL-6, IL-1β), reactive oxygen species (ROS) and glutathione (GSH). The expression levels of hypoxia and hypoxia-related proteins in myocardial tissues from each experimental group were assessed using Western blot analysis. Following a review of the existing literature, the traditional regulatory mechanisms of ferroptosis were examined. Immunofluorescence staining of cardiac tissues and Western blotting techniques were utilized to investigate the impact of Ginsenoside Rg3 on cardiomyocyte ferroptosis through the RhoA/ROCK signaling pathway under conditions of hypobaric hypoxia exposure., Results: Pre-treatment with Ginsenoside Rg3 improved high altitude-induced arrhythmias, reduced cardiomyocyte damage, decreased cardiac injury biomarkers and inflammatory cytokines, and lowered the expression of hypoxia-related proteins in myocardial tissues. Both Western blotting and immunofluorescence staining of cardiac tissues demonstrated that exposure to high-altitude hypobaric hypoxia results in elevated expression of ferroptosis and proteins related to the RhoA/ROCK pathway. Experimental validation corroborated that the role of the RhoA/ROCK signaling pathway in mediating ferroptosis., Conclusions: The findings of our study suggest that preconditioning with Ginsenoside Rg3 may attenuate cardiac injury caused by high-altitude hypobaric hypoxia exposure in mice by inhibiting ferroptosis through the suppression of the RhoA/ROCK signaling pathway. These findings contribute to the current knowledge of Ginsenoside Rg3 and high-altitude cardiac injury, suggesting that Ginsenoside Rg3 shows potential as a therapeutic agent for high-altitude cardiac injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

High-altitude pulmonary edema (HAPE) is a life-threatening disease, and autophagy deficiency is implicated in the pathogenesis of HAPE. Eleutheroside B (EB), which is the main bioactive component of Acanthopanax senticosus, exhibits various pharmacological activities. Our previous research demonstrated that autophagic structures were widely found in the ultrastructure of lung tissue in HAPE rats. However, whether EB regulates autophagy deficiency in HAPE remains unknown. This study aimed to investigate the protective effects of EB on hypobaric hypoxia-induced HAPE and explore the underlying molecular mechanism of regulating autophagy. The rat model of high-altitude pulmonary edema was replicated using a hypobaric hypoxic chamber. Rats were pretreated with EB or in combination with chloroquine or compound C. The pulmonary edema was assessed by the lung wet/dry ratio, total protein concentration in bronchoalveolar lavage fluid, and histological analysis. Inflammation and oxidative stress were measured using commercial biochemical kits. Autophagy and autophagic flux were evaluated by western blotting, transmission electron microscopy, and adeno-associated virus-mRFP-GFP-labeled tandem fluorescence LC3. The AMPK/mTOR signaling pathway was detected by western blotting. EB alleviated hypobaric hypoxia-induced pulmonary edema, hypoxemia, acid-base imbalance in the blood, inflammation, and oxidative stress in a dose-dependent manner. EB restored impaired autophagic flux by activating the AMPK/mTOR signaling pathway. However, chloroquine or compound C abolished eleutheroside B-mediated autophagy flux restoration. EB has the potential to restore impaired autophagic flux in the lung of hypobaric hypoxia-induced HAPE rats, which could be attributed to the activation of AMPK/mTOR signaling pathway., (© 2024 John Wiley & Sons Ltd.)

Inflammation and oxidative stress caused by fine particulate matter (PM2.5) increase the incidence and mortality rates of respiratory disorders. Rosavin is the main chemical component of Rhodiola plants, which exerts anti-oxidative and antiinflammatory effects. In this research, the potential therapeutic effect of rosavin was investigated by the PM2.5-induced lung injury rat model. Rats were instilled with PM2.5 (7.5 mg/kg) suspension intratracheally, while rosavin (50 mg/kg, 100 mg/kg) was delivered by intraperitoneal injection before the PM2.5 injection. It was observed that rosavin could prevent lung injury caused by PM2.5. PM2.5 showed obvious ferroptosis-related ultrastructural alterations, which were significantly corrected by rosavin. The pretreatment with rosavin downregulated the levels of tissue iron, malondialdehyde, and 4-hydroxynonenal, and increased the levels of glutathione. The expression of nuclear factor E2-related factor 2 (Nrf2) was upregulated by rosavin, together with other ferroptosis-related proteins. RSL3, a specific ferroptosis agonist, reversed the beneficial impact of rosavin. The network pharmacology approach predicted the activation of rosavin on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. LY294002, a potent PI3K inhibitor, decreased the upregulation of Nrf2 induced by rosavin. In conclusion, rosavin prevented lung injury induced by PM2.5 stimulation and suppressed ferroptosis via upregulating PI3K/Akt/Nrf2 signaling pathway., (© 2022 John Wiley & Sons Ltd.)