βAR-mTOR-lipin1 pathway mediates PKA-RIIβ deficiency-induced adipose browning.

Enhancing white adipose tissue (WAT) browning combats obesity. The RIIβ subunit of cAMP-dependent protein kinase (PKA) is primarily expressed in the brain and adipose tissue. Deletion of the hypothalamic RIIβ gene centrally induces WAT browning, yet the peripheral mechanisms mediating this process remain unexplored.

Cerebrospinal fluid efflux through dynamic paracellular pores on venules as a missing piece of the brain drainage system.

The glymphatic system plays a key role in the clearance of waste from the parenchyma, and its dysfunction has been associated with the pathogenesis of Alzheimer's disease (AD). However, questions remain regarding its complete mechanisms. Here, we report that efflux of cerebrospinal fluid (CSF)/interstitial fluid (ISF) solutes occurs through a triphasic process that cannot be explained by the current model, but rather hints at the possibility of other, previously undiscovered routes from paravenous spaces to the blood.

SN-38, an active metabolite of irinotecan, inhibits transcription of nuclear factor erythroid 2-related factor 2 and enhances drug sensitivity of colorectal cancer cells.

Nuclear factor erythroid 2-related factor 2 (Nrf2) significantly contributes to drug resistance of cancer cells, and Nrf2 inhibitors have been vigorously pursued. Repurposing of existing drugs, especially anticancer drugs, is a straightforward and promising strategy to find clinically available Nrf2 inhibitors and effective drug combinations. Topoisomerase inhibitors SN-38 (an active metabolite of irinotecan), topotecan, mitoxantrone, and epirubicin were found to significantly suppress Nrf2 transcriptional activity in cancer cells.

Anemoside B4 attenuates RANKL-induced osteoclastogenesis by upregulating Nrf2 and dampens ovariectomy-induced bone loss.

Increased numbers and functional overactivity of osteoclasts are the pathological basis for bone loss diseases such as osteoporosis, which are characterized by cortical bone thinning, decreased trabecular bone quantity, and reduced bone mineral density. Effective inhibition of osteoclast formation and bone resorption are important means of treating such skeletal diseases. Anemoside B4 (AB4), the main active component of Pulsatilla chinensis, possesses a wide range of anti-inflammatory and immunoregulatory effects.

Succinate pretreatment attenuates intestinal ischemia-reperfusion injury by inhibiting necroptosis and inflammation via upregulating Klf4.

Intestinal ischemia-reperfusion (I/R) injury is a common pathophysiological process in various diseases, and the disruption of the intestinal barrier composed of tight junction proteins is the initiating factor, which then leads to a large number of bacteria and endotoxins in the intestine into the bloodstream causing stress and distant organ damage. The release of inflammatory mediators and abnormal programmed death of intestinal epithelial cells are important factors of intestinal barrier damage. Succinate is an intermediate product of the tricarboxylic acid cycle with anti-inflammatory and pro-angiogenic activities, but its role in the maintenance of intestinal barrier homeostasis after I/R has not been fully elucidated.

Hydrogen sulfide alleviates particulate matter-induced emphysema and airway inflammation by suppressing ferroptosis.

Background: Redox imbalance is an vital mechanism for COPD. At present, insufficient researches have been conducted on the protective effect of hydrogen sulfide (HS) on PM-induced COPD. However, whether HS exerts the anti-injury role by blocking ferroptosis and restoring redox equilibrium remain to be investigated.

Long-term exposure to air pollution, habitual physical activity and risk of non-alcoholic fatty liver disease: A prospective cohort study.

Background: Emerging studies suggest a positive association between air pollution exposure and risk of non-alcoholic fatty liver disease (NAFLD), however, the combined effects of long-term exposure to air pollution, physical activity (PA), and risk of NAFLD is unclear.

Methods: We included 58,026 Taiwan residents who received a standard medical screening program between 2001 and 2016. Levels of fine particulate matter (PM) at each participant's residential address were estimated using multiple satellite-based aerosol optical depth data combined with a chemical transport model.

Association between Protein Intake and the Risk of Hypertension among Chinese Men and Women: A Longitudinal Study.

This study aimed to examine the relationship between hypertension risk and protein intake in Chinese individuals. Our analysis included 7007 men and 7752 women from 9 China Health and Nutrition Survey waves (1991−2015). The main outcome was incident hypertension.

The potential roles of Nrf2/Keap1 signaling in anticancer drug interactions.

Nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2), together with its suppressive binding partner Kelch-like ECH-associated protein 1 (Keap1), regulates cellular antioxidant response and drug metabolism. The roles of Nrf2/Keap1 signaling in the pathology of many diseases have been extensively investigated, and small molecules targeting Nrf2/Keap1 signaling have been developed to prevent or treat diseases such as multiple sclerosis, chronic kidney disease and cancer. Notably, Nrf2 plays dual roles in cancer development and treatment.

Isoangustone A induces autophagic cell death in colorectal cancer cells by activating AMPK signaling.

Phytochemicals, especially flavonoids, have been widely investigated for their diversified pharmacological activities including anticancer activities. Previously we identified isoangustone A from licorice-derived compounds as a potent inducer of cell death. In the present study, the exact mechanism by which isoangustone A induced cell death was further investigated, with autophagy as an indispensible part of this process.

Hydrogen Sulfide Attenuates Particulate Matter-Induced Emphysema and Airway Inflammation Through Nrf2-Dependent Manner.

Purpose: To investigate whether hydrogen sulfide provide protective effects on atmosphere particulate matter (PM)-induced emphysema and airway inflammation and its mechanism.

Methods: Wild type C57BL/6 and Nrf2 knockout mice were exposed to PM (200 g per mouse). Hydrogen sulfide or propargylglycine were administered by intraperitoneal injection respectively 30 min before PM exposure, mice were anesthetized 29th day after administration.

Nrf2 Activation Enhances Muscular MCT1 Expression and Hypoxic Exercise Capacity.

Introduction: Skeletal muscle is the major producing and metabolizing site of lactic acid. A family of monocarboxylate transporter (MCT) proteins, especially MCT1 and MCT4, are involved in the lactate-pyruvate exchange and metabolism. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal coordinator of antioxidant response and energy metabolism, and has been reported to associate with the physiological functions of the skeletal muscle.

Dietary Nonheme, Heme, and Total Iron Intake and the Risk of Diabetes in Adults: Results From the China Health and Nutrition Survey.

Objective: Excessive iron intake has been linked to diabetes risk. However, the evidence is inconsistent. This study examined the association between dietary heme and nonheme iron intake and diabetes risk in the Chinese population.

Hypoxia preconditioning promotes endurance exercise capacity of mice by activating skeletal muscle Nrf2.

Elite endurance athletes are used to train under hypoxic/high-altitude conditions, which can elicit certain stress responses in skeletal muscle and helps to improve their physical performance. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates cellular redox homeostasis and metabolism in skeletal muscle, playing important roles in adaptation to various stresses. In this study, Nrf2 knockout (KO) and wild-type (WT) mice were preconditioned to 48 h of hypoxia exposure (11.

Gadolinium chloride promotes proliferation of HEK293 human embryonic kidney cells by activating EGFR/PI3K/Akt and MAPK pathways.

Prolonged exposure to gadolinium-based contrast agents has been reported to trigger nephrogenic systemic fibrosis in end stage renal disease patients. However, the exact molecular mechanisms are not fully understood, and no effective therapy is available to date. In the present study, we report that gadolinium chloride (Gd) concentration- and time-dependently promoted the proliferation of HEK293 human embryonic kidney cells by increasing DNA synthesis.

Oncogenic Activation of Nrf2, Though as a Master Antioxidant Transcription Factor, Liberated by Specific Knockout of the Full-Length Nrf1α that Acts as a Dominant Tumor Repressor.

Liver-specific knockout of Nrf1 in the mouse leads to spontaneous development of non- alcoholic steatohepatitis with dyslipidemia, and then its deterioration results in hepatoma, but the underlying mechanism remains elusive to date. A similar pathological model is reconstructed here by using human Nrf1α-specific knockout cell lines. Our evidence has demonstrated that a marked increase of the inflammation marker COX2 definitely occurs in cells.

Effects of acute hypoxia exposure with different durations on activation of Nrf2-ARE pathway in mouse skeletal muscle.

Background: Hypoxia training enhances the endurance capacity of athletes. This response may in part be attributed to the hypoxia-induced increase in antioxidant capacity in skeletal muscles. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor which regulates the expression of genes via binding to the antioxidant-response element (ARE) of these genes, plays a crucial role in stimulating the body's defense system and potentially responds to hypoxia.

The Leptin Resistance.

Leptin is an adipocyte-derived hormone, which contributes to the homeostatic regulation of energy balance and metabolism through humoral and neural pathways. Leptin acts on the neurons in certain brain areas such as the hypothalamus, hippocampus, and brain stem to regulate food intake, thermogenesis, energy expenditure, and homeostasis of glucose/lipid metabolism. The pathologically increased circulating leptin is a biomarker of leptin resistance, which is common in obese individuals.

The Leptin Signaling.

Leptin plays a critical role in the regulation of energy balance and metabolic homeostasis. Impairment of leptin signaling is closely involved in the pathogenesis of obesity and metabolic diseases, including diabetes, cardiovascular disease, etc. Leptin initiates its intracellular signaling in the leptin-receptor-expressing neurons in the central nervous system to exert physiological function, thereby leading to a suppression of appetite, a reduction of food intake, a promotion of mitochondrial oxidation, an enhancement of thermogenesis, and a decrease in body weight.

Mechanisms controlling the multistage post-translational processing of endogenous Nrf1α/TCF11 proteins to yield distinct isoforms within the coupled positive and negative feedback circuits.

To gain a better understanding of the multistep processing of Nrf1 to yield various isoforms with confused molecular masses, we herein establish a generally acceptable criterion required for identification of its endogenous full-length proteins and derivative isoforms expressed differentially in distinct experimental cell lines. Further work has been focused on the molecular mechanisms that dictate the successive post-translational modifications (i.e.

The Novel Triazolonaphthalimide Derivative LSS-11 Synergizes the Anti-Proliferative Effect of Paclitaxel via STAT3-Dependent MDR1 and MRP1 Downregulation in Chemoresistant Lung Cancer Cells.

Multidrug resistance (MDR) is a major cause of the inefficacy and poor response to paclitaxel-based chemotherapy. The combination of conventional cytotoxic drugs has been a plausible strategy for overcoming paclitaxel resistance. Herein, we investigated the cytotoxic effects and underlying mechanism of , a novel naphthalimide derivative-based topoisomerase inhibitor, in paclitaxel-resistant A549 (A549/T) lung cancer cells.