Asperuloside as a Novel NRF2 Activator to Ameliorate Endothelial Dysfunction in High Fat Diet-Induced Obese Mice.

AIMS: Current treatments are inadequate in alleviating obesity-associated vascular diseases. The development of effective therapies to ameliorate endothelial dysfunction and attenuate oxidative stress is of utmost importance. Asperuloside (ASP), a bioactive compound extracted from Eucommia species, exhibits anti-obesity properties. However, the effects of ASP on vasculopathy have not been investigated. Therefore, the effects of ASP on vascular dysfunction and related mechanisms were elucidated. RESULTS: ASP significantly reversed the impaired endothelium-dependent relaxations (EDRs) in obese mice and IL-1ß-treated aortas. ASP suppressed endothelial activation in obese mice aortas and IL-1ß-treated endothelial cells. ASP attenuated oxidative stress, scavenged mitochondrial ROS and upregulated HO-1 expression in endothelium, independently of its anti-inflammatory properties. HO-1 knockdown diminished the protective effects of ASP against impaired EDRs, ROS overproduction and endothelial activation. Endothelial cell-specific Nrf2 knockdown eliminated the ASP-mediated vascular protective effects and endothelial HO-1 upregulation, emphasizing that ASP improves endothelial function by activating Nrf2/HO-1 signaling. ASP facilitated Nrf2 nuclear translocation and the direct binding of Nrf2 to ARE, thereby enhancing HO-1 transcription and scavenging ROS. CETSA results provide the first experimental characterization of the direct binding of ASP to Nrf2. INNOVATION: Effective Nrf2 activators targeting obesity-associated endothelial dysfunction are not available. This study demonstrates that Asperuloside could be a novel Nrf2 activator to alleviate obesity-associated endothelial dysfunction, suggesting a promising redox-based therapy for vasculopathy. CONCLUSIONS: These findings demonstrate that ASP ameliorates obesity-associated endothelial dysfunction by activating Nrf2/HO-1 signaling and maintaining redox hemostasis, demonstrating its potential as a novel Nrf2-targeted therapeutic agent and dietary supplement for vasculopathy.

Transcriptomic decoding of regional cortical vulnerability to major depressive disorder.

Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.

Characterizing human spontaneous thoughts and its application in major depressive disorder.

BACKGROUND: Spontaneous thought is a universal, complex, and heterogeneous cognitive activity that significantly impacts mental activity and strongly correlates with mental disorders. METHODS: Utilizing the think-aloud method, we captured spontaneous thoughts during rest from 38 diagnosed with depression, alongside 36 healthy controls and 137 healthy individuals. Through a comprehensive assessment of various dimensions of thought content, we compared thought content between individuals with depression and healthy controls, and between healthy women and men. Finally, we employed natural language processing (NLP) to develop regression models for multidimensional content assessment and a classification model to differentiate between individuals with and without depression. RESULTS: Compared to healthy controls, individuals with depression had more internally oriented and less externally oriented spontaneous thoughts. They focused more on themselves and negative things, and less on positive things, experiencing higher levels of negative emotions and lower levels of positive emotions. Besides, we found that compared to healthy men, healthy women's spontaneous thoughts focus more on interoception, the self, past events, and negative events, and they experience higher levels of negative emotions. Meanwhile, we identified the potential application of the think-aloud method to collect spontaneous thoughts and integrate NLP in the field of depression. CONCLUSIONS: This study offers direct insights into the stream of thought during individuals' resting state, revealing differences between individuals with depression and healthy controls, as well as sex differences in the content of spontaneous thoughts. It enhances our understanding of spontaneous thought and offers a new perspective for preventing, diagnosing, and treating depression.

Humoral immune responses primed by the alteration of gut microbiota were associated with galactose-deficient IgA1 production in IgA nephropathy.

Introduction: Galactose-deficient IgA1 (GdIgA1) is critical in the formation of immunodeposits in IgA nephropathy (IgAN), whereas the origin of GdIgA1 is unknown. We focused on the immune response to fecal microbiota in patients with IgAN. Methods: By running 16S ribosomal RNA gene sequencing, we compared IgAN samples to the control samples from household-matched or non-related individuals. Levels of plasma GdIgA1 and poly-IgA complexes were measured, and candidate microbes that can either incite IgA-directed antibody response or degrade IgA through specific IgA protease activities were identified. Results: The IgAN group showed a distinct composition of fecal microbiota as compared to healthy controls. Particularly, high abundance of Escherichia-Shigella was associated with the disease group based on analyses using receiver operating characteristic (area under curve, 0.837; 95% CI, 0.738-0.914), principle coordinates, and the linear discriminant analysis effect size algorithm (linear discriminant analysis score, 4.56; p < 0.001). Accordingly, the bacterial levels directly correlated with high titers of plasma GdIgA1(r = 0.36, p < 0.001), and patients had higher IgA1 against stx2(2.88 ± 0.46 IU/mL vs. 1.34 ± 0.35 IU/mL, p = 0.03), the main antigen of Escherichia-Shigella. Conversely, the healthy controls showed relatively higher abundance of the commensal bacteria that produce IgA-degrading proteases. Particularly, the abundance of some intestinal bacteria expressing IgA proteases showed an inverse correlation with the levels of plasma GdIgA1 in IgAN. Conclusion: Our data suggest that mucosal IgA production, including those of GdIgA1, is potentially linked to the humoral response to gut Escherichia-Shigella as one of the sources of plasma GdIgA1. Conversely, the IgA protease-producing microbiota in the gut are suppressed in patients with IgAN.

[Personalized glycemic management for patients with diabetic ketoacidosis based on machine learning].

OBJECTIVE: To explore the optimal blood glucose-lowering strategies for patients with diabetic ketoacidosis (DKA) to enhance personalized treatment effects using machine learning techniques based on the United States Critical Care Medical Information Mart for Intensive Care- IV (MIMIC- IV). METHODS: Utilizing the MIMIC- IV database, the case data of 2 096 patients with DKA admitted to the intensive care unit (ICU) at Beth Israel Deaconess Medical Center from 2008 to 2019 were analyzed. Machine learning models were developed, and receiver operator characteristic curve (ROC curve) and precision-recall curve (PR curve) were plotted to evaluate the model's effectiveness in predicting four common adverse outcomes: hypoglycemia, hypokalemia, reductions in Glasgow coma scale (GCS), and extended hospital stays. The risk of adverse outcomes was analyzed in relation to the rate of blood glucose decrease. Univariate and multivariate Logistic regression analyses were conducted to examine the relationship between relevant factors and the risk of hypokalemia. Personalized risk interpretation methods and predictive technologies were applied to individualize the analysis of optimal glucose control ranges for patients. RESULTS: The machine learning models demonstrated excellent performance in predicting adverse outcomes in patients with DKA, with areas under the ROC curve (AUROC) and 95% confidence interval (95%CI) for predicting hypoglycemia, hypokalemia, GCS score reduction, and extended hospital stays being 0.826 (0.803-0.849), 0.850 (0.828-0.870), 0.925 (0.903-0.946), and 0.901 (0.883-0.920), respectively. Analysis of the relationship between the rate of blood glucose reduction and the risk of four adverse outcomes showed that a maximum glucose reduction rate > 6.26 mmol×L-1×h-1 significantly increased the risk of hypoglycemia (P < 0.001); a rate > 2.72 mmol×L-1×h-1 significantly elevated the risk of hypokalemia (P < 0.001); a rate > 5.53 mmol×L-1×h-1 significantly reduced the risk of GCS score reduction (P < 0.001); and a rate > 8.03 mmol×L-1×h-1 significantly shortened the length of hospital stay (P < 0.001). Multivariate Logistic regression analysis indicated significant correlations between maximum bicarbonate levels, blood urea nitrogen levels, and total insulin doses with the risk of hypokalemia (all P < 0.01). In terms of establishing personalized optimal treatment thresholds, assuming optimal glucose reduction thresholds for hypoglycemia, hypokalemia, GCS score reduction, and extended hospital stay were x1, x2, x3, x4, respectively, the recommended glucose reduction rates to minimize the risks of hypokalemia and hypoglycemia should be ≤min{x1, x2}, while those to reduce GCS score decline and extended hospital stay should be ≥ max{x3, x4}. When these ranges overlap, i.e., max{x3, x4} ≤ min{x1, x2}, this interval was the recommended optimal glucose reduction range. If there was no overlap between these ranges, i.e., max{x3, x4} > min{x1, x2}, the treatment strategy should be dynamically adjusted considering individual differences in the risk of various adverse outcomes. CONCLUSIONS: The machine learning models shows good performance in predicting adverse outcomes in patients with DKA, assisting in personalized blood glucose management and holding important clinical application prospects.

Association of healthy and unhealthy plant-based diets with telomere length.

BACKGROUND & AIMS: Previous studies have shown that plant-rich dietary patterns, such as the Mediterranean diet, are associated with longer telomeres. However, no association has been found between vegetarian diet and telomere length. We hypothesized that the quality of plant-based diets plays an important role in telomere length. METHODS: Data were obtained from the National Health and Nutrition Examination Survey 1999-2002. Diet was assessed using a 24-h recall method. Plant-based diet quality was assessed using the overall plant-based diet index (PDI), healthy PDI (hPDI), and unhealthy PDI (uPDI). Telomere length was measured using quantitative PCR. Linear and ordinal logistic regression models were used to assess the association of PDIs with log-transformed telomere length and ordinal quintiles of telomere length in descending order, respectively. RESULTS: In both regression models, the overall PDI was not associated with telomere length. The hPDI was associated with longer telomere length [percentage change = 2.34%, 95% confidence interval (CI): 0.42%, 4.31%, Ptrend = 0.016; odds ratio (OR) = 0.81, 95% CI: 0.69, 0.95, Ptrend = 0.013]. However, uPDI was associated with shorter telomere length (percentage change = -3.17%, 95% CI: -5.65%, -0.62%, Ptrend = 0.017; OR = 1.25, 95% CI:1.03, 1.53, Ptrend = 0.014) and this inverse association was stronger in the non-Hispanic white population (Pinteraction = 0.001 in both regression models). CONCLUSIONS: A plant-based dietary pattern rich in healthy plant foods is associated with longer telomeres. However, plant-based dietary patterns rich in unhealthy plant-based foods are associated with shorter telomere lengths, especially in non-Hispanic white populations.

Satellite Tracking Reveals the Speed Up of the Lacustrine Algal Bloom Drift in Response to Climate Change.

Satellite evidence indicates a global increase in lacustrine algal blooms. These blooms can drift with winds, resulting in significant changes of the algal biomass spatial distribution, which is crucial in bloom formation. However, the lack of long-term, large-scale observational data has limited our understanding of bloom drift. Here, we have developed a novel method to track the drift using multi-source remote sensing satellites and presented a comprehensive bloom drift data set for four typical lakes: Lake Taihu (China, 2011-2021), Lake Chaohu (China, 2011-2020), Lake Dianchi (China, 2003-2021), and Lake Erie (North America, 2003-2021). We found that blooms closer to the water surface tend to drift faster. Higher temperatures and lower wind speeds bring blooms closer to the water surface, therefore accelerating drift and increasing biomass transportation. Under ongoing climate change, algal blooms are increasingly likely to spread over larger areas and accumulate in downwind waters, thereby posing a heightened risk to water resources. Our research greatly improves the understanding of algal bloom dynamics and provides new insights into the driving factors behind the global expansion of algal blooms. Our bloom-drift-tracking methodology also paves the way for the development of high-precision algal bloom prediction models.

A multimodal physiological and psychological dataset for human with mental stress induced myocardial ischemia.

Accurate differentiation between angina with no obstructive coronary arteries (ANOCA) and mental stress-induced myocardial ischemia (MSIMI) is crucial for tailored treatment strategies, yet public data scarcity hampers understanding. Given the higher incidence of both conditions in women, this study prospectively enrolled 80 female ANOCA and 39 age-matched female controls, subjecting them to three types of mental stress tasks. ECGs were continuously monitored across Rest, Stress, and Recover stages of the mental stress tasks, with PET/CT imaging during the Stress stage to evaluate myocardial perfusion. With PET/CT serving as the gold standard for MSIMI diagnosis, 35 of the 80 ANOCA patients were diagnosed as MSIMI. Using ECG variables from different stages of mental stress tasks, we developed five machine learning models to diagnose MSIMI. The results showed that ECG data from different stages provide valuable information for MSIMI classification. Additionally, the dataset encompassed demographic details, physiological, and blood sample test results of the patients. We anticipate this new dataset will significantly push further progress in ANOCA and MSIMI research.

Recent Advances in Photodynamic Therapy for Vascular Abnormalities.

Abstract Background: Photodynamic therapy (PDT) is a minimally invasive therapy that was gradually established as a first-line treatment for vascular abnormalities. Its action depends on the appropriate wavelength of light and photosensitizer to produce toxic oxygen species and cause cell death. Objective: Several new clinical improvements and trends in PDT have been described in recent years. The aim of this review is to provide an overview of the current data from clinical trials. Methods: In this review, we introduce and generalize the wavelength, duration, dose, strength, and photosensitizer of PDT for the treatment of vascular abnormalities, such as circumscribed choroidal hemangiomas (CCH), choroidal neovascularization (CNV) and capillary malformation (CM). Results: The systematic review findings indicate that the application of PDT is a safe effective method to treat CCH, CNV and CM. However, PDT also has early onset side effects and late onset side effects. Conclusions: Based on the discussion of the effectiveness of PDT, we conclude that PDT has great potential for clinical use, although PDT has possible side effects.

Identification of neurological complications in childhood influenza: a random forest model.

BACKGROUND: Among the neurological complications of influenza in children, the most severe is acute necrotizing encephalopathy (ANE), with a high mortality rate and neurological sequelae. ANE is characterized by rapid progression to death within 1-2 days from onset. However, the knowledge about the early diagnosis of ANE is limited, which is often misdiagnosed as simple seizures/convulsions or mild acute influenza-associated encephalopathy (IAE). OBJECTIVE: To develop and validate an early prediction model to discriminate the ANE from two common neurological complications, seizures/convulsions and mild IAE in children with influenza. METHODS: This retrospective case-control study included patients with ANE (median age 3.8 (2.3,5.4) years), seizures/convulsions alone (median age 2.6 (1.7,4.3) years), or mild IAE (median age 2.8 (1.5,6.1) years) at a tertiary pediatric medical center in China between November 2012 to January 2020. The random forest algorithm was used to screen the characteristics and construct a prediction model. RESULTS: Of the 433 patients, 278 (64.2%) had seizures/convulsions alone, 106 (24.5%) had mild IAE, and 49 (11.3%) had ANE. The discrimination performance of the model was satisfactory, with an accuracy above 0.80 from both model development (84.2%) and internal validation (88.2%). Seizures/convulsions were less likely to be wrongly classified (3.7%, 2/54), but mild IAE (22.7%, 5/22) was prone to be misdiagnosed as seizures/convulsions, and a small proportion (4.5%, 1/22) of them was prone to be misdiagnosed as ANE. Of the children with ANE, 22.2% (2/9) were misdiagnosed as mild IAE, and none were misdiagnosed as seizures/convulsions. CONCLUSION: This model can distinguish the ANE from seizures/convulsions with high accuracy and from mild IAE close to 80% accuracy, providing valuable information for the early management of children with influenza.

Mapping the neural mechanism that distinguishes between holistic thinking and analytic thinking.

Holistic and analytic thinking are two distinct modes of thinking used to interpret the world with relative preferences varying across cultures. While most research on these thinking styles has focused on behavioral and cognitive aspects, a few studies have utilized functional magnetic resonance imaging (fMRI) to explore the correlations between brain metrics and self-reported scale scores. Other fMRI studies used single holistic and analytic thinking tasks. As a single task may involve processing in spurious low-level regions, we used two different holistic and analytic thinking tasks, namely the frame-line task and the triad task, to seek convergent brain regions to distinguish holistic and analytic thinking using multivariate pattern analysis (MVPA). Results showed that brain regions fundamental to distinguish holistic and analytic thinking include the bilateral frontal lobes, bilateral parietal lobes, bilateral precentral and postcentral gyrus, bilateral supplementary motor areas, bilateral fusiform, bilateral insula, bilateral angular gyrus, left cuneus, and precuneus, left olfactory cortex, cingulate gyrus, right caudate and putamen. Our study maps brain regions that distinguish between holistic and analytic thinking and provides a new approach to explore the neural representation of cultural constructs. We provide initial evidence connecting culture-related brain regions with language function to explain the origins of cultural differences in cognitive styles.

Effects of tire-road wear particles on the adsorption of tetracycline by aquatic sediments.

Tire-road wear particles (TRWPs) are formed by friction between the tire and the road. TRWPs are ubiquitous across the globe, especially in sediments. However, the possible effects of TRWPs on tetracycline (TC) in aquatic sediments are unknown. To investigate the potential role of TRWPs as carriers of co-pollutants, this study investigated the pore surface properties and TC adsorption behavior of TRWP-contaminated sediments and explored the TC behavior in water sediments, as well as the role of aging processes and TRWPs abundance. The results showed that the surface morphology of TRWP-contaminated sediments changed and the adsorption capacity of sediments to TC increased. The TC adsorption capacity of sediments contaminated by 2% TRWPs increased from 3.15 to 3.48 mg/g. Moreover, the surface physical and chemical properties of TRWPs after UV aging changed, which further increased the TC adsorption capacity. The TC adsorption capacity of the sediments contaminated by aged TRWPs increased from 3.48 to 3.65 mg/g. Changing the proportion of aged TRWPs, we found that the adsorption capacity of sediments contaminated by different proportions of TRWPs for TC was 2% > 1% > 0.5% > 4% > blank sediment. These results may contribute to predicting the potential environmental risks of TRWPs in aquatic sediments.

Frontostriatal circuit dysfunction leads to cognitive inflexibility in neuroligin-3 R451C knockin mice.

Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.

[Design and application of a warming fixation device for premature infants].

OBJECTIVE: A warming fixation device for premature infants was made and its clinical application effect was discussed. METHODS: The warming fixation device for premature infants was designed and used in clinic. Sixty premature infants admitted to the neonatal ward of Baoding Hospital, Beijing Children's Hospital, Capital Medical University from January to June 2022 were selected as the control group, and 60 premature infants admitted from July to December 2022 were selected as the experimental group. In the control group, umbilical vein catheterization or central vein catheterization were performed using Astro Boy heating box, restraint band or artificial restraint. The preterm infants in the experimental group were radiated into the Astro Boy warm box with self-designed preterm warming fixation device for catheterization. The time of catheterization, the number of limb protrusion, the number of participants in catheterization operation, and the body temperature from 20 minutes of catheterization operation to the end of catheterization operation were recorded in the two groups. The frequency of hypothermia (< 36.5 centigrade) was calculated, and the differences in various indexes between the two groups were compared. RESULTS: (1) The warming fixation device for premature babies consists of two parts: warm sleeping bag and soft pad. The warm sleeping bag includes 4 parts: head, arm, chest and abdomen, and lower limbs. The chest and abdomen were designed with rectangular covering cloth, which can be opened to facilitate umbilical vein puncture for premature infants. There were 3 groups of restraint belts on the rectangular soft pad, which can respectively fix the arms, chest and abdomen of the warm sleeping bag and the lower limbs. During the catheterization operation, use Velcro to secure the warm sleeping bag to the cushioned surface, and select the area of exposed skin according to the piercing site. (2) There were no significant differences in gender, body weight and gestational age between the experimental group and the control group [male: 48.3% vs. 46.7%, body weight (kg): 1.86±0.06 vs. 1.82±0.06, gestational age (weeks): 31.33±0.31 vs. 32.25±0.34, all P > 0.05]. Compared with the control group, the catheterization time of experimental group was significantly shortened (minutes: 21.30±0.43 vs. 30.02±0.64, P < 0.01), the number of limb protrusion was significantly reduced (0 time: 70.0% vs. 33.3%, 1 time: 26.7% vs. 50.0%, P < 0.01), and the number of participants in catheterization operation was significantly reduced (people: 1.77±0.06 vs. 2.37±0.06, P < 0.01). The frequency of hypothermia in experimental group was significantly lower than that in the control group [6.12% (6/98) vs. 26.50% (31/117), χ2 = 15.536, P < 0.01]. CONCLUSIONS: The warming fixation device for premature infants is convenient to use, which can effectively shorten the tube placement time, save human resources, and reduce the incidence of hypothermia in premature infants.

Up-regulation of GPR139 in the medial septum ameliorates cognitive impairment in two mouse models of Alzheimer's disease.

G-protein coupled receptors (GPCRs) constitute the largest class of cell surface receptors and present prominent drug targets. GPR139 is an orphan GPCR detected in the septum of the brain. However, its roles in cognition are still unclear. Here we first established a mouse model of cognitive impairment by a single intracerebroventricular injection of aggregated amyloid-beta peptide 1-42 (Aß1-42). RNA-sequencing data analysis showed that Aß1-42 induced a significant decrease of GPR139 mRNA in the basal forebrain. Using GPR139 agonist JNJ-63533054 and behavioral tests, we found that GPR139 activation in the brain ameliorated Aß1-42-induced cognitive impairment. Using western blot, TUNEL apoptosis and Golgi staining assays, we showed that GPR139 activation alleviated Aß1-42-induced apoptosis and synaptotoxicity in the basal forebrain rather than prefrontal cortex and hippocampus. The further study identified that GPR139 was widely expressed in cholinergic neurons of the medial septum (MS). Using the overexpression virus and transgenic animal model, we showed that up-regulation of GPR139 in MS cholinergic neurons ameliorated cognitive impairment, apoptosis and synaptotoxicity in APP/PS1 transgenic mice. These findings reveal that GPR139 of MS cholinergic neurons could be a critical node in cognition and potentially provides insight into the pathogenesis of Alzheimer's disease.

The role of TRPV4 in programmed cell deaths.

Programmed cell death is a major life activity of both normal development and disease. Necroptosis is early recognized as a caspase-independent form of programmed cell death followed obviously inflammation. Apoptosis is a gradually recognized mode of cell death that is characterized by a special morphological changes and unique caspase-dependent biological process. Ferroptosis, pyroptosis and autophagy are recently identified non-apoptotic regulated cell death that each has its own characteristics. The transient receptor potential vanilloid 4 (TRPV4) is a kind of nonselective calcium-permeable cation channel, which is received more and more attention in biology studies. It is widely expressed in human tissues and mainly located on the membrane of cells. Several researchers have identified that the influx Ca2+ from TRPV4 acts as a key role in the loss of cells by apoptosis, ferroptosis, necroptosis, pyroptosis and autophagy via mediating endoplasmic reticulum (ER) stress, oxidative stress and inflammation. This effect is bad for the normal function of organs on the one hand, on the other hand, it is benefit for anticancer activities. In this review, we will summarize the current discovery on the role and impact of TRPV4 in these programmed cell death pathological mechanisms to provide a new prospect of gene therapeutic target of related diseases.

Amiodarone Advances the Apoptosis of Cardiomyocytes by Repressing Sigmar1 Expression and Blocking KCNH2-related Potassium Channels.

BACKGROUND: Heart failure (HF) is the ultimate transformation result of various cardiovascular diseases. Mitochondria-mediated cardiomyocyte apoptosis has been uncovered to be associated with this disorder. OBJECTIVE: This study mainly delves into the mechanism of the anti-arrhythmic drug amiodarone on mitochondrial toxicity of cardiomyocytes. METHODS: The viability of H9c2 cells treated with amiodarone at 0.5, 1, 2, 3, and 4 µM was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and Sigmar1 expression was examined by quantitative real-time PCR (qRTPCR). After transfection, the viability, apoptosis, reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), and potassium voltage-gated channel subfamily H member 2 (KCNH2) expression in H9c2 cells were assessed by MTT, flow cytometry, ROS assay kit, mitochondria staining kit, and Western blot. RESULTS: Amiodarone at 1-4 µM notably weakened H9c2 cell viability with IC50 value of 2.62 ± 0.43 µM. Amiodarone at 0.5-4 µM also evidently suppressed the Sigmar1 level in H9c2 cells. Amiodarone repressed H9c2 cell viability and KCNH2 level and triggered apoptosis, ROS production and mitochondrial depolarization, while Sigmar1 upregulation reversed its effects. Moreover, KCNH2 silencing neutralized the combined modulation of amiodarone and Sigmar1 up-regulation on H9c2 cell viability, apoptosis, and ROS production. CONCLUSION: Amiodarone facilitates the apoptosis of H9c2 cells by restraining Sigmar1 expression and blocking KCNH2-related potassium channels.