Water exchange across the blood-brain barrier and epilepsy: Review on pathophysiology and neuroimaging.

The blood-brain barrier (BBB) is a barrier protecting the brain and a milieu of continuous exchanges between blood and brain. There is emerging evidence that the BBB plays a major role in epileptogenesis and drug-resistant epilepsy, through several mechanisms, such as water homeostasis dysregulation, overexpression of drug transporters, and inflammation. Studies have shown abnormal water homeostasis in epileptic tissue and altered aquaporin-4 water channel expression in animal epilepsy models. This review focuses on abnormal water exchange in epilepsy and describes recent non-invasive MRI methods of quantifying water exchange. PLAIN LANGUAGE SUMMARY: Abnormal exchange between blood and brain contribute to seizures and epilepsy. The authors describe why correct water balance is necessary for healthy brain functioning and how it is impacted in epilepsy. This review also presents recent MRI methods to measure water exchange in human brain. These measures would improve our understanding of factors leading to seizures.

miR-29a-5p rescues depressive-like behaviors in a CUMS-induced mouse model by facilitating microglia M2-polarization in the prefrontal cortex via TMEM33 suppression.

BACKGROUND: Depression accounts for a high proportion of neuropsychiatric disorders and is associated with abnormal states of neurons in specific brain regions. Microglia play a pivotal role in the inflammatory state during depression development; however, the exact mechanism underlying chronic mood states remains unknown. Thus, the present study aimed to determine whether microRNAs (miRNAs) alleviate stress-induced depression-like behavior in mice by regulating the expression levels of their target genes, explore the role of neuroinflammation induced by microglial activation in the pathogenesis and progression of depression, and determine whether the role of the miR-29a-5p/transmembrane protein 33 (TMEM33) axis. METHODS: In this study, chronic unpredictable mild stress (CUMS) mouse depression model, various behavioral tests, western blotting, dual-luciferase reporter assay, enzyme-linked immunosorbent assay, real-time quantitative reverse transcription PCR, immunofluorescence and lentivirus-mediated gene transfer were used. RESULTS: After exposure to the CUMS paradigm, miR-29a-5p was significantly down-regulated. This downregulation subsequently promoted the polarization of microglia M1 by upregulating the expression of TMEM33, resulting in enhanced inflammatory chemokines affecting neurons. Conversely, the upregulation of miR-29a-5p within the prefrontal cortex (PFC) suppressed TMEM33 expression, facilitated microglia M2-polarization, and ameliorated depressive-like behavior. LIMITATIONS: Only rodent models of depression were used, and human samples were not included. CONCLUSIONS: The results of this study suggest that miR-29a-5p deficits within the PFC mediate microglial anomalies and contribute to depressive-like behaviors. miR-29a-5p and TMEM33 may, therefore, serve as potential therapeutic targets for the treatment of depression.

miR-141-3p attenuates RSL3-induced ferroptosis and intestinal epithelial-mesenchymal transition via directly inhabits ZEB1 in intestinal Behçet's syndrome.

The aims of this study were to investigate whether the ferroptosis is involved in intestinal Behçet's syndrome (IBS), and to identify if miR-141-3p could attenuate RAS-selective lethal 3 (RSL3)-induced ferroptosis and intestinal epithelial to mesenchymal transition (EMT) via directly inhabits zinc fnger E-box binding homeobox 1 (ZEB1). The expressions of ferroptosis-related proteins in the intestinal tissues of patients with IBS were investigated by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Malondialdehyde (MDA) contents of the intestinal tissues and cells were detected. Serum from IBS patients and RSL3 were co-cultured with intestinal epithelial cells in vitro. In order to investigate whether RSL3-induced ferroptosis can be ameliorated by miR-141-3p, the intestinal epithelial cells were firstly stimulated with RSL3 and then incubated with miR-141-3p mimics. Western blot was used to measure the expression of EMT and ferroptosis-related proteins. Expression of GPX4 (22.51% ± 2.05%, 51.75% ± 3.47%, t = - 7.77, p = 0.000) and xCT (17.49% ± 1.57%, 28.73% ± 1.75%, t = - 4.38, p = 0.003) were significantly lower in intestinal mucosal tissues of patients with IBS compared with HC group. Compared with the HC samples, the IBS specimens had significantly higher MDA (t = 4.32, p = 0.01). Moreover, the relative mRNA levels of ferritin light chain (FTL) (t = 4.07, p = 0.02) and ferritin heavy chain (FTH) (t = 8.82, p = 0.001) in the intestinal tissues were significant higher in IBS patients than in HC group. Serum from IBS patients could induce intestinal epithelial cell ferroptosis in vitro. Moreover, miR-141-3p could attenuate intestinal epithelial cell ferroptosis-induced by RSL3 and intestinal EMT via targeting ZEB1 in vitro. Ferroptosis were induced in patients with IBS. Moreover, the serum from IBS patients could induce ferroptosis in vitro. miR-141-3p could attenuate intestinal epithelial cell ferroptosis and intestinal EMT via targeting ZEB1. Therefore, miR-141-3p may open new avenues for the treatment of IBS in the future. Key Points • Ferroptosis in IBS is first reported in this study. • In this study, we explored that the serum from IBS patients could induce ferroptosis in vitro and miR-141-3p could attenuate intestinal epithelial cell ferroptosis and intestinal EMT via targeting ZEB1.

Congenital epiblepharon in Chinese school-age children: a cross-sectional study.

PURPOSE: To investigate the prevalence and body mass index (BMI) associations of congenital lower epiblepharon in children in China and the difference in the refractive errors between children with and without epiblepharon. METHODS: Children 6-12 years of age in Beichen District of Tianjin were screened for congenital epiblepharon from September to October 2017. All children underwent slit-lamp examination, strabismus screening, visual acuity examination and refraction. Weight and height were also recorded. The prevalence of lower epiblepharon in school-age children was evaluated, and its association with age, sex, BMI, and refractive error was analyzed. RESULTS: A total of 28,225 children were examined; 564 had epiblepharon. The prevalence of epiblepharon was found to be, for 6-year-olds, 2.50%; for 7-year-olds, 2.13%; for 8-year-olds, 2.10%; for 9-year-olds, 1.97%; for 10-year-olds, 1.85%; for 11-year-olds, 1.67%; and for 12-year-olds, 1.19% (P < 0.05). The prevalence of overweight and obesity in children with epiblepharon was found to be 16.7% and 47.2%, respectively. The prevalence and degree of astigmatism was higher than in nonepiblepharon children. We found a possible association between severity of astigmatism and severity of epiblepharon. CONCLUSIONS: In our study, the prevalence of epiblepharon decreased with advancing age, and the majority of children with epiblepharon were found to be overweight or obese. Epiblepharon was associated with astigmatism.

Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis.

BACKGROUND: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. METHODS: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. FINDINGS: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. INTERPRETATION: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. FUNDING: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

Evolutionary trajectory of TRPM2 channel activation by adenosine diphosphate ribose and calcium.

Ion channel activation upon ligand gating triggers a myriad of biological events and, therefore, evolution of ligand gating mechanism is of fundamental importance. TRPM2, a typical ancient ion channel, is activated by adenosine diphosphate ribose (ADPR) and calcium and its activation has evolved from a simple mode in invertebrates to a more complex one in vertebrates, but the evolutionary process is still unknown. Molecular evolutionary analysis of TRPM2s from more than 280 different animal species has revealed that, the C-terminal NUDT9-H domain has evolved from an enzyme to a ligand binding site for activation, while the N-terminal MHR domain maintains a conserved ligand binding site. Calcium gating pattern has also evolved, from one Ca2+-binding site as in sea anemones to three sites as in human. Importantly, we identified a new group represented by olTRPM2, which has a novel gating mode and fills the missing link of the channel gating evolution. We conclude that the TRPM2 ligand binding or activation mode evolved through at least three identifiable stages in the past billion years from simple to complicated and coordinated. Such findings benefit the evolutionary investigations of other channels and proteins.

The Performance of Spot Photoscreener in 6 to 10 Weeks Infants in China: A Cross-Sectional Study.

Purpose: To compare the refractive errors measured by the Spot photoscreener (with or without cycloplegia) to cycloplegic retinoscopy in 6- to 10-week-old infants. Materials and Methods: 101 right eyes from 101 healthy infants aged 6 to 10 weeks were recruited for this cross-sectional observational study. Refractive errors were measured using Spot photoscreener before and after cycloplegia, as well as cycloplegic retinoscopy. Comparisons between the refractive measurements were performed using one-way ANOVA with the post hoc Tukey HSD test or Kruskal-Wallis test with the Steel-Dwass test according to the data normality. Pearson's correlation test and 95% confidence intervals were calculated. The agreement was evaluated using a Bland-Altman plot with 95% limits of agreement of the differences. Results: Spot photoscreener was found to underestimate the spherical equivalent by 2.33 Diopters (D) in these infants. Following the induction of cycloplegia, the spherical equivalent measured by Spot photoscreener was in excellent agreement with cycloplegic retinoscopy with the mean difference of 0.01 D. Spot photoscreener overestimated cylindrical parameter by 0.2 D with poor agreement with cycloplegic retinoscopy no matter whether cycloplegia was induced. It had good agreement with cycloplegic retinoscopy in the J0 vector than the J45 vector measurement. Conclusions: With the induction of cycloplegia, Spot photoscreener can accurately evaluate spherical equivalent in hyperopic infants with mild-to-moderate astigmatism. While it may provide valuable measurements of astigmatism, discrepancies in cylinder and axis should be taken into account.

Longitudinal Changes in Refractive Development in Highly Hyperopic Children: A 2.6-11.2 Year Follow-up of Preschoolers Diagnosed with High Hyperopia.

PURPOSE: This study aims to elucidate the longitudinal refractive and ocular biometric alterations in preschool children with high hyperopia who underwent early interventions. METHODS: We conducted a retrospective analysis of preschool children diagnosed with high hyperopia at Tianjin Medical University Eye Hospital between 2011 and 2023. Inclusion criteria required an initial examination with cycloplegic refraction, bilateral spherical equivalent power (SE) ≥ +5.00D with a difference <1.00D, a minimum two-year follow-up, and at least three ocular biometric measurements. The annual axial growth rate evaluated emmetropization in highly hyperopic children. We applied Restricted Cubic Spline (RCS) models to explore potential nonlinear relationships between age and spherical equivalent, axial length, corneal curvature, and axial length-to-corneal curvature ratio. Additionally, Mixed-effects models were employed to investigate factors associated with changes in refractive error and axial length. RESULTS: The study enrolled 60 eligible subjects, with a median initial diagnosis age of 3.5 years (IQR, 2.8-4.9 years) and a median last visit age of 9.3 years (IQR, 8.1-10.8 years). The average follow-up duration was 5.7 years. RCS analysis revealed notable nonlinear changes in spherical equivalent power, axial length, and axial length-to-corneal curvature ratio, although corneal curvature displayed no statistically significant nonlinear trend. Factors affecting SE changes included the presence of strabismus, the use of cycloplegia, baseline SE, and age. Conversely, changes in axial length solely correlated with baseline axial length and age. CONCLUSION: Highly hyperopic preschool children undergoing early intervention display a marked emmetropization tendency, though most still remain moderately to highly hyperopic, with the progression of refractive changes showing non-uniform patterns with respect to age.

Exploration of cardiac rehabilitation nursing for elderly patients with myocardial infarction based on individualized cardiac rehabilitation.

BACKGROUND: Myocardial infarction is a high-risk condition prevalent among the elderly population, often leading to adverse clinical manifestations such as reduced cardiopulmonary function, anxiety, and depression post-surgery. Consequently, cardiac rehabilitation holds immense importance in mitigating these complications. AIM: To evaluate the effect of individualized cardiac rehabilitation on blood pressure variability (BPV) and baroreflex sensitivity (BRS) in elderly patients with myocardial infarction. METHODS: A cohort of 74 elderly patients diagnosed with myocardial infarction and admitted to our hospital between January 2021 and January 2022 were subjected to random selection. Subsequently, all patients were divided into two groups, namely the research group (n = 37) and the control group (n = 37), utilizing the number table method. The control group received conventional drug treatment and nursing guidance intervention, while the study group underwent individualized cardiac rehabilitation in addition to the interventions received by the control group. All patients were continuously intervened for 12 wk, and the BPV of these two groups in the 1st wk (T0), the 4th wk (T1) and the 12th wk (T2) were compared, BRS, changes in cardiopulmonary function measures, and adverse cardiovascular events. RESULTS: Of 24 h diastolic BPV, 24 h systolic BPV, carbon dioxide ventilation equivalent slope of the research group were lower than those of the control group at T1 and T2, BRS, peak heart rate and systolic blood pressure product, 1 min heart rate recovery were higher than those of the control group, and the incidence of adverse events in the research group was lower than that of the control group, the difference was statistically significant (P < 0.05). CONCLUSION: In this study, we found that after individualized cardiac rehabilitation in elderly patients with myocardial infarction, BPV and BRS can be effectively improved, cardiac function is significantly enhanced, and a better prognosis is obtained.

The impact of Covid-19 vaccination in Aotearoa New Zealand: A modelling study.

Aotearoa New Zealand implemented a Covid-19 elimination strategy in 2020 and 2021, which enabled a large majority of the population to be vaccinated before being exposed to the virus. This strategy delivered one of the lowest pandemic mortality rates in the world. However, quantitative estimates of the population-level health benefits of vaccination are lacking. Here, we use a validated mathematical model of Covid-19 in New Zealand to investigate counterfactual scenarios with differing levels of vaccine coverage in different age and ethnicity groups. The model builds on earlier research by adding age- and time-dependent case ascertainment, the effect of antiviral medications, improved hospitalisation rate estimates, and the impact of relaxing control measures. The model was used for scenario analysis and policy advice for the New Zealand Government in 2022 and 2023. We compare the number of Covid-19 hospitalisations, deaths, and years of life lost in each counterfactual scenario to a baseline scenario that is fitted to epidemiological data between January 2022 and June 2023. Our results estimate that vaccines saved 6650 (95% credible interval [4424, 10180]) lives, and prevented 74500 [51000, 115400] years of life lost and 45100 [34400, 55600] hospitalisations during this 18-month period. Making the same comparison before the benefit of antiviral medications is accounted for, the estimated number of lives saved by vaccines increases to 7604 [5080, 11942]. Due to inequities in the vaccine rollout, vaccination rates among Maori were lower than in people of European ethnicity. Our results show that, if vaccination rates had been equitable, an estimated 11%-26% of the 292 Maori Covid-19 deaths that were recorded in this time period could have been prevented. We conclude that Covid-19 vaccination greatly reduced health burden in New Zealand and that equity needs to be a key focus of future vaccination programmes.

Accelerated transcranial magnetic stimulation for major depressive disorder: A quick path to relief?

Transcranial magnetic stimulation (TMS) is a safe, tolerable, and evidence-based intervention for major depressive disorder (MDD). However, even after decades of research, nearly half of the patients with MDD fail to respond to conventional TMS, with responding slowly and requiring daily attendance at the treatment site for 4-6 weeks. To intensify antidepressant efficacy and shorten treatment duration, accelerated TMS protocols, which involve multiple sessions per day over a few days, have been proposed and evaluated for safety and viability. We reviewed and summarized the current knowledge in accelerated TMS, including stimulation parameters, antidepressant efficacy, anti-suicidal efficacy, safety, and adverse effects. Limitations and suggestions for future directions are also addressed, along with a brief discussion on the application of accelerated TMS during the COVID-19 pandemic. This article is categorized under: Neuroscience > Clinical Neuroscience.

Near-Infrared Photothermal Manipulates Cellular Excitability and Animal Behavior in Caenorhabditis elegans.

Near-infrared (NIR) photothermal manipulation has emerged as a promising and noninvasive technology for neuroscience research and disease therapy for its deep tissue penetration. NIR stimulated techniques have been used to modulate neural activity. However, due to the lack of suitable in vivo control systems, most studies are limited to the cellular level. Here, a NIR photothermal technique is developed to modulate cellular excitability and animal behaviors in Caenorhabditis elegans in vivo via the thermosensitive transient receptor potential vanilloid 1 (TRPV1) channel with an FDA-approved photothermal agent indocyanine green (ICG). Upon NIR stimuli, exogenous expression of TRPV1 in AFD sensory neurons causes Ca2+ influx, leading to increased neural excitability and reversal behaviors, in the presence of ICG. The GABAergic D-class motor neurons can also be activated by NIR irradiation, resulting in slower thrashing behaviors. Moreover, the photothermal manipulation is successfully applied in different types of muscle cells (striated muscles and nonstriated muscles), enhancing muscular excitability, causing muscle contractions and behavior changes in vivo. Altogether, this study demonstrates a noninvasive method to precisely regulate the excitability of different types of cells and related behaviors in vivo by NIR photothermal manipulation, which may be applied in mammals and clinical therapy.

TRPM2 as a conserved gatekeeper determines the vulnerability of DA neurons by mediating ROS sensing and calcium dyshomeostasis.

Different dopaminergic (DA) neuronal subgroups exhibit distinct vulnerability to stress, while the underlying mechanisms are elusive. Here we report that the transient receptor potential melastatin 2 (TRPM2) channel is preferentially expressed in vulnerable DA neuronal subgroups, which correlates positively with aging in Parkinson's Disease (PD) patients. Overexpression of human TRPM2 in the DA neurons of C. elegans resulted in selective death of ADE but not CEP neurons in aged worms. Mechanistically, TRPM2 activation mediates FZO-1/CED-9-dependent mitochondrial hyperfusion and mitochondrial permeability transition (MPT), leading to ADE death. In mice, TRPM2 knockout reduced vulnerable substantia nigra pars compacta (SNc) DA neuronal death induced by stress. Moreover, the TRPM2-mediated vulnerable DA neuronal death pathway is conserved from C. elegans to toxin-treated mice model and PD patient iPSC-derived DA neurons. The vulnerable SNc DA neuronal loss is the major symptom and cause of PD, and therefore the TRPM2-mediated pathway serves as a promising therapeutic target against PD.

Arriving late and lean at a stopover site is selected against in a declining migratory bird population.

Loss and/or deterioration of refuelling habitats have caused population declines in many migratory bird species but whether this results from unequal mortality among individuals varying in migration traits remains to be shown. Based on 13 years of body mass and size data of great knots (Calidris tenuirostris) at a stopover site of the Yellow Sea, combined with resightings of individuals marked at this stopover site along the East Asian-Australasian Flyway, we assessed year to year changes in annual apparent survival rates, and how apparent survival differed between migration phenotypes (i.e. migration timing and fuel stores). The measurements occurred over a period of habitat loss and/or deterioration in this flyway. We found that the annual apparent survival rates of great knots rapidly declined from 2006 to 2018, late-arriving individuals with small fuel stores exhibiting the lowest apparent survival rate. There was an advancement in mean arrival date and an increase in the mean fuel load of stopping birds over the study period. Our results suggest that late-arriving individuals with small fuel loads were selected against. Thus, habitat loss and/or deterioration at staging sites may cause changes in the composition of migratory phenotypes at the population-level.

Cux1+ proliferative basal cells promote epidermal hyperplasia in chronic dry skin disease identified by single-cell RNA transcriptomics.

Pathological dry skin is a disturbing and intractable healthcare burden, characterized by epithelial hyperplasia and severe itch. Atopic dermatitis (AD) and psoriasis models with complications of dry skin have been studied using single-cell RNA sequencing (scRNA-seq). However, scRNA-seq analysis of the dry skin mouse model (acetone/ether/water (AEW)-treated model) is still lacking. Here, we used scRNA-seq and in situ hybridization to identify a novel proliferative basal cell (PBC) state that exclusively expresses transcription factor CUT-like homeobox 1 (Cux1). Further in vitro study demonstrated that Cux1 is vital for keratinocyte proliferation by regulating a series of cyclin-dependent kinases (CDKs) and cyclins. Clinically, Cux1+ PBCs were increased in patients with psoriasis, suggesting that Cux1+ PBCs play an important part in epidermal hyperplasia. This study presents a systematic knowledge of the transcriptomic changes in a chronic dry skin mouse model, as well as a potential therapeutic target against dry skin-related dermatoses.

Can the new adipokine asprosin be a metabolic troublemaker for cardiovascular diseases? A state-of-the-art review.

Adipokines play a significant role in cardiometabolic diseases. Asprosin, a newly discovered adipokine, was first identified as a glucose-raising protein hormone. Asprosin also stimulates appetite and regulates glucose and lipid metabolism. Its identified receptors so far include Olfr734 and Ptprd. Clinical studies have found that asprosin may be associated with cardiometabolic diseases. Asprosin may have diagnostic and therapeutic potential in obesity, diabetes, metabolic syndrome and atherosclerotic cardiovascular diseases. Herein, the structure, receptors, and functions of asprosin and its relationship with cardiometabolic diseases are summarized based on recent findings.

Dapagliflozin-affected endothelial dysfunction and altered gut microbiota in mice with heart failure.

Aim: To investigate the potential microbiome profile of a mouse model with heart failure (HF) during dapagliflozin treatment. Method: An HF model was constructed in 8-week-old male mice, and cardiac tissues were analyzed using histological staining. Hemodynamic indexes were measured, and fecal samples were collected for 16S rDNA sequencing. Chao1, Shannon, and Simpson were used for α-diversity analysis. b-Diversity analysis was conducted using principal coordinate analysis (PCoA) and non-metric multidimensional scaling (NMDS) based on the Bray-Curtis distance. Linear discriminant analysis coupled with effect size measurements (LEfSe) was used to identify signature gut microbiota, and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was used to predict the function of altered gut microbiota. Result: Dapagliflozin treatment reduced inflammation, infarction area, and cardiac fibrosis in HF mice. It also increased endothelial-dependent dilation and inflammation in mice with HF. Dapagliflozin decreased the ratio of Firmicutes/Bacteroidetes, which was increased in HF mice. There was no significant statistical difference in α-diversity among the control, HF, and HF+dapagliflozin groups. Desulfovibrio, AF12, and Paraprevotella were enriched in HF+dapagliflozin, while Rikenella and Mucispirillum were enriched in HF based on LEfSe. KEGG analysis revealed that altered gut microbiota was associated with fermentation, amino acid biosynthesis, nucleoside and nucleotide biosynthesis/degradation, fatty acid and lipid biosynthesis, carbohydrate biosynthesis/degradation, and cofactor/prosthetic group/electron carrier/vitamin biosynthesis. Conclusion: Understanding the microbiome profile helps elucidate the mechanism of dapagliflozin for HF. The signature genera identified in this study could be used as a convenient method to distinguish between HF patients and healthy individuals.

TRPM2 Mediates Hepatic Ischemia-Reperfusion Injury via Ca2+-Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression.

Hepatic ischemia-reperfusion (IR) injury is a serious clinical problem that complicates liver resection and transplantation. Despite recent advances in understanding of the pathophysiology of hepatic IR injury, effective interventions and therapeutics are still lacking. Here, we examined the role of transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable, non-selective cation channel, in mediating hepatic IR injury. Our data showed that TRPM2 deficiency attenuated IR-induced liver dysfunction, inflammation, and cell death in mice. Moreover, RNA sequencing analysis indicated that TRPM2-induced IR injury occurs via ferroptosis-related pathways. Consistently, as a ferroptosis inducer, (1S,3R)-RSL3 treatment induced mitochondrial dysfunction in hepatocytes and a TRPM2 inhibitor suppressed this. Interestingly, TRPM2-mediated calcium influx caused mitochondrial calcium accumulation via the mitochondrial Ca2+-selective uniporter and increased the expression level of arachidonate 12-lipoxygenase (ALOX12), which results in mitochondrial lipid peroxidation during hepatic IR injury. Furthermore, hepatic IR injury-induced ferroptosis was obviously relieved by a TRPM2 inhibitor or calcium depletion, both in vitro and in vivo. Collectively, these findings demonstrate a crucial role for TRPM2-mediated ferroptosis in hepatic IR injury via increased Ca2+-induced ALOX12 expression, indicating that pharmacological inhibition of TRPM2 may provide an effective therapeutic strategy for hepatic IR injury-related diseases, such as during liver resection and transplantation.

rTMS ameliorates depressive-like behaviors and regulates the gut microbiome and medium- and long-chain fatty acids in mice exposed to chronic unpredictable mild stress.

INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) is a clinically useful therapy for depression. However, the effects of rTMS on the metabolism of fatty acids (FAs) and the composition of gut microbiota in depression are not well established. METHODS: Mice received rTMS (15 Hz, 1.26 T) for seven consecutive days after exposure to chronic unpredictable mild stress (CUMS). The subsequent depressive-like behaviors, the composition of gut microbiota of stool samples, as well as medium- and long-chain fatty acids (MLCFAs) in the plasma, prefrontal cortex (PFC), and hippocampus (HPC) were evaluated. RESULTS: CUMS induced remarkable changes in gut microbiotas and fatty acids, specifically in community diversity of gut microbiotas and PUFAs in the brain. 15 Hz rTMS treatment alleviates depressive-like behaviors and partially normalized CUMS induced alterations of microbiotas and MLCFAs, especially the abundance of Cyanobacteria, Actinobacteriota, and levels of polyunsaturated fatty acids (PUFAs) in the hippocampus and PFC. CONCLUSION: These findings revealed that the modulation of gut microbiotas and PUFAs metabolism might partly contribute to the antidepressant effect of rTMS.

Relationship between ambulatory arterial stiffness index and the severity of angiographic atherosclerosis in patients with H-type hypertension and coronary artery disease.

OBJECTIVE: To investigate coronary artery disease (CAD) and its correlation with the ambulatory arterial stiffness index (AASI) in patients with H-type hypertension (essential hypertension combined with hyper-homocysteinemia) and coronary heart disease (CHD). METHODS: Patients with essential hypertension and CHD who were undergoing coronary angiography were enrolled. The general clinical data, biochemical indicators, ambulatory blood pressure monitoring results and coronary angiography results of the selected patients were collected, and the AASI and Gensini scores were calculated. According to homocysteine (Hcy) levels, the patients were divided into two groups: a study group and a control group. The differences in general clinical data, biochemical indexes, AASI scores and degree of coronary artery lesions between the two groups were compared. The correlation between the AASI and the Gensini score and the relationship between the AASI and the Gensini score of CAD and various factors were analyzed. RESULTS: Compared with the control group, the Hcy level in the study group was significantly increased (8.16 ± 2.33 vs 19.20 ± 2.36, P = .001). The 24-h diastolic blood pressure (DBP) in the study group was significantly lower than that in the control group (76.38 ± 9.33 vs 79.91 ± 9.25, P = .002), and the AASI was significantly higher than in the control group (0.62 ± 0.81 vs 0.420 ± 0.70, P = .001). The number of patients having coronary stenoses with a Gensini score of ≤ 38 was significantly lower in the study group than in the control group (21.3% vs 49.4%, P < .001). The number of patients with a Gensini score of ≥ 51 in the study group was significantly higher than in the control group (22.0% vs 18.8%, P < .001). There was a significant positive correlation between the AASI and the Gensini score in the study group (R = 0.732, P < .001). Hypertension duration (ß = 0.168), diabetes history (ß = 0.236), 24-h SBP (ß = 0.122), 24-h DBP (ß = -0.131), low-density lipoprotein cholesterol (ß = 0.134) and Hcy (ß = 0.233) were the influencing factors for AASI (P < .05). Both Hcy * AASI (ß = 0.356) and Hcy × 24-h HR (ß = 0.331) had a synergistic effect on the Gensini score (P = .017), with Hcy * AASI having a more significant effect on the Gensini score (P < .001). CONCLUSION: The AASI was significantly increased in patients with H-type hypertension and CHD, which was associated with the severity of CAD. Therefore, Hcy levels and the AASI have a synergistic effect when evaluating the severity of CAD in patients with hypertensive CHD.