PL-ReliefTMplus Alleviates Atopic Dermatitis and Regulates Inflammatory Responses via Inhibiting NF-κB Signaling Pathway.

BACKGROUND: Atopic dermatitis (AD) has various detrimental effects on individuals with limited drug cure rates which necessitate the development of new treatment methods. PL-ReliefTMplus (PLR) is composed of SupraOlive, Crocus Sativus extracts and Citrus reticulata extracts. The effect of PLR on AD remains to be explored. METHODS: 2,4-dinitrofluorobenzene-induced AD model mice were involved and the histopathology of the skin lesions was observed along with the levels of inflammatory chemokines levels were measured. To further validate the molecular mechanism of PLR, RNA-seq was performed in HaCaT cells. Western blotting and immunofluorescence were performed to investigate NF-κB signaling pathways response in AD. RESULTS: Due to PLR treatment, the thickening of the epidermis and dermis was inhibited and the number of eosinophils, mast cells, and CD4+ T cells in the skin lesion was decreased. In addition, the levels of inflammatory cytokines were decreased in dorsal skin tissues and LPS-stimulated HaCat cells. Furthermore, KEGG pathway analysis suggested that most identified downstream biological functions were associated with inflammatory response. PLR inhibited NF-κB signaling in AD mice and HaCaT cells. CONCLUSIONS: These results indicate that PLR is a potent therapeutic agent for attenuating symptoms of AD.

Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy.

Cerebral palsy (CP) is the most common motor disability in children. To ascertain the role of major genetic variants in the etiology of CP, we conducted exome sequencing on a large-scale cohort with clinical manifestations of CP. The study cohort comprised 505 girls and 1,073 boys. Utilizing the current gold standard in genetic diagnostics, 387 of these 1,578 children (24.5%) received genetic diagnoses. We identified 412 pathogenic and likely pathogenic (P/LP) variants across 219 genes associated with neurodevelopmental disorders, and 59 P/LP copy number variants. The genetic diagnostic rate of children with CP labeled at birth with perinatal asphyxia was higher than the rate in children without asphyxia (P = 0.0033). Also, 33 children with CP manifestations (8.5%, 33 of 387) had findings that were clinically actionable. These results highlight the need for early genetic testing in children with CP, especially those with risk factors like perinatal asphyxia, to enable evidence-based medical decision-making.

Targeting Fatty Acid Desaturase I Inhibits Renal Cancer Growth Via ATF3-mediated ER Stress Response.

Monounsaturated fatty acids (MUFAs) play a pivotal role in maintaining endoplasmic reticulum (ER) homeostasis, an emerging hallmark of cancer. However, the role of polyunsaturated fatty acid (PUFAs) desaturation in persistent ER stress driven by oncogenic abnormalities remains elusive. Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain PUFAs. Our previous research has demonstrated the significant role of FADS1 in cancer survival, especially in kidney cancers. We explored the underlying mechanism in this study. We found that pharmacological inhibition or knockdown of the expression of FADS1 effectively inhibits renal cancer cell proliferation and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we show that while FADS1 inhibition induces ER stress, its expression is also augmented by ER-stress inducers. Notably, FADS1-inhibition sensitized cellular response to ER stress inducers, providing evidence of FADS1's role in modulating the ER stress response in cancer cells. We show that, while FADS1 inhibition-induced ER stress leads to activation of ATF3, ATF3-knockdown rescues the FADS1 inhibition-induced ER stress and cell growth suppression. In addition, FADS1 inhibition results in the impaired biosynthesis of nucleotides and decreases the level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response. Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target.

China Trends in Physical Inactivity from 2013 to 2019: An Analysis of 4.23 Million Participants.

INTRODUCTION: This study aimed to evaluate recent trends in physical inactivity prevalence by sociodemographic characteristics and the province of China's residence between 2013 and 2019. METHODS: The study included 4,229,616 participants 40 yr or older from 414 geographically defined localities in China during the 7-yr period. Self-reported total physical inactivity was collected to determine the standardized prevalence of physical inactivity. Logistic regression analysis was used to examine the association between physical inactivity and stroke risk, obtaining odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Results showed that the standardized prevalence of physical inactivity increased from 22.12% (95% CI = 21.99%-22.45%) in 2013 to 28.79% (95% CI = 28.48%-29.19%) in 2019, with an absolute difference of 6.67% (95% CI = 6.15% to 7.16%) and a yearly increase rate of 5.03% (95% CI = 4.85% to 5.21%). In 2019, physical inactivity was higher in female and rural participants (female = 29.55%, rural = 29.46%) than in male and urban participants (male = 28.03%, urban = 28.26%). The prevalence of physical inactivity also varied by race/ethnic groups, with the highest prevalence observed among Uyghur (47.21%) and the lowest among Yizu (14.84%). Additionally, the prevalence of physical inactivity differed by province, ranging from 14.44% in Beijing to 50.09% in Tianjin in 2019. Multivariate analyses showed that physical inactivity was associated with a higher risk of stroke (OR = 1.17, 95% CI = 1.12-1.21, P < 0.001). CONCLUSIONS: In conclusion, our study found an overall increase in physical inactivity prevalence among Chinese adults ≥40 yr old from 2013 to 2019, with significant variation across regions, sex, ages, and race/ethnic groups.

Prevalence, risk factors, and prognosis of central nervous system manifestations in antiphospholipid syndrome.

The central nervous system (CNS) is considered as one of the most frequently affected organs in antiphospholipid syndrome (APS). This study investigated the prevalence of CNS manifestations in APS and associated risk factors and evaluated stroke recurrence. We carried out this retrospective study from 2009 to 2021 at Peking University People's Hospital, which enrolled 342 APS patients, and 174 neurologic events were suffered by 119 patients (34.8%). Patients with and without CNS involvement were compared regarding demographics and laboratory parameters. The analysis showed that older age, livedo reticularis, and dyslipidaemia were significant related factors for CNS manifestations (P = 0.047, 0.038, and 0.030 respectively). The use of anticoagulants (P = 0.004), and/or hydroxychloroquine (P = 0.016) appeared to associated with a lower incidence of CNS manifestations. During a median follow-up of 4.1 years, 10 individuals developed new episodes of stroke in APS patients with previous ischemic strokes. Livedo reticularis, smoking and male gender may predict the risk of recurrent stroke (P = 0.020, 0.006, and 0.026 respectively). Collectively, our results indicated the protective and risk factors for CNS manifestations, as well as demonstrated that APS patients appeared at high risk of stroke recurrence despite current therapy.

Impacts of exposure to ambient temperature and altitude on the burden of stroke.

OBJECTIVE: To evaluate the impact of ambient temperature and altitude exposure on the burden of stroke in a Chinese cohort. METHODS: This study was conducted using data from the National Stroke High-Risk Population Screening System 2020, which assess the overall prevalence, incidence, and mortality rate of stroke in China. For this study, we obtained the annual mean ambient temperature, diurnal temperature range, and altitude for each city. Body mass index (BMI) of participants were calculated. RESULT: The sample comprised 676,394 adults aged 40 years or older from 170 cities in 31 provinces in China. A negative linear relationship between mean ambient temperature and stroke risk (incidence and prevalence) as well as a negative association between mean ambient temperature and stroke mortality had been found. A nonlinear relationship with decreased risk in both high and low diurnal temperature range is observed for stroke burden (incidence, prevalence, and mortality). There is no significant correlation between city altitude and stroke burden. The U-shaped relationships of BMI with the incidence and prevalence of stroke indicate that the lowest incidence and prevalence are observed when BMI is approximately 20. CONCLUSION: Overall, our study provides important insights into the environmental and individual factors that contribute to the burden of stroke in China, and may inform public health interventions aimed at reducing this burden.

Studying the imaging features and infarction mechanism of vertebrobasilar dolichoectasia with high-resolution magnetic resonance imaging.

The mechanisms underlying ischemic infarction in patients with vertebrobasilar dolichoectasia (VBD) remain unclear. In this study, we retrospectively analyzed the imaging characteristics of high-resolution magnetic resonance imaging (HR-MRI) in patients with VBD to explore the possible mechanisms of ischemic stroke (IS) in patients with VBD. Patients with VBD were recruited from the HR-MRI database between July 2017 and June 2021. HR-MRI was used to evaluate the diameter, bifurcation height, laterality, arterial dissection, and atherosclerotic plaques of the basilar artery (BA). Transcranial Doppler was used to measure the vertebrobasilar mean velocity (Vm), peak systolic velocity (Vs), end-diastolic velocity (Vd), and pulsatile index. Twenty-six patients with VBD were enrolled, of which 15 had IS and 11 did not. The incidence of classical vascular risk factors, including age, sex, hypertension, diabetes, and hypercholesterolemia, did not differ significantly between the two groups. The BA diameters of the stroke group were significantly higher than that of the nonstroke group (6.57 ± 1.00 mm vs. 5.06 ± 0.50 mm, p = 0.000). The height of the BA bifurcation in the stroke and nonstroke groups was statistically significant (p = 0.002). Compared with the nonstroke group, the Vm, Vs, and Vd of the BA in the stroke group were lower, but the difference was not significant. In the 16 patients with atherosclerotic stenosis, 30 atherosclerotic plaques were found in the BA, 18 (60%) in the greater curvature, and 12 (40%) in the lesser curvature. In addition, one artery dissection (on the lesser curvature) and two dissecting aneurysms (on the greater curvature) were found in the BA of three patients, respectively. The BA diameter and bifurcation height are factors related to IS in patients with VBD. The mechanism of stroke in patients with VBD may involve abnormal hemodynamics, artery dissection, and atherosclerosis. HR-MRI is a useful method for evaluating the risk and underlying mechanism of stroke in patients with VBD.

Stroke and Risk Factors in Antiphospholipid Syndrome.

Stroke is considered one of the most common and life-threatening manifestations of antiphospholipid syndrome (APS), which leads to high mortality and permanent disability. This study investigated the prevalence and the potential risk factors of stroke in APS. We enrolled 361 APS patients retrospectively from 2009 to 2022 at Peking University People's Hospital. Stroke was found in 25.8% (93/361) of the participants. The multivariate logistic regression showed that hypertension, diabetes, livedo reticularis, and other central nervous system involvements were significant related factors for stroke. The use of hydroxychloroquine appeared to relate to a lower incidence of stroke. During a median follow-up of 3.0 years, 11.8% (11/93) of the individuals with a previous stroke developed stroke recurrence, and thrombocytopenia seemed to be a predictor of stroke recurrence.

Obesity-Associated Anxiety Is Prevalent among College Students and Alleviated by Calorie Restriction.

Anxiety is a common disorder among college students, especially those with obesity. Obesity contributes to metabolic disorders and disturbs the neural functions, further leading to anxiety. In this cross-sectional study, we aimed to determine the association between obesity and anxiety among college students and identified the potential factors for obesity-associated anxiety. We evaluated the intervention effects of calorie restriction on anxiety. Self-reported questionnaires were distributed to 1381 college students from January to March in 2021. Anxiety was measured by the State-Trait Anxiety Inventory (STAI). Participants were classified into anxiety and non-anxiety groups according to their STAI scores. Chi-squared test and logistic regression were used to analyze the potential factors. We found that 383 college students exhibited anxiety, accounting for 30.1% among all included college students, which was higher than the global average. The association between anxiety and obesity was observed among college students (p = 0.009), especially in males (p = 0.007). We identified that pre-obesity (p = 0.012), unhealthy calorie intake (p = 0.001), dieting (p = 0.003) and high academic year (p = 0.006) as the risk factors for anxiety and found that the long sleep duration was a protective factor for anxiety (p < 0.001). We found that more obese students showed an improvement of anxiety than the underweight students after calorie restriction (p < 0.001). Collectively, our findings suggest that obesity-associated anxiety is prevalent among the college students and could be alleviated by moderate calorie restriction. It is necessary for students to receive anxiety management in their college life. Additionally, the proper calorie restriction should be promoted to help students protect against obesity and obesity-associated anxiety.

A novel aGAPSS-based nomogram for the prediction of ischemic stroke in patients with antiphospholipid syndrome.

Background: Ischemic stroke (IS) is the most common and life-threatening arterial manifestation of antiphospholipid syndrome (APS). It is related to high mortality and severe permanent disability in survivors. Thus, it is essential to identify patients with APS at high risk of IS and adopt individual-level preventive measures. This study was conducted to identify risk factors for IS in patients with APS and to develop a nomogram specifically for IS prediction in these patients by combining the adjusted Global Anti-Phospholipid Syndrome Score (aGAPSS) with additional clinical and laboratory data. Methods: A total of 478 consecutive patients with APS were enrolled retrospectively. All patients were randomly assigned to the training and validation cohorts. Univariate and multivariate binary logistic analyses were conducted to identify predictors of IS in the training cohort. Then, a nomogram was developed based on these predictors. The predictive performance of the nomogram for the training and validation cohorts was evaluated by determining areas under the receiver operating characteristic curve (AUROC) and creating calibration plots. A decision curve analysis (DCA) was conducted to compare the potential net benefits of the nomogram with those of the aGAPSS. Results: During a mean follow-up period of 2.7 years, 26.9% (129/478) of the patients were diagnosed with IS. Binary logistic regression analysis revealed that five risk factors were independent clinical predictors of IS: age (P < 0.001), diabetes (P = 0.030), hyperuricemia (P < 0.001), the platelet count (P = 0.001), and the aGAPSS (P = 0.001). These predictors were incorporated into the nomogram, named the aGAPSS-IS. The nomogram showed satisfactory performance in the training [AUROC = 0.853 (95% CI, 0.802-0.896] and validation [AUROC = 0.793 (95% CI, 0.737-0.843)] cohorts. Calibration curves showed good concordance between observed and nomogram-predicted probability in the training and validation cohorts. The DCA confirmed that the aGAPSS-IS provided more net benefits than the aGAPSS in both cohorts. Conclusion: Age, diabetes, hyperuricemia, the platelet count, and the aGAPSS were risk factors for IS in patients with APS. The aGAPSS-IS may be a good tool for IS risk stratification for patients with APS based on routinely available data.

DNAJB2 c.184C>T mutation associated with distal hereditary motor neuropathy with rimmed vacuolar myopathy.

Distal hereditary motor neuropathy (dHMN), also known as distal spinal muscular atrophy (dSMA), comprises a group of inherited peripheral neuropathies with great clinical and genetic heterogeneity, mainly characterized by progressive atrophy and weakness of distal muscle without clinical or electrophysiological sensory abnormalities. Next-generation sequencing is widely applied as an effective diagnostic technique to discover pathogenic genes in patients with dHMN. To date, at least 23 causal genes have been identified to be associated with dHMN, several of which encode chaperones. Here, we report a dHMN patient due to a homozygous c.184C>T variant in the DNAJB2 gene with rare neuropathic and myopathic characteristics on pathological examination. These findings might broaden the mutational spectrum of DNAJB2 and expand the tissue involvement of DNAJB2-related presentations.

Loss of aryl hydrocarbon receptor suppresses the response of colonic epithelial cells to IL22 signaling by upregulating SOCS3.

IL22 signaling plays an important role in maintaining gastrointestinal epithelial barrier function, cell proliferation, and protection of intestinal stem cells from genotoxicants. Emerging studies indicate that the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, promotes production of IL22 in gut immune cells. However, it remains to be determined if AhR signaling can also affect the responsiveness of colonic epithelial cells to IL22. Here, we show that IL22 treatment induces the phosphorylation of STAT3, inhibits colonic organoid growth, and promotes colonic cell proliferation in vivo. Notably, intestinal cell-specific AhR knockout (KO) reduces responsiveness to IL22 and compromises DNA damage response after exposure to carcinogen, in part due to the enhancement of suppressor of cytokine signaling 3 (SOCS3) expression. Deletion of SOCS3 increases levels of pSTAT3 in AhR KO organoids, and phenocopies the effects of IL22 treatment on wild-type (WT) organoid growth. In addition, pSTAT3 levels are inversely associated with increased azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon tumorigenesis in AhR KO mice. These findings indicate that AhR function is required for optimal IL22 signaling in colonic epithelial cells and provide rationale for targeting AhR as a means of reducing colon cancer risk.NEW & NOTEWORTHY AhR is a key transcription factor controlling expression of IL22 in gut immune cells. In this study, we show for the first time that AhR signaling also regulates IL22 response in colonic epithelial cells by modulating SOCS3 expression.

Total Cerebral Small Vessel Disease Burden on MRI Correlates With Cognitive Impairment in Outpatients With Amnestic Disorders.

Objectives: The main markers of cerebral small vessel disease (cSVD) on MRI may be entered into a scoring system, with the total score representing the overall burden of cSVD. An association between total cSVD score and cognitive dysfunction has been reported in several cohorts. The present study aimed to investigate this association in outpatients with amnestic disorders. Materials and Methods: Outpatients with amnestic complaints in a memory clinic (n = 289) were recruited retrospectively. All the patients had undergone clinical and cognitive evaluation at first presentation. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) scale. The total cSVD score was based on the following markers on MRI: lacune; white matter hyperintensities, microbleed, and enlarged perivascular spaces. The association between total cSVD score and MoCA score was tested via Spearman's analysis and a linear regression model. Results: Among the 289 patients, rates for 0-4 cSVD markers respectively ranged from 30.4 to 2.8%. A multiple linear regression model revealed an inverse correlation between the total cSVD score and MoCA score. The association remained significant after adjusting for gender, age, education, levels of medial temporal lobe atrophy, and classical vascular risk factors [ß = -0.729, 95% CI (-1.244, -0.213); P = 0.006]. When individual markers were individually analyzed after adjusting for the same factors, only microbleed associated with MoCA score [ß = -3.007, 95% CI (-4.533, -1.480), P < 0.001]. Conclusions: A significant association was demonstrated between total cSVD score and cognitive performance in the outpatients with amnestic disorders.

Total Cerebral Small Vessel Disease Burden on MRI Correlates With Medial Temporal Lobe Atrophy and Cognitive Performance in Patients of a Memory Clinic.

Background: Cerebral small vessel disease (cSVD) and neurodegeneration are the two main causes of dementia and are considered distinct pathological processes, while studies have shown overlaps and interactions between the two pathological pathways. Medial temporal atrophy (MTA) is considered a classic marker of neurodegeneration. We aimed to investigate the relationship of total cSVD burden and MTA on MRI using a total cSVD score and to explore the impact of the two MRI features on cognition. Methods: Patients in a memory clinic were enrolled, who underwent brain MRI scan and cognitive evaluation within 7 days after the first visit. MTA and total cSVD score were rated using validated visual scales. Cognitive function was assessed by using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scales. Spearman's correlation and regression models were used to test (i) the association between MTA and total cSVD score as well as each cSVD marker and (ii) the correlation of the MRI features and cognitive status. Results: A total of 312 patients were finally enrolled, with a median age of 75.0 (66.0-80.0) years and 40.7% (127/312) males. All of them finished MRI and MMSE, and 293 subjects finished MoCA. Of note, 71.8% (224/312) of the patients had at least one of the cSVD markers, and 48.7% (152/312) of them had moderate-severe MTA. The total cSVD score was independently associated with MTA levels, after adjusting for age, gender, years of education, and other vascular risk factors (OR 1.191, 95% CI 1.071-1.324, P = 0.001). In regard to individual markers, a significant association existed only between white matter hyperintensities and MTA after adjusting for the factors mentioned above (OR 1.338, 95% CI 1.050-1.704, P = 0.018). Both MTA and total cSVD score were independent risk factors for MMSE ≤ 26 (MTA: OR 1.877, 95% CI 1.407-2.503, P < 0.001; total cSVD score: OR 1.474, 95% CI 1.132-1.921, P = 0.004), and MoCA < 26 (MTA: OR 1.629, 95% CI 1.112-2.388, P = 0.012; total cSVD score: OR 1.520, 95% CI 1.068-2.162, P = 0.020). Among all the cSVD markers, microbleed was found significantly associated with MMSE ≤ 26, while no marker was demonstrated a relationship with MoCA < 26. Conclusion: Cerebral small vessel disease was related to MTA in patients of a memory clinic, and both the MRI features had a significant association with cognitive impairment.

Role of the Aryl Hydrocarbon Receptor (AhR) in Mediating the Effects of Coffee in the Colon.

SCOPE: This study investigates the mechanism of action and functional effects of coffee extracts in colonic cells, on intestinal stem cell growth, and inhibition of dextran sodium sulfate (DSS)-induced intestinal barrier damage in mice. METHODS AND RESULTS: Aqueous coffee extracts induced Ah receptor (AhR) -responsive CYP1A1, CYP1B1, and UGT1A1 gene expression in colon-derived Caco2 and YAMC cells. Tissue-specific AhR knockout (AhRf/f x Lgr5-GFP-CreERT2 x Villin-Cre), wild-type (Lgr5-CreERT2 x Villin-Cre) mice are sources of stem cell enriched organoids and both coffee extracts and norharman, an AhR-active component of these extracts inhibited stem cell growth. Coffee extracts also inhibit DSS-induced damage to intestinal barrier function and DSS-induced mucosal inflammatory genes such as IL-6 and TGF-ß1 in wild-type (AhR+/+ ) but not AhR-/- mice. In contrast, coffee does not exhibit protective effects in intestinal-specific AhR knockout mice. Coffee extracts also enhanced overall formation of AhR-active microbial metabolites. CONCLUSIONS: In colon-derived cells and in the mouse intestine, coffee induced several AhR-dependent responses including gene expression, inhibition of intestinal stem cell-enriched organoid growth, and inhibition of DSS-induced intestinal barrier damage. We conclude that the anti-inflammatory effects of coffee in the intestine are due, in part, to activation of AhR signaling.

Assessment of Plasma Membrane Fatty Acid Composition and Fluidity Using Imaging Flow Cytometry.

Phospholipid fatty acid (FA) composition influences the biophysical properties of the plasma membrane and plays an important role in cellular signaling. Our previous work has demonstrated that plasma membrane fatty acid composition is an important determinant of oncogenic Ras signaling and that dietary (exogenous) modulation of membrane composition may underlie the chemoprotective benefits of long chain n-3 polyunsaturated fatty acids (PUFA). In this chapter, we describe in vitro methods to modulate membrane phospholipid fatty acid composition of cultured cells using fatty acids complexed to bovine serum albumin (BSA). Furthermore, we describe a method to quantify the biophysical properties of plasma membranes in live cells using Di-4-ANEPPDHQ (Di4) and image-based flow cytometry.

Fatty Acid Desaturase 1 Influences Hepatic Lipid Homeostasis by Modulating the PPARα-FGF21 Axis.

The fatty acid desaturase 1 (FADS1), also known as delta-5 desaturase (D5D), is one of the rate-limiting enzymes involved in the desaturation and elongation cascade of polyunsaturated fatty acids (PUFAs) to generate long-chain PUFAs (LC-PUFAs). Reduced function of D5D and decreased hepatic FADS1 expression, as well as low levels of LC-PUFAs, were associated with nonalcoholic fatty liver disease. However, the causal role of D5D in hepatic lipid homeostasis remains unclear. In this study, we hypothesized that down-regulation of FADS1 increases susceptibility to hepatic lipid accumulation. We used in vitro and in vivo models to test this hypothesis and to delineate the molecular mechanisms mediating the effect of reduced FADS1 function. Our study demonstrated that FADS1 knockdown significantly reduced cellular levels of LC-PUFAs and increased lipid accumulation and lipid droplet formation in HepG2 cells. The lipid accumulation was associated with significant alterations in multiple pathways involved in lipid homeostasis, especially fatty acid oxidation. These effects were demonstrated to be mediated by the reduced function of the peroxisome proliferator-activated receptor alpha (PPARα)-fibroblast growth factor 21 (FGF21) axis, which can be reversed by treatment with docosahexaenoic acid, PPARα agonist, or FGF21. In vivo, FADS1-knockout mice fed with high-fat diet developed increased hepatic steatosis as compared with their wild-type littermates. Molecular analyses of the mouse liver tissue largely corroborated the observations in vitro, especially along with reduced protein expression of PPARα and FGF21. Conclusion: Collectively, these results suggest that dysregulation in FADS1 alters liver lipid homeostasis in the liver by down-regulating the PPARα-FGF21 signaling axis.

The Association Study of IL-23R Polymorphisms With Cerebral Palsy in Chinese Population.

Background: Cerebral palsy (CP) is a syndrome of non-progressive motor dysfunction caused by early brain development injury. Recent evidence has shown that immunological abnormalities are associated with an increased risk of CP. Methods: We recruited 782 children with CP as the case group and 770 healthy children as the control group. The association between IL-23R single nucleotide polymorphisms (SNPs; namely, rs10889657, rs6682925, rs1884444, rs17375018, rs1004819, rs11805303, and rs10889677) and CP was studied by using a case-control method and SHEsis online software. Subgroup analysis based on complications and clinical subtypes was also carried out. Results: There were differences in the allele and genotype frequencies between CP cases and controls at the rs11805303 and rs10889677 SNPs (Pallele = 0.014 and 0.048, respectively; Pgenotype = 0.023 and 0.008, respectively), and the difference in genotype frequency of rs10889677 remained significant after Bonferroni correction (Pgenotype = 0.048). Subgroup analysis revealed a more significant association of rs10889677 with CP accompanied by global developmental delay (Pgenotype = 0.024 after correction) and neonatal encephalopathy (Pgenotype = 0.024 after correction). Conclusion: The present results showed a significant association between IL-23R and CP, suggesting that IL-23R may play a potential role in CP pathogenesis.

Twenty-Four-Hour Ambulatory Blood Pressure Variability Associated With Cerebral Small Vessel Disease MRI Burden and Its Progression in Inpatients With Cerebrovascular Disease.

Background: Lacunar infarcts, white matter lesions, cerebral microbleed, enlarged perivascular space and brain atrophy are regarded as magnetic resonance imaging (MRI) manifestations of cerebral small vessel disease (cSVD). 24-hour blood pressure variability (BPV) has been reported to relate with cerebral small vessel disease, but the impact of 24-h BPV on the total MRI cSVD burden and its progression in inpatients with cerebrovascular disease has not been investigated yet. Methods: We enrolled inpatients with cerebrovascular disease, who underwent the 24-h ambulatory blood pressure monitoring (ABPM) and the brain MRI scan at baseline and had the follow-up brain MRI images stored in the clinical information system of our hospital. BPV was quantified by the calculation of standard deviation (SD), coefficient of variation (CV), weighted standard deviation (wSD) of blood pressure record. We evaluated the total cSVD score on baseline MRI and the MRI followed-up to obtain the total burden of cSVD. The cSVD burden progression was estimated through the comparison of the total cSVD score on the two MRIs. Results: A total of 140 patients with an average age of 65.6 years were finally enrolled, 82.9% (116/140) of whom had one or more cSVD markers. After a median of 4.4 years follow-up, cSVD score progression were found in 50.7% (71/140) of the patients. Both SD and CV of SBP and DBP during 24-h and daytime as well as the SBP wSD differed significantly among different total cSVD score groups. The SBP SD and CV during 24-h and daytime, the SBP SD in nighttime, the DBP SD and CV during the daytime were significantly higher in the cSVD progression group than those in the cSVD no-progression group. The SBP wSD and the DBP wSD were significantly higher in the cSVD progression group than those in the cSVD no-progression group. Logistic regression analyses revealed that daytime SBP SD and SBP wSD were independent risk factors for total cSVD burden [daytime SBP SD: OR = 1.628, 95% CI = 1.105-2.398 (per 5 mmHg increase in SD), P = 0.014; SBP wSD: OR = 2.248, 95% CI = 1.564-3.230 (per 5 mmHg increase in wSD), P < 0.001)] and SBP wSD was a significant predictor for cSVD progression [OR = 2.990, 95% CI = 1.053-8.496 (per 5 mmHg increase in wSD), P = 0.040]. Conclusion: Higher BPV were significantly related with total cSVD burden in inpatients with cerebrovascular disease. SBP SD during daytime and SBP wSD were independent risk factor for total cSVD burden and SBP wSD was an predictive factor for cSVD progression.

Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells.

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that senses xenobiotics, diet, and gut microbial-derived metabolites, is increasingly recognized as a key regulator of intestinal biology. However, its effects on the function of colonic stem and progenitor cells remain largely unexplored. Here, we observed that inducible deletion of AhR in Lgr5+ stem cells increases the percentage of colonic stem cells and enhances organoid initiating capacity and growth of sorted stem and progenitor cells, while AhR activation has the opposite effect. Moreover, intestinal-specific AhR knockout increases basal stem cell and crypt injury-induced cell proliferation and promotes colon tumorigenesis in a preclinical colitis-associated tumor model by upregulating FoxM1 signaling. Mechanistically, AhR transcriptionally suppresses FoxM1 expression. Activation of AhR in human organoids recapitulates phenotypes observed in mice, such as reduction in the percentage of colonic stem cells, promotion of stem cell differentiation, and attenuation of FoxM1 signaling. These findings indicate that the AhR-FoxM1 axis, at least in part, mediates colonic stem/progenitor cell behavior.