Spinal cord and brain atrophy patterns in neuromyelitis optica spectrum disorder and multiple sclerosis.

BACKGROUND: Spinal cord and brain atrophy are common in neuromyelitis optica spectrum disorder (NMOSD) and relapsing-remitting multiple sclerosis (RRMS) but harbor distinct patterns accounting for disability and cognitive impairment. METHODS: This study included 209 NMOSD and 304 RRMS patients and 436 healthy controls. Non-negative matrix factorization was used to parse differences in spinal cord and brain atrophy at subject level into distinct patterns based on structural MRI. The weights of patterns were obtained using a linear regression model and associated with Expanded Disability Status Scale (EDSS) and cognitive scores. Additionally, patients were divided into cognitive impairment (CI) and cognitive preservation (CP) groups. RESULTS: Three patterns were observed in NMOSD: (1) Spinal Cord-Deep Grey Matter (SC-DGM) pattern was associated with high EDSS scores and decline of visuospatial memory function; (2) Frontal-Temporal pattern was associated with decline of language learning function; and (3) Cerebellum-Brainstem pattern had no observed association. Patients with CI had higher weights of SC-DGM pattern than CP group. Three patterns were observed in RRMS: (1) DGM pattern was associated with high EDSS scores, decreased information processing speed, and decreased language learning and visuospatial memory functions; (2) Frontal-Temporal pattern was associated with overall cognitive decline; and (3) Occipital pattern had no observed association. Patients with CI trended to have higher weights of DGM and Frontal-Temporal patterns than CP group. CONCLUSION: This study estimated the heterogeneity of spinal cord and brain atrophy patterns in NMOSD and RRMS patients at individual level, and evaluated the clinical relevance of these patterns, which may contribute to stratifying participants for targeted therapy.

Case report: Novel NUS1 variant in a Chinese patient with tremors and intellectual disability.

Introduction: Nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) gene variants are associated with a range of phenotypes, including epilepsy, intellectual disability, cerebellar ataxia, Parkinson's disease, dystonia, and congenital disorders of glycosylation. Additionally, cases describing genotypes and clinical features are rare. Case Presentation: Herein, we report the case of a 23-year-old Chinese female patient who presented with tremors, intellectual disability, and epilepsy. A history of carbon monoxide exposure, brain trauma, or encephalitis was not present in this case. Trio whole-exome sequencing analysis revealed a de novo pathogenic variant of c.750del in exon 4, leading to p.Leu251* amino acid substitution. Genetic analysis failed to identify the identical mutations in the remaining family members who underwent screening. The patient was diagnosed with a rare congenital disease, "congenital glycosylation disorder, type 1aa, autosomal dominant, type 55, with seizures (MRD-55)." Conclusion: We provide further evidence for the role of variants in NUS1 in the development of tremors, epilepsy, and intellectual disabilities. These findings expand our understanding of the clinical phenotypes of NUS1 variants.

Effects of total saikosaponins on CYP3A4 and CYP1A2 in HepaRG cells.

Total saikosaponins (TSS) form a group of chemically and biologically active components that can be extracted from Bupleurum, with reported antidepressive, anti-inflammatory, antiviral, antiendotoxin, antitumor, anti-pulmonary fibrosis and anti-gastric ulcer effects. Bupleurum or TSS is frequently utilized in clinical practice alongside other medications (such as entecavir, lamivudine, compound paracetamol and amantadine hydrochloride capsules), leading to an increased risk of drug-drug interactions. The cytochrome P450 (CYP) family serves a critical role in the metabolism of numerous essential drugs (such as tamoxifen, ibuprofen and phenytoin), where the majority of drug interactions involve CYP-mediated metabolism. It is therefore essential to understand the effects of key components of Bupleurum on CYPs when administering combination therapies containing TSS or Bupleurum. The present study aimed to investigate the effects of TSS on the mRNA and protein expression of CYP3A4 and CYP1A2 in HepaRG cells. The effects of TSS on the survival of HepaRG cells was investigated using the Cell Counting Kit-8 (CCK-8) method. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) analysis were used to assess the effects of different concentrations of TSS (0, 5, 10 and 15 µg/ml) on CYP3A4 and CYP1A2 mRNA and protein expression in HepaRG cells. Based on the CCK-8 assay results, it was observed that the cell viability remained above 80% when treated with 1, 5, 10 and 15 µg/ml TSS. Although there was a statistically significant reduced cell viability at TSS concentrations of 10 and 15 µg/ml compared with the control group, the findings indicated that TSS did not exhibit notable cytotoxic effects at these concentrations. Furthermore, RT-qPCR results revealed that compared with those in the control group, TSS at concentrations of 10 and 15 µg/ml reduced CYP3A4 mRNA expression but increased CYP1A2 mRNA expression in HepaRG cells at concentrations of 15 µg/ml. WB analysis found that TSS at concentrations of 10 and 15 µg/ml downregulated CYP3A4 protein expression in HepaRG cells while increasing CYP1A2 protein expression at concentrations of 15 µg/ml. Results in the present study suggest that TSS can inhibit CYP3A4 mRNA and protein expression, but exerts opposite effects on their CYP1A2 counterparts. These findings suggest that it is necessary to consider drug interactions between clinical preparations containing TSS or Bupleurum and drugs metabolized by CYP3A4 and CYP1A2 to avoid potential adverse drug reactions in clinical practice.

Celastrol Elicits Antitumor Effects through Inducing Immunogenic Cell Death and Downregulating PD-L1 in ccRCC.

BACKGROUND: Targeting immunogenic cell death (ICD) is considered a promising therapeutic strategy for cancer. However, the commonly identified ICD inducers promote the expression of programmed cell death ligand 1 (PD-L1) in tumor cells, thus aiding them to evade the recognition and killing by the immune system. Therefore, the finding of novel ICD inducers to avoid enhanced PD-L1 expression is of vital significance for cancer therapy. Celastrol (CeT), a triterpene isolated from Tripterygium wilfordii Hook. F induces various forms of cell death to exert anti-cancer effects, which may make celastrol an attractive candidate as an inducer of ICD. METHODS: In the present study, bioinformatics analysis was combined with experimental validation to explore the underlying mechanism by which CeT induces ICD and regulates PD-L1 expression in clear cell renal cell carcinoma (ccRCC). RESULTS: The results showed that EGFR, IKBKB, PRKCQ and MAPK1 were the crucial targets for CeT-induced ICD, and only MAPK1 was an independent prognostic factor for the overall survival (OS) of ccRCC patients. In addition, CeT triggered autophagy and up-regulated the expressions of HMGB1 and CRT to induce ICD in 786-O cells in vitro. Importantly, CeT can down-regulate PD-L1 expression through activating autophagy. At the molecular level, CeT suppressed PD-L1 via the inhibition of MAPK1 expression. Immunologically, the core target of celastrol, MAPK1, was tightly correlated with CD8+ T cells and CD4+ T cells in ccRCC. CONCLUSION: These findings indicate that CeT not only induces ICD but also suppresses PD-L1 by down-regulating MAPK1 expression, which will provide an attractive strategy for ccRCC immunotherapy.

Susceptibility-weighted image features in AQP4-negative-NMOSD versus MS.

OBJECTIVE: To characterize the susceptibility-weighted image (SWI) features including paramagnetic rim and nodular lesions with signal intensity changes and central vein sign (CVS) associated with aquaporin 4 (AQP4)-immunoglobulin G (IgG)-negative neuromyelitis optica spectrum disorder (NMOSD), and explore whether they can be used as potential imaging biomarkers for differentiating multiple sclerosis (MS) from this disorder. METHODS: We prospectively recruited NMOSD with AQP4-IgG-negative (AQP4- NMOSD) and IgG-positive (AQP4+ NMOSD), and MS subjects from the Clinical and Imaging Patterns of Neuroinflammation Diseases in China (CLUE) project (NCT0410683) between 2019 and 2021. The SWI features including paramagnetic rim and nodular lesions with signal intensity changes and CVS were analyzed and compared among groups, and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined for distinguishing MS from AQP4- NMOSD. RESULTS: We enrolled a total of 160 consecutive patients (22 AQP4- NMOSD, 65 AQP4+ NMOSD, and 73 MS). We observed paramagnetic rim lesion (0/120 lesions, 0 %) and nodular (1/120, 1 %) lesions with hypointense signals on SWI in the AQP4- NMOSD group. These characteristics were similar to those recorded from AQP4+ NMOSD patients (rim: 0/369 lesions, 0 %, P = 1.000; nodular: 10/369 lesions, 2.7 %, P = 1.000), but differed significantly from those observed in the MS group (rim: 162/1665 lesions, 9.7 %, P<0.001; nodular: 392/1665 lesions, 23.5 %, P < 0.001). AQP4- NMOSD patients had fewer average CVS+ rate (12 %) than MS patients (46 %, p<0.001), similar to AQP4+ NMOSD (13 %, p = 1.000). The SWI imaging features denoting lesions with paramagnetic rim or nodular hypointense SWI signals showed 90.4 % sensitivity, 95.5 % specificity, 98.5 % PPV, and 75 % NPV, and the criteria with≥3 CVS lesions showed sensitivity of 91.8 %, specificity of 90.9 %%, PPV of 97.1 %, and NPV of 76.9 % in distinguishing MS from AQP4- NMOSD. DISCUSSION: The SWI imaging features including lesions with paramagnetic rim or nodular hypointense SWI signals and 3 CVS lesions carries useful information in distinguishing MS from AQP4- NMOSD.

Steering CO2 Electroreduction Selectivity U-Turn to Ethylene by Cu-Si Bonded Interface.

Copper (Cu), with the advantage of producing a deep reduction product, is a unique catalyst for the electrochemical reduction of CO2 (CO2RR). Designing a Cu-based catalyst to trigger CO2RR to a multicarbon product and understanding the accurate structure-activity relationship for elucidating reaction mechanisms still remain a challenge. Herein, we demonstrate a rational design of a core-shell structured silica-copper catalyst (p-Cu@m-SiO2) through Cu-Si direct bonding for efficient and selective CO2RR. The Cu-Si interface fulfills the inversion in CO2RR product selectivity. The product ratio of C2H4/CH4 changes from 0.6 to 14.4 after silica modification, and the current density reaches a high of up to 450 mA cm-2. The kinetic isotopic effect, in situ attenuated total reflection Fourier-transform infrared spectra, and density functional theory were applied to elucidate the reaction mechanism. The SiO2 shell stabilizes the *H intermediate by forming Si-O-H and inhibits the hydrogen evolution reaction effectively. Moreover, the direct-bonded Cu-Si interface makes bare Cu sites with larger charge density. Such bare Cu sites and Si-O-H sites stabilized the *CHO and activated the *CO, promoting the coupling of *CHO and *CO intermediates to form C2H4. This work provides a promising strategy for designing Cu-based catalysts with high C2H4 catalytic activity.

Decreased expression of GEM in osteoarthritis cartilage regulates chondrogenic differentiation via Wnt/ß-catenin signaling.

BACKGROUND: GEM (GTP-binding protein overexpressed in skeletal muscle) is one of the atypical small GTPase subfamily members recently identified as a regulator of cell differentiation. Abnormal chondrogenesis coupled with an imbalance in the turnover of cartilaginous matrix formation is highly relevant to the onset and progression of osteoarthritis (OA). However, how GEM regulates chondrogenic differentiation remains unexplored. METHODS: Cartilage tissues were obtained from OA patients and graded according to the ORASI and ICRS grading systems. The expression alteration of GEM was detected in the Grade 4 cartilage compared to Grade 0 and verified in OA mimic culture systems. Next, to investigate the specific function of GEM during these processes, we generated a Gem knockdown (Gem-Kd) system by transfecting siRNA targeting Gem into ATDC5 cells. Acan, Col2a1, Sox9, and Wnt target genes of Gem-Kd ATDC5 cells were detected during induction. The transcriptomic sequencing analysis was performed to investigate the mechanism of GEM regulation. Wnt signaling pathways were verified by real-time PCR and immunoblot analysis. Finally, a rescue model generated by treating Gem-KD ATDC5 cells with a Wnt signaling agonist was established to validate the mechanism identified by RNA sequencing analysis. RESULTS: A decreased expression of GEM in OA patients' cartilage tissues and OA mimic chondrocytes was observed. While during chondrogenesis differentiation and cartilage matrix formation, the expression of GEM was increased. Gem silencing suppressed chondrogenic differentiation and the expressions of Acan, Col2a1, and Sox9. RNA sequencing analysis revealed that Wnt signaling was downregulated in Gem-Kd cells. Decreased expression of Wnt signaling associated genes and the total ß-CATENIN in the nucleus and cytoplasm were observed. The exogenous Wnt activation exhibited reversed effect on Gem loss-of-function cells. CONCLUSION: These findings collectively validated that GEM functions as a novel regulator mediating chondrogenic differentiation and cartilage matrix formation through Wnt/ß-catenin signaling.

The Role of Remnant Cholesterol Beyond Low-Density Lipoprotein Cholesterol in Arterial Stiffness: A Cross-Sectional Study.

Background: Previous evidence has demonstrated that elevated low-density lipoprotein cholesterol (LDL-C) was associated with atherosclerosis. However, there is scarce population-based evidence for the role of remnant cholesterol (remnant-C) in arterial stiffness, an imaging marker for subclinical atherosclerosis. Herein, we aimed to evaluate the correlation of remnant-C with arterial stiffness beyond LDL-C in a check-up population. Methods: The study included consecutive subjects who visited the Murakami Memorial Hospital for health check-ups between 2004 and 2012. The calculation of remnant-C occurred as total cholesterol minus high-density lipoprotein cholesterol (HDL-C) minus LDL-C. The brachial-ankle pulse wave velocity (baPWV) >1400 cm/sec was defined as arterial stiffness or baPWV abnormality. The independent correlation of remnant-C level to arterial stiffness was evaluated using adjusted regression models. Results: A total of 909 participants were included (mean age 51.1 ± 9.6 years, male sex 64.9%). In multivariate linear regression analyses, remnant-C remained an independent predictor of the baPWV predictor [ß: 94.76, 95% confidence interval (CI) 42.19-147.33, P < 0.001] after adjusting for confounders. After multivariable adjustment, including LDL-C, the highest remnant-C quartile odd ratio (OR) (95% CI) was 2.79 (1.27-6.09) for baPWV abnormality compared to the lowest quartile. Furthermore, each 10-mg/dL increase in remnant-C correlated with a 28% increased risk for baPWV abnormality (OR: 1.28, 95% CI: 1.04-1.57). Moreover, the correlation between remnant-C and baPWV abnormality was still significant in the participant subgroup with optimal levels of LDL-C. Conclusions: Our findings demonstrated that remnant-C levels correlated to arterial stiffness with the dependence of LDL-C and other cardiovascular risk factors in a check-up population.

"Soap bubble" sign as an imaging marker for posterior fossa ependymoma Group B.

PURPOSE: To investigate the predictive value of the "soap bubble" sign on molecular subtypes (Group A [PFA] and Group B [PFB]) of posterior fossa ependymomas (PF-EPNs). METHODS: MRI scans of 227 PF-EPNs (internal retrospective discovery set) were evaluated by two independent neuroradiologists to assess the "soap bubble" sign, which was defined as clusters of cysts of various sizes that look like "soap bubbles" on T2-weighted images. Two independent cohorts (external validation set [n = 31] and prospective validation set [n = 27]) were collected to validate the "soap bubble" sign. RESULTS: Across three datasets, the "soap bubble" sign was observed in 21 PFB cases (7.4% [21/285] of PF-EPNs and 12.9% [21/163] of PFB); none in PFA. Analysis of the internal retrospective discovery set demonstrated substantial interrater agreement (1st Rating: κ = 0.71 [0.53-0.90], 2nd Rating: κ = 0.83 [0.68-0.98]) and intrarater agreement (Rater 1: κ = 0.73 [0.55-0.91], Rater 2: κ = 0.74 [0.55-0.92]) for the "soap bubble" sign; all 13 cases positive for the "soap bubble" sign were PFB (p = 0.002; positive predictive value [PPV] = 100%, negative predictive value [NPV] = 44%, sensitivity = 10%, specificity = 100%). The findings from the external validation set and the prospective validation set were similar, all cases positive for the "soap bubble" sign were PFB (p < 0.001; PPV = 100%). CONCLUSION: The "soap bubble" sign represents a highly specific imaging marker for the PFB molecular subtype of PF-EPNs.

Association of remnant cholesterol with intracranial atherosclerosis in community-based population: The ARIC study.

OBJECTIVE: To evaluate the association between remnant cholesterol (remnant-C) and intracranial atherosclerotic disease (ICAD) in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). METHODS: We studied 1,564 participants with data on lipid profiles and high-resolution vessel wall MRI (VWMRI) from the ARIC-NCS. Remnant-C was computed as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDL-C). The primary outcomes were the presence of intracranial plaques and luminal stenosis. Contributors were separated into four different groups based on remnant-C (22 mg/dL) and LDL-C (100 mg/dL) levels to investigate the function of remnant-C vs. LDL-C on ICAD. Multivariable logistic regression models were utilized to estimate the correlation among the discordant/concordant remnant-C and LDL-C, and ICAD. RESULTS: A total of 1,564 participants were included (age 76.2 ± 5.3). After multivariable adjustment, log remnant-C was correlated with greater ICAD risk [odds ratio (OR) 1.36, 95% confidence interval (CI) 1.01 to 1.83]. The lower remnant-C/higher LDL-C group and the higher remnant-C/lower LDL-C group manifested a 1.53-fold (95% CI 1.06 to 2.20) and 1.52-fold (95% CI 1.08 to 2.14) greater risk of ICAD, relative to those having lower remnant-C/low LDL-C. Additionally, remnant-C ≥ 22 mg/dL distinguished participants at a greater risk of the presence of any stenosis compared to those at lower levels, even in participants with optimal levels of LDL-C. CONCLUSIONS: Elevated levels of remnant-C were connected to ICAD independent of LDL-C and traditional risk factors. The mechanisms of remnant-C association with ICAD probably offer insight into preventive risk-factor of ischemic stroke.

Solution-Processed Hydrogen-Bonded Organic Framework Nanofilms for High-Performance Resistive Memory Devices.

The integration of hydrogen-bonded organic frameworks (HOFs) into electronic devices holds great promise due to their high crystallinity, intrinsic porosity, and easy regeneration. However, despite their potential, the utilization of HOFs in electronic devices remains largely unexplored, primarily due to the challenges associated with fabricating high-quality films. Herein, a controlled synthesis of HOF nanofilms with smooth surface, good crystallinity, and high orientation is achieved using a solution-processed approach. The memristors exhibit outstanding bipolar switching performance with a low set voltage of 0.86 V, excellent retention of 1.64 × 104 s, and operational endurance of 60 cycles. Additionally, these robust memristors display remarkable thermal stability, maintaining their performance even at elevated temperatures of up to 200 °C. More strikingly, scratched HOF films can be readily regenerated through a simple solvent rinsing process, enabling their reuse for the fabrication of new memristors, which is difficult to achieve with traditional resistive switching materials. Additionally, a switching mechanism based on the reversible formation and annihilation of conductive filaments is revealed. This work provides novel and invaluable insights that have a significant impact on advancing the widespread adoption of HOFs as active layers in electronic devices.

Identification of Immune-Linked Hub Genes and Diagnostic Model Construction in Schizophrenia.

Schizophrenia (SCZ) is a prevalent, severe, and persistent mental disorder with an unknown etiology. Growing evidence indicates that immunological dysfunction is vital in the development of SCZ. Our study aims to uncover potential immune-linked hub genes and immune infiltration characteristics of SCZ, as well as to develop a diagnostic model based on immune-linked central genes. GSE38484 and GSE54913 chip expression data for patients with SCZ and healthy controls were retrieved. Weighted gene co-expression network analysis (WGCNA) was performed to identify major module genes and critical immune-linked genes. Functional enrichment analysis was conducted to elucidate the involvement of key genes in the immunological response to SCZ, along with the examination of their protein interactions. Moreover, 202 peripheral blood samples were examined using the single-sample gene set enrichment analysis (ssGSEA) method to detect distinct immune cell types. Hub immune-linked genes in SCZ were identified using the minimal absolute contraction and selection operator analysis. Receptor profiles of central immune-linked genes were analyzed to distinguish the two groups. Finally, the association between immune-linked hub genes and various types of immune cells was assessed. Our findings revealed ten immune cell types and nine key genes involved in SCZ, including effector memory CD4+ T cells, activated CD8+ T cells, mast cells, naive CD8+ T cells, PBMC, type 17 helper cells (Th17), central memory CD8+ T cells, CD56 bright NK cells, memory B cells, and regulatory T cells. Diagnostic models constructed using LASSO regression exhibited an average area under the curve (AUC) of 0.866. Our results indicate immunological dysfunction as a factor in the development of SCZ. ASGR2, ADRM1, AHANK, S100A8, FUCA1, AKNA, GATA3, AHCYL2, and PTRH2 are the key regulatory genes of immune cells, highlighting their potential as novel therapeutic targets for SCZ.

A Comparable icELISA and Lateral Flow Immunoassay for the Sensitive and Rapid Detection of 4,4'-Dinitrocarbanilide in Chicken.

4,4'-dinitrocarbanilide (DNC) is a key component and marker residue of nicarbazin, which forms residues in edible tissue and then causes nephrotoxicity and hepatotoxicity in humans if used excessively. To simplify sample preparation and monitor the DNC rapidly and accurately, a comparable icELISA and lateral flow immunoassay (LFIA) was developed in this study. Briefly, the reaction parameters were explored for improving the sensitivity of icELISA and LFIA. Under the optimal conditions, methanol was selected as the extracting solvent for DNC in chicken, and 20- and 10-fold dilutions of sample extraction eliminated the matrix effect for icELISA and LFIA, separately. After sample pretreatment, the analysis properties of icELISA and LFIA were compared. The limit of detection of icELISA for DNC was 0.8 µg/kg, and the visual and quantitative limits of detection of LFIA were 8 and 2.5 µg/kg. Compared with icELISA, LFIA showed lower sensitivity but obvious advantages in terms of matrix tolerance and detection time (within 15 min). The sensitivity, specificity, and accuracy of the developed assays satisfied the detection requirement even if using simple sample pretreatment. This comparable icELISA and LFIA provided mutual verifiability methods for the accurate detection of DNC in chicken.

Celastrol functions as an emerging manager of lipid metabolism: Mechanism and therapeutic potential.

Lipid metabolism disorders are pivotal in the development of various lipid-related diseases, such as obesity, atherosclerosis, non-alcoholic fatty liver disease, type 2 diabetes, and cancer. Celastrol, a bioactive compound extracted from the Chinese herb Tripterygium wilfordii Hook F, has recently demonstrated potent lipid-regulating abilities and promising therapeutic effects for lipid-related diseases. There is substantial evidence indicating that celastrol can ameliorate lipid metabolism disorders by regulating lipid profiles and related metabolic processes, including lipid synthesis, catabolism, absorption, transport, and peroxidation. Even wild-type mice show augmented lipid metabolism after treatment with celastrol. This review aims to provide an overview of recent advancements in the lipid-regulating properties of celastrol, as well as to elucidate its underlying molecular mechanisms. Besides, potential strategies for targeted drug delivery and combination therapy are proposed to enhance the lipid-regulating effects of celastrol and avoid the limitations of its clinical application.

The types of brewing water affect tea infusion flavor by changing the tea mineral dissolution.

The effects of different brewing water samples, including natural drinking water (NDW), pure water (PW), mineral water (MW), distilled water (DW), and tap water (TW) on flavor and quality of green tea infusion were investigated. The results showed the dissolution rate of mineral substances varied greatly depend on the type of water used. Notably, the tea infusion brewed with MW showed the highest taste response and darker but higher brightness in color. Furthermore, the content of volatile compounds was highest in tea infusion brewed with NDW and lowest in tea infusion brewed with MW. The mineral substances content and pH were the main factors affecting volatile compounds in green tea infusion. Thereinto, Ca2+ and Fe3+ remarkably affected the content of alcohols and aldehydes in volatile compounds. These results suggested that water with a neutral pH value and lower mineral substance content is more conducive for brewing green tea.

An ultrasensitive GSH-specific fluorescent probe unveils celastrol-induced ccRCC ferroptosis.

Glutathione (GSH) is closely related to the occurrence and development of tumors. The intracellular GSH levels are abnormally altered when tumor cells undergo programmed cell death. Therefore, real-time monitoring of the dynamic changes of intracellular GSH levels can better enable the early diagnosis of diseases and evaluate the effects of cell death-inducing drugs. In this study, a stable and highly selective fluorescent probe AR has been designed and synthesized for the fluorescence imaging and rapid detection of GSH in vitro and in vivo, as well as patient-derived tumor tissue. More importantly, the AR probe can be used to track changes in GSH levels and fluorescence imaging during the treatment of clear cell renal cell carcinoma (ccRCC) with celastrol (CeT) via inducing ferroptosis. These findings demonstrate that the developed fluorescent probe AR exhibits high selectivity and sensitivity, as well as good biocompatibility and long-term stability, which can be used to image endogenous GSH in living tumors and cells. Also, a significant decrease in GSH levels was observed by the fluorescent probe AR during the treatment of ccRCC with CeT-induced ferroptosis in vitro and in vivo. Overall, these findings will provide a novel strategy for celastrol targeting ferroptosis in the treatment of ccRCC and the application of fluorescent probes to help reveal the underlying mechanism of CeT in the treatment of ccRCC.

A review of edible plant-derived natural compounds for the therapy of liver fibrosis.

Liver fibrosis has a high incidence worldwide and is the common pathological basis of many chronic liver diseases. Liver fibrosis is caused by the excessive deposition of extracellular matrix and concomitant collagen accumulation in livers and can lead to the development of liver cirrhosis and even liver cancer. A large number of studies have provided evidence that liver fibrosis can be blocked or even reversed by appropriate medical interventions. However, the antifibrosis drugs with ideal clinical efficacy are still insufficient. The edible plant-derived natural compounds have been reported to exert effective antifibrotic effects with few side-effects, representing a kind of promising source for the treatment of liver fibrosis. In this article, we reviewed the current progress of the natural compounds derived from dietary plants in the treatment of liver fibrosis, including phenolic compounds (capsaicin, chlorogenic acid, curcumin, ellagic acid, epigallocatechin-3-gallate, resveratrol, sinapic acid, syringic acid, vanillic acid and vitamin E), flavonoid compounds (genistein, hesperidin, hesperetin, naringenin, naringin and quercetin), sulfur-containing compounds (S-allylcysteine, ergothioneine, lipoic acid and sulforaphane) and other compounds (betaine, caffeine, cucurbitacin B, lycopene, α-mangostin, γ-mangostin, ursolic acid, vitamin C and yangonin). The pharmacological effects and related mechanisms of these compounds in in-vivo and in-vitro models of liver fibrosis are focused.

Association between Serum Amyloid A Level and White Matter Hyperintensity Burden: a Cross-Sectional Analysis in Patients with Acute Ischemic Stroke.

INTRODUCTION: This work aimed to determine the potential link between white matter hyperintensity (WMH) burden and serum amyloid A (SAA) level in patients with acute ischemic stroke. METHODS: Consecutive patients with acute large artery atherosclerosis (LAA) stroke between April 2021 and May 2022 were included. WMH volumes (periventricular, deep, and total) were measured using the Fazekas score and a semiautomated volumetric analysis on fluid-attenuated inversion recovery-magnetic resonance imaging. The burdens of WMH were scored to assess the dose-dependent association between SAA and WMH volume. Multivariate regression and a two-piecewise linear regression model were used to evaluate whether SAA levels are an independent predictor of WMH, and to discover the threshold effect or saturation effect of SAA levels with respect to WMH volume. RESULTS: The mean age of patients was 63.2 ± 11.5 years, with 65.9% men. The median SAA level was 3.93 mg/L and the total WMH volume of 6.86 cm3. In the multivariable analysis, SAA remained an independent predictor of total WMH volume [ß = 0.82, 95% confidence interval (CI) = 0.49-1.07, p < 0.001], periventricular WMH volume (adjusted ß = 0.76, 95% CI = 0.46-1.07, p < 0.001), and deep WMH volume (adjusted ß = 0.26, 95% CI = 0.06-0.45, p = 0.011) after controlling for confounders. Furthermore, SAA levels were associated with periventricular Fazekas score, deep Fazekas score, and Fazekas grades. Threshold effect and saturation effect analyses demonstrated a nonlinear relationship between SAA levels and periventricular white matter hyperintensity (PVWMH) volumes, with SAA levels (2.12-19.89 mg/L) having significant dose-dependent relationships with periventricular WMH volumes (adjusted ß = 1.98, 95% CI = 1.12-2.84, p < 0.001). CONCLUSION: SAA level ranging from 2.12 to 19.89 mg/L is dose-dependently associated with periventricular WMH development. These findings point the way forward for future research into the pathophysiology of WMH.

Application of the clearance rate of inflammatory markers for evaluation of the therapeutic effect in adult bacterial bloodstream infection.

BACKGROUND: Bloodstream infection (BSI) is a serious systemic infectious disease. This study aimed to investigate the application of the clearance rate of interleukin-6, procalcitonin, and C-reactive protein for the evaluation of antimicrobial efficacy in adult bacterial BSI without other inflammatory factors. METHODS: Patients with positive blood culture and without other inflammatory factors in The First Hospital of Hebei Medical University from January 2017 to December 2019, who received continuous detection interleukin-6, procalcitonin, and C-reactive protein, were selected. The clearance rate of these inflammatory markers was calculated, and the consistency test (kappa test) was performed to analyze the clinical outcomes (cure, improvement, delay, deterioration, or death). RESULTS: For adult patients with bacterial BSI without other inflammatory factors, the testing speculation based on the clearance rate of interleukin-6 and C-reactive protein was consistent with the clinical outcome of the patients, with kappa values of 0.784 and 0.714, respectively (P=0.000). The testing speculation based on the procalcitonin clearance rate was generally consistent with the clinical outcome, with a kappa value of 0.685 (P=0.000). The testing speculation based on the procalcitonin clearance rate showed good consistency with the clinical outcome of patients with Gram-positive cocci infection, kappa =0.813 (P=0.000); for patients with gram-negative bacilli infection, the consistency of clinical outcomes was general, kappa =0.649 (P=0.000). CONCLUSIONS: In adult patients with bacterial BSI without other inflammatory factors, the clearance rate of interleukin-6, procalcitonin, and C-reactive protein can predict the clinical outcome within 24 hours, among which the procalcitonin clearance rate can better predict the clinical outcome of patients with Gram-negative bacilli infection. This approach can be used to evaluate the effectiveness of anti-infection treatment in early-stage BSI.

Wnt5a/Ror2 promotes vascular smooth muscle cells proliferation via activating PKC.

INTRODUCTION: Abnormal proliferation of vascular smooth muscle cells (VSMCs) can cause various vascular diseases, such as atherosclerosis, restenosis, and pulmonary hypertension. However, the effect and underlying mechanism of Wnt5a on the proliferation of VSMCs remain unclear. Our study aimed to investigate whether Wnt5a/Ror2 promotes vascular smooth muscle cell proliferation via activating protein kinase C (PKC), thereby effectively alleviating vascular proliferative diseases. MATERIAL AND METHODS: The proliferation of HA-VSMC cell line was evaluated by CCK-8, EdU, and Plate clone formation assays. The Wnt5a gene knockdown and overexpression were carried out by standard methods. The interaction between Wnt5a and Ror2 was explored by co-immunoprecipitation. Western blotting and immunofluorescence were used to determine the expression levels of key proteins in VSMCs. RESULTS: The present study found that the expression of Wnt5a protein increased significantly in the proliferation of VSMCs stimulated by 10% serum in a time-dependent manner. Furthermore, the proliferative rate of VSMCs overexpressing Wnt5a was dramatically accelerated, whereas Wnt5a knockdown using siWnt5a reversed thisproliferative effect. Wnt5a up-regulated the expression of receptor tyrosine kinase-like orphan receptor 2 (Ror2) by binding to it. Further studies indicated that Wnt5a induces the PKC expression in VSMCs and knockdown of Wnt5a or Ror2 could inhibit PKC phosphorylation. CONCLUSIONS: Wnt5a could effectively promote the proliferation of VSMCs, which might be related to the binding of Wnt5a and Ror2 to activate PKC.