Inflammatory corpuscle AIM2 facilitates macrophage foam cell formation by inhibiting cholesterol efflux protein ABCA1.

The inflammatory corpuscle recombinant absents in melanoma 2 (AIM2) and cholesterol efflux protein ATP binding cassette transporter A1(ABCA1) have been reported to play opposing roles in atherosclerosis (AS) plaques. However, the relationship between AIM2 and ABCA1 remains unclear. In this study, we explored the potential connection between AIM2 and ABCA1 in the modulation of AS by bioinformatic analysis combined with in vitro experiments. The GEO database was used to obtain AS transcriptional profiling data; screen differentially expressed genes (DEGs) and construct a weighted gene co-expression network analysis (WGCNA) to obtain AS-related modules. Phorbol myristate acetate (PMA) was used to induce macrophage modelling in THP-1 cells, and ox-LDL was used to induce macrophage foam cell formation. The experiment was divided into Negative Control (NC) group, Model Control (MC) group, AIM2 overexpression + ox-LDL (OE AIM2 + ox-LDL) group, and AIM2 short hairpin RNA + ox-LDL (sh AIM2 + ox-LDL) group. The intracellular cholesterol efflux rate was detected by scintillation counting; high-performance liquid chromatography (HPLC) was used to detect intracellular cholesterol levels; apoptosis levels were detected by TUNEL kit; levels of inflammatory markers (IL-1ß, IL-18, ROS, and GSH) were detected by ELISA kits; and levels of AIM2 and ABCA1 proteins were detected by Western blot. Bioinformatic analysis revealed that the turquoise module correlated most strongly with AS, and AIM2 and ABCA1 were co-expressed in the turquoise module with a trend towards negative correlation. In vitro experiments demonstrated that AIM2 inhibited macrophage cholesterol efflux, resulting in increased intracellular cholesterol levels and foam cell formation. Moreover, AIM2 had a synergistic effect with ox-LDL, exacerbating macrophage oxidative stress and inflammatory response. Silencing AIM2 ameliorated the above conditions. Furthermore, the protein expression levels of AIM2 and ABCA1 were consistent with the bioinformatic analysis, showing a negative correlation. AIM2 inhibits ABCA1 expression, causing abnormal cholesterol metabolism in macrophages and ultimately leading to foam cell formation. Inhibiting AIM2 may reverse this process. Overall, our study suggests that AIM2 is a reliable anti-inflammatory therapeutic target for AS. Inhibiting AIM2 expression may reduce foam cell formation and, consequently, inhibit the progression of AS plaques.

Human-multimodal deep learning collaboration in 'precise' diagnosis of lupus erythematosus subtypes and similar skin diseases.

BACKGROUND: Lupus erythematosus (LE) is a spectrum of autoimmune diseases. Due to the complexity of cutaneous LE (CLE), clinical skin image-based artificial intelligence is still experiencing difficulties in distinguishing subtypes of LE. OBJECTIVES: We aim to develop a multimodal deep learning system (MMDLS) for human-AI collaboration in diagnosis of LE subtypes. METHODS: This is a multi-centre study based on 25 institutions across China to assist in diagnosis of LE subtypes, other eight similar skin diseases and healthy subjects. In total, 446 cases with 800 clinical skin images, 3786 multicolor-immunohistochemistry (multi-IHC) images and clinical data were collected, and EfficientNet-B3 and ResNet-18 were utilized in this study. RESULTS: In the multi-classification task, the overall performance of MMDLS on 13 skin conditions is much higher than single or dual modals (Sen = 0.8288, Spe = 0.9852, Pre = 0.8518, AUC = 0.9844). Further, the MMDLS-based diagnostic-support help improves the accuracy of dermatologists from 66.88% ± 6.94% to 81.25% ± 4.23% (p = 0.0004). CONCLUSIONS: These results highlight the benefit of human-MMDLS collaborated framework in telemedicine by assisting dermatologists and rheumatologists in the differential diagnosis of LE subtypes and similar skin diseases.

Multi-omics study reveals different pathogenesis of the generation of skin lesions in SLE and IDLE patients.

Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01, HLA-C*03:02:02:01, and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies.

Diversity of Arbuscular Mycorrhizal Fungi of the Rhizosphere of Lycium barbarum L. from Four Main Producing Areas in Northwest China and Their Effect on Plant Growth.

Arbuscular mycorrhizal fungi (AMF) can help plants absorb more mineral nutrients after they colonize plant roots, and the mycelia harmonize the soil structure and physical and chemical properties by secreting compounds. AMF species co-evolve with their habitat's geographic conditions and hosts; this gradually causes differences in the AMF species. By using Melzer's reagent to analyze the morphology and using Illumina Miseq sequencing technology to perform the molecular identification of AMF communities among the four typical L. barbarum planting areas (Zhongning, Guyuan, Jinghe, and Dulan) investigated, the variety of L. barbarum roots and rhizosphere AMF communities was greater in the Zhongning area, and every region additionally had endemic species. The successfully amplified AMF was re-applied to the L. barbarum seedlings. We found that the total dry weight and accumulation of potassium increased significantly (p < 0.05), and the root volume and number of root branches were significantly higher in the plants that were inoculated with Paraglomus VTX00375 in the pot experiment, indicating that AMF improves root development and promotes plant growth. We have investigated AMF germplasm species in four regions, and we are committed to the development of native AMF resources. The multiplication and application of AMF will be conducive to realizing the potential role of biology in the maintenance of agroecology.

Characterization of Two Gonadal Genes, zar1 and wt1b, in Hermaphroditic Fish Asian Seabass (Lates calcarifer).

Zygote arrest-1 (Zar1) and Wilms' tumor 1 (Wt1) play an important role in oogenesis, with the latter also involved in testicular development and gender differentiation. Here, Lczar1 and Lcwt1b were identified in Asian seabass (Lates calcarifer), a hermaphrodite fish, as the valuable model for studying sex differentiation. The cloned cDNA fragments of Lczar1 were 1192 bp, encoding 336 amino acids, and contained a zinc-binding domain, while those of Lcwt1b cDNA were 1521 bp, encoding a peptide of 423 amino acids with a Zn finger domain belonging to Wt1b family. RT-qPCR analysis showed that Lczar1 mRNA was exclusively expressed in the ovary, while Lcwt1b mRNA was majorly expressed in the gonads in a higher amount in the testis than in the ovary. In situ hybridization results showed that Lczar1 mRNA was mainly concentrated in oogonia and oocytes at early stages in the ovary, but were undetectable in the testis. Lcwt1b mRNA was localized not only in gonadal somatic cells (the testis and ovary), but also in female and male germ cells in the early developmental stages, such as those of previtellogenic oocytes, spermatogonia, spermatocytes and spermatids. These results indicated that Lczar1 and Lcwt1b possibly play roles in gonadal development. Therefore, the findings of this study will provide a basis for clarifying the mechanism of Lczar1 and Lcwt1b in regulating germ cell development and the sex reversal of Asian seabass and even other hermaphroditic species.

[Immune Reconstitution after BTKi Treatment in Chronic Lymphocytic Leukemia].

OBJECTIVE: To analyze the immune reconstitution after BTKi treatment in patients with chronic lymphocytic leukemia (CLL). METHODS: The clinical and laboratorial data of 59 CLL patients admitted from January 2017 to March 2022 in Fujian Medical University Union Hospital were collected and analyzed retrospectively. RESULTS: The median age of 59 CLL patients was 60.5(36-78). After one year of BTKi treatment, the CLL clones (CD5 +/CD19 +) of 51 cases (86.4%) were significantly reduced, in which the number of cloned-B cells decreased significantly from (46±6.1)×109/L to (2.3±0.4)×109/L (P =0.0013). But there was no significant change in the number of non-cloned B cells (CD19 + minus CD5 +/CD19 +). After BTKi treatment, IgA increased significantly from (0.75±0.09)g/L to (1.31±0.1)g/L (P <0.001), while IgG and IgM decreased from (8.1±0.2)g/L and (0.52±0.6)g/L to (7.1±0.1)g/L and (0.47±0.1)g/L, respectively (P <0.001, P =0.002). BTKi treatment resulted in a significant change in T cell subpopulation of CLL patients, which manifested as both a decrease in total number of T cells from (2.1±0.1)×109/L to (1.6±0.4)×109/L and NK/T cells from (0.11±0.1)×109/L to (0.07±0.01)×109/L (P =0.042, P =0.038), both an increase in number of CD4 + cells from (0.15±6.1)×109/L to (0.19±0.4)×109/L and CD8 + cells from (0.27±0.01)×109/L to (0.41±0.08)×109/L (both P <0.001). BTKi treatment also up-regulated the expression of interleukin (IL)-2 while down-regulated IL-4 and interferon (IFN)-γ. However, the expression of IL-6, IL-10, and tumor necrosis factor (TNF)-α did not change significantly. BTKi treatment could also restored the diversity of TCR and BCR in CLL patients, especially obviously in those patients with complete remission (CR) than those with partial remission (PR). Before and after BTKi treatment, Shannon index of TCR in patients with CR was 0.02±0.008 and 0.14±0.001 (P <0.001), while in patients with PR was 0.01±0.03 and 0.05±0.02 (P >0.05), respectively. Shannon index of BCR in patients with CR was 0.19±0.003 and 0.33±0.15 (P <0.001), while in patients with PR was 0.15±0.009 and 0.23±0.18 (P <0.05), respectively. CONCLUSIONS: BTKi treatment can shrink the clone size in CLL patients, promote the expression of IgA, increase the number of functional T cells, and regulate the secretion of cytokines such as IL-2, IL-4, and IFN-γ. BTKi also promote the recovery of diversity of TCR and BCR. BTKi treatment contributes to the reconstitution of immune function in CLL patients.

Photodynamic therapy combined with CO2 laser for the treatment of seborrheic keratosis in the auricle: A case report.

Seborrheic keratosis(SK) is a very common skin tumor which is mostly frequently observed in the trunck, head, neck. SK in the auricle is rare and this condition should be excluded the possibility of malignancy by pathologic diagnosis. We report a case of 66-year-old man who presented with a brownish, papillomatous, verrucous mass in the auricle for the past seven years, which began to growing faster during the previous year. Dermoscopy and histopathological examination were performed and the patient was diagnosed with SK. He was treated with the carbon dioxide(CO2) laser and aminolevulinate photodynamic therapy (ALA-PDT). The CO2 laser was used for the removal of the thick hypertrophic lesions and to enhance the transdermal absorption efficiency of ALA. A 20% ALA cream(118 mg/cm2) was applied to his lesion and sealed for 3 h without light, followed by irradiation with 630-nm LED light (96 J/cm2, 80 mw/cm2). We use fluorescent diagnosis with aminolevulinic acid to define the tumor margins at the first session of ALA-PDT. After 4 sessions of ALA-PDT, the lesion was completely removed and did not recur. Therefore, we consider that ALA-PDT combined with CO2 laser is a safe and effective choice for the treatment of seborrheic keratosis in the auricle.

Identification of genes related to growth from transcriptome profiles of the muscle and liver of Chinese longsnout catfish (Leiocassis longirostris).

The Chinese longsnout catfish (Leiocassis longirostris) is a commercially important freshwater fish species in China. To understand the molecular mechanisms underlying its growth, we performed a comparative transcriptomic analysis of muscle and liver tissues of fast- and slow-growing L. longirostris. A total of 580 and 511 differentially expressed genes (DEGs) were obtained in the muscle and liver tissues, respectively. We selected 10 DEGs each from muscle and liver tissues by qRT-PCR to verify the reliability of RNA-seq, and it was found that the expression patterns of these genes were consistent with RNA-seq analysis results. According to the differential expression and functional enrichment analysis of genes, we found differences in the expression of several growth-related genes between fast- and slow-growing individuals. These genes may contribute to the differences in the growth of L. longirostris by influencing muscle growth and the metabolism of substances and energy. In particular, the pk and fabp genes were highly expressed in fast-growing individuals, while the cart, leptin, pepck, murf1, trim32, and pparα genes exhibited higher levels in slow-growing individuals. It was speculated that genes related to feeding behavior might be the key genes in regulating the growth of L. longirostris, while glycolytic/gluconeogenic metabolic pathway, lipid metabolism, and ubiquitin-proteasome pathway might be the main pathways involved in regulating body weight of L. longirostris. This study could enrich the available gene resources and provide a valuable basis for further studies on the regulatory mechanisms of growth in L. longirostris.

Molecular cloning and expression analysis of rad51 gene associated with gametogenesis in Chinese soft-shell turtle (Pelodiscus sinensis).

Rad51 is a recA-like recombinase that plays a crucial role in repairing DNA double-strand breaks through homologous recombination during mitosis and meiosis in mammals and other organisms. However, its role in reptiles remains largely unclear. In this study, we aimed to investigate the physiological role of the rad51 gene in reptiles, particularly in Pelodiscus sinensis. Firstly, the cDNA of rad51 gene was cloned and analyzed in P. sinensis. The cloned cDNA contained an open reading frame (ORF) of 1020 bp and encodeed a peptide of 339 amino acids. The multiple alignments and phylogenetic tree analysis of Rad51 showed that P. sinensis shares the high identity with Chelonia mydas (97.95%) and Mus musculus (95.89%). Secondly, reverse transcription-polymerase chain reaction (RT-PCR) and real-time quantitative polymerase chain reaction (RT-qPCR) analysis showed that rad51 mRNA was highly expressed in both ovary and testis, while being weak in the somatic tissues examined in this study. Furthermore, chemical in situ hybridization (CISH) was performed to examine the expression profile of rad51 mRNA in germ cells at different stages. In the testis, rad51 mRNA expression was found to be stronger in the germ cells at early stages, specifically in spermatogonia and spermatocytes, but it was undetectable in spermatids. In the ovary, rad51 mRNA exhibited a uniform distribution in the cytoplasm of oocytes at early stages. The signal intensity of rad51 mRNA was highest in primary oocytes and gradually declined during oogenesis as the oocytes developed. These results suggest that rad51 plays a vital role in the development of germ cells, particularly during the early stages of gametogenesis in P. sinensis. The dynamic expression pattern of rad51 mRNA provides insights into the mechanisms underlying germ cell development and differentiation into gametes in turtles, even in reptiles.

Efficient biosynthesis of Vibegron intermediate using a novel carbonyl reductase based on molecular modification of hydrogen bonding network regulation.

Vibegron is a novel, potent, highly selective ß3-adrenergic receptor agonist for the treatment of overactive bladder with higher therapeutic capacity and lower side effects. Methyl(2S,3R)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate ((2S,3R)-aminohydroxy ester) is a key chiral intermediate for the synthesis of Vibegron. A novel carbonyl reductase from Exiguobacterium sp. s126 (EaSDR6) was isolated using data mining technology from GenBank database with preferable catalytic activity. Hydrogen bond network regulation was performed using site-directed saturation mutagenesis and combination mutagenesis. The mutant EaSDR6A138L/S193A was obtained with the activity improvement by 4.58 folds compared with the wild type EaSDR6. The Km of EaSDR6A138L/S193A was decreased from 1.57 mM to 0.67 mM, kcat was increased by 2.17 folds, and the overall catalytic efficiency kcat/Km was increased by 5.07 folds. The organic-aqueous biphasic bioreaction system for the asymmetric synthesis of (2S,3R)-aminohydroxy ester was constructed for the first time. Under the substrate concentration of 150 g/L, the yield of (2S,3R)-aminohydroxy ester was > 99.99%, the e.e. was > 99.99%, and the spatiotemporal yield was 1.55 g/(L·h·g DCW) after 12 h reaction. While the substrate concentration was increased to 200 g/L and the reaction lasted for 36 h, the yield of (2S,3R)-aminohydroxy ester was > 99.99%, the e.e. was > 99.99% and the spatiotemporal yield was 1.05 g/(L·h·g DCW). The substrate concentration and spatiotemporal yield were higher than ever reported.

Enhancing prognostic accuracy in head and neck squamous cell carcinoma chemotherapy via a lipid metabolism-related clustered polygenic model.

OBJECTIVE: Systemic chemotherapy is the first-line therapeutic option for head and neck squamous cell carcinoma (HNSCC), but it often fails. This study aimed to develop an effective prognostic model for evaluating the therapeutic effects of systemic chemotherapy. METHODS: This study utilized CRISPR/cas9 whole gene loss-of-function library screening and data from The Cancer Genome Atlas (TCGA) HNSCC patients who have undergone systemic therapy to examine differentially expressed genes (DEGs). A lipid metabolism-related clustered polygenic model called the lipid metabolism related score (LMRS) model was established based on the identified functionally enriched DEGs. The prediction efficiency of the model for survival outcome, chemotherapy, and immunotherapy response was evaluated using HNSCC datasets, the GEO database and clinical samples. RESULTS: Screening results from the study demonstrated that genes those were differentially expressed were highly associated with lipid metabolism-related pathways, and patients receiving systemic therapy had significantly different prognoses based on lipid metabolism gene characteristics. The LMRS model, consisting of eight lipid metabolism-related genes, outperformed each lipid metabolism gene-based model in predicting outcome and drug response. Further validation of the LMRS model in HNSCCs confirmed its prognostic value. CONCLUSION: In conclusion, the LMRS polygenic prognostic model is helpful to assess outcome and drug response for HNSCCs and could assist in the timely selection of the appropriate treatment for HNSCC patients. This study provides important insights for improving systemic chemotherapy and enhancing patient outcomes.

SYT7 regulates the progression of chronic lymphocytic leukemia through interacting and regulating KNTC1.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is one of the most frequent occurring types of leukemia. It typically occurs in elderly patients and has a highly variable clinical course. At present, the molecular mechanism driving the pathogenesis and progression of CLL is not fully understood. The protein Synaptotagmin 7 (SYT7) encoded by the SYT7 gene has been found to be closely related to the development of various solid tumors, but its role in CLL is unclear. In this study, we investigated the function and molecular mechanism of SYT7 in CLL. METHODS: The expression level of SYT7 in CLL was determined by immunohistochemical staining and qPCR. The role of SYT7 in promoting CLL development was verified by in vivo and in vitro experiments. The molecular mechanism of SYT7 in CLL was elucidated by methods such as GeneChip analysis and Co-immunoprecipitation assay. RESULTS: Malignant behaviors such as proliferation, migration, and anti-apoptosis of CLL cells were significantly inhibited after SYT7 gene knockdown. In contrast, SYT7 overexpression promoted CLL development in vitro. Consistently, the knockdown of SYT7 also inhibited xenograft tumor growth of CLL cells. Mechanistically, SYT7 promoted CLL development by inhibiting SYVN1-mediated KNTC1 ubiquitination. The KNTC1 knockdown also attenuated the effects of SYT7 overexpression on development of CLL. CONCLUSIONS: SYT7 regulates the progression of CLL through SYVN1-mediated KNTC1 ubiquitination, which has potential value for molecular targeted therapy of CLL.

Tumor-infiltrating lymphocytes predict efficacy of immunotherapy in advanced non-small cell lung cancer: a single-center retrospective cohort study.

BACKGROUND/PURPOSE: The current study aimed to investigate the correlation between tumor-infiltrating lymphocytes (TILs) and immunotherapy efficacy in patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Eighty-nine patients with advanced NSCLC who received immune checkpoint inhibitors (ICIs) monotherapy were retrospectively enrolled in this study. The density of TILs in paraffin-embedded pathological tissues taken before receiving ICIs was quantitatively analyzed by immunohistochemical staining. The density of TILs was treated as a dichotomous variable using the median as the cutoff value. The Kaplan-Meier analysis was used to assess survival differences between groups. Univariate and multivariate Cox analyses were applied to screen out independent prognostic factors and further construct a nomogram prediction model to predict survival. RESULTS: Survival analysis showed that CD8+ TILs, CD4+ TILs, and IFN-γ+ Th1 were significant positive indicators for predicting progression-free survival (PFS) and overall survival (OS) (p < 0.05), whereas Foxp3+ Treg were a significant negative predictor (p < 0.05). The predictive role of IL-4+ Th2 was not apparent in this study and requires further investigation and exploration (p > 0.05). The nomogram prediction model exhibited good discriminative ability, with C-index values of 0.723 (95% CI 0.682-0.764) and 0.793 (95% CI, 0.738-0.848) in the training cohort and validation cohort, respectively. The AUC values indicated that the nomogram prediction model had high predictive value and the calibration curve presented good prediction accuracy. CONCLUSIONS: TILs could predict the efficacy of immunotherapy and may become a promising predictor.

Spatio-temporal pattern of c-Jun N-terminal kinase isoforms in the cochleae of C57BL/6J mice with presbycusis.

The c-Jun N-terminal kinase (JNK) pathway is a vital component of the mitogen-activated protein kinase cascade, which regulates cell death and survival. The present study aimed to explore the Spatio-temporal changes in all JNK isoforms in the cochleae of C57/BL6J mice with age-related hearing loss. Changes in the three isoforms of JNKs in the cochleae of an animal model with presbycusis and the senescent HEI-OC1 cell line were tested by immunohistochemistry staining and western blotting. Our results demonstrated that all three JNK isoforms are distributed in the cochleae, and the expression patterns of JNK1, JNK2, and JNK3 differed in hair cells, spiral ganglion neurons, and stria vascularis, with great significance in the cochleae of adult C57BL/6J mice. The levels of JNK1, JNK2, and JNK3 showed various spatio-temporal changes in the aging mice. In a senescent hair cell model, changes in JNK1, JNK2, and JNK3 expression levels were similar to those observed in the cochleae. Our study is the first to show that JNK3 is highly expressed in the hair cells of C57BL/6J mice and further increases in conjunction with age-related hearing loss, suggesting that it may play a more critical role than previously believed in hair cell loss and spiral ganglion degeneration.

The role of plasma cortisol in dementia, epilepsy, and multiple sclerosis: A Mendelian randomization study.

Background: Many clinical studies have shown a correlation between plasma cortisol and neurological disorders. This study explored the causal relationship between plasma cortisol and dementia, epilepsy and multiple sclerosis based on Mendelian randomization (MR) method. Methods: Data were taken from the summary statistics of a genome-wide association study, FinnGen consortium and United Kingdom Biobank. Dementia, epilepsy, and multiple sclerosis were used as outcomes, and genetic variants associated with plasma cortisol were used as instrumental variables. The main analysis was performed using the inverse variance weighted method, and the results were assessed according to the odds ratio (OR) and 95% confidence interval. Heterogeneity tests, pleiotropy tests, and leave-one-out method were conducted to evaluate the stability and accuracy of the results. Results: In two-sample MR analysis, the inverse variance weighted method showed that plasma cortisol was associated with Alzheimer's disease (AD) [odds ratio (95% confidence interval) = 0.99 (0.98-1.00), P = 0.025], vascular dementia (VaD) [odds ratio (95% confidence interval) = 2.02 (1.00-4.05), P = 0.049)], Parkinson's disease with dementia (PDD) [odds ratio (95% confidence interval) = 0.24 (0.07-0.82), P = 0.023] and epilepsy [odds ratio (95% confidence interval) = 2.00 (1.03-3.91), P = 0.042]. There were no statistically significant associations between plasma cortisol and dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and multiple sclerosis. Conclusion: This study demonstrates that plasma cortisol increase the incidence rates of epilepsy and VaD and decrease the incidence rates of AD and PDD. Monitoring plasma cortisol concentrations in clinical practice can help prevent diseases, such as AD, PDD, VaD and epilepsy.

Comparative efficacy and safety of antidepressant therapy for the agitation of dementia: A systematic review and network meta-analysis.

Background: Dementia is a clinical syndrome commonly seen in the elderly individuals. With the prevalence of dementia, the incidence of neuropsychiatric symptoms in dementia patients is increasing annually. Agitation, as one of the neuropsychiatric symptoms, has a serious impact on the quality of life of patients with dementia. Several antidepressant drugs have been shown to be effective for treating agitated behavior symptoms in patients with dementia, but there are no direct comparisons among those drugs. Therefore, we carried out a network meta-analysis (NMA) to examine the efficacy and safety of those antidepressant drugs. Methods: We searched eight databases (PubMed, Cochrane Library, Web of Science, Embase, Wanfang Database, China National Knowledge Infrastructure, VIP Database and China biomedical literature service) from their inception to 6 November 2022. Randomized controlled trials (RCTs) reporting the efficacy and safety of antidepressant drugs in treating agitated behavior symptoms in patients with dementia were included in our analysis. The quality assessment was carried out by two researchers individually and the analysis was based on the frequency method. Results: Twelve articles with 1,146 participants were included in our analysis. Based on the outcome of the agitation score, treatment with citalopram (standardized mean difference, SMD = -0.44, 95% confidence interval, 95% CI = -0.72 to -0.16) showed significant benefits over the placebo group. Treatment with trazodone (odds ratio, OR = 4.58, 95% CI = 1.12-18.69) was associated with a higher risk of total adverse events compared with a placebo treatment. Conclusion: Among the antidepressant drugs included in this study, treatment with citalopram was probably the only optimal intervention, when considering the improvement from baseline to the end of the intervention, and there was not a statistically significant difference in safety when compared with a placebo treatment. Systematic review registration: https://www.crd.york.ac.uk/prospero/#recordDetails, identifier: PROSPERO, CRD42022320932.

Ultrasound-enhanced brain delivery of edaravone provides additive amelioration on disease progression in an ALS mouse model.

BACKGROUND: Although amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and unfortunately incurable yet, incremental attention has been drawn to targeting the health of corticospinal motor neurons. Focused ultrasound combined with systemically circulating microbubbles (FUS/MB) is an emerging modality capable of site-specific molecular delivery temporarily and noninvasively within a range of appropriate parameters. OBJECTIVE: To investigate the effect of FUS/MB-enhanced delivery of therapeutics to the motor cortex on the disease progression by using a transgenic mouse model of ALS. METHODS: Multiple FUS/MB-enhanced deliveries of Edaravone (Eda) to the motor cortex were performed on the SOD1G93A mouse model of ALS. The motor function of the animals was evaluated by gait analysis, grip strength and wire hanging tests. Corticospinal and spinal motor neuronal health, misfolded SOD1 protein and neuroinflammation after treatments were evaluated by histological examination. RESULTS: Ultrasound-enhanced delivery of Eda in the targeted motor cortex was achieved by a two-fold increase without gross tissue damage. Compared with the ALS mice administered Eda treatments only, the animals given additionally FUS/MB-enhanced brain delivery of Eda (FUS/MB + Eda) exhibited further improvements in neuromuscular functions characterized by gait patterns, muscular strength, and motor coordination along with rescued muscle atrophy. FUS/MB + Eda treatments conferred remarkable neuroprotection to both upper and lower motor neurons revealed by normalized neuronal morphology with increasing cell body size and profoundly alleviated neuroinflammation and misfolded SOD1 protein in the brains and lumbar spinal cords. CONCLUSION: We report a pilot study that non-invasive ultrasound-enhanced brain delivery of Eda provides additive amelioration on disease progression of ALS and suggest that broadening the target from spinal to cortical network functions using the FUS/MB-enhanced delivery can be a rational therapeutic strategy of this debilitating disorder.

Circular RNA PVT1 Regulates Cell Proliferation, Migration, and Apoptosis by Stabilizing c-Myc and Downstream Target CXCR4 Expression in Acute Myeloid Leukemia

Objective: This study aimed to investigate the role and mechanism of circular RNA PVT1 (circPVT1) in patients with acute myeloid leukemia (AML). Materials and Methods: The expression of circPVT1 in 23 patients with de novo AML (not acute promyelocytic leukemia, not APL) and cell lines were detected by RT-qPCR. Loss of function assays were carried out to explore the influence of silenced circPVT1 on the proliferation, migration, and apoptosis in the THP-1 cell line. CCK-8 assays, trans-well assays, and annexin V/PI staining assays were performed to assess proliferation, migration, and apoptosis, respectively. Results: CircPVT1 was highly expressed in AML patients and myeloid cell lines compared to healthy controls. Higher expression of circPVT1 was related to shorter overall survival (OS) and relapse-free survival (RFS) in AML patients. Cell viability and migration were inhibited and apoptosis was increased when circPVT1 was knocked down in THP-1 cells. Knockdown of circPVT1 resulted in marked suppression of c-Myc protein with no significant change in mRNA levels. We also found that circPVT1 knockdown markedly increased the phosphorylation of c-Myc Thr-58, which was responsible for c-Myc degradation. Silencing of c-Myc caused a significant decrease in CXCR4 mRNA and protein expression, whereas the overexpression of c-Myc caused the opposite result, suggesting that CXCR4 is a target molecule of c-Myc. Finally, we found that overexpression of c-Myc could partially reverse circPVT1 knockdown-induced anti-tumor effects on THP-1 cells in vitro. Conclusion: Our findings showed that circPVT1 was highly expressed in AML patients and was related to shorter OS and RFS. CircPVT1 may exert an oncogenic effect in THP-1 cells by stabilizing c-Myc protein expression and downstream target CXCR4 expression. These data indicate that circPVT1 may be a promising therapeutic target for AML.

Progress on Prevention and Treatment of Cerebral Small Vascular Disease Using Integrative Medicine.

Cerebral small vessel disease (CSVD) is a senile brain lesion caused by the abnormal structure and function of arterioles, venules and capillaries in the aging brain. The etiology of CSVD is complex, and disease is often asymptomatic in its early stages. However, as CSVD develops, brain disorders may occur, such as stroke, cognitive dysfunction, dyskinesia and mood disorders, and heart, kidney, eye and systemic disorders. As the population continues to age, the burden of CSVD is increasing. Moreover, there is an urgent need for better screening methods and diagnostic markers for CSVD, in addition to preventive and asymptomatic- and mild-stage treatments. Integrative medicine (IM), which combines the holistic concepts and syndrome differentiations of Chinese medicine with modern medical perspectives, has unique advantages for the prevention and treatment of CSVD. In this review, we summarize the biological markers, ultrasound and imaging features, disease-related genes and risk factors relevant to CSVD diagnosis and screening. Furthermore, we discuss IM-based CSVD prevention and treatment strategies to stimulate further research in this field.