Identification and validation of a prognostic signature based on six immune-related genes for colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a prevalent malignancy with high mortality and morbidity rates. Although the significant efficacy of immunotherapy is well established, it is only beneficial for a limited number of individuals with CRC. METHODS: Differentially expressed immune-related genes (DE-IRGs) were retrieved from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ImmPort databases. A prognostic signature comprising DE-IRGs was developed using univariate, LASSO, and multivariate Cox regression analyses. A nomogram integrating the independent prognostic factors was also developed. CIBERSORT was used to assess immune cell infiltration (ICI). Furthermore, wound-healing, colony formation, migration, and invasion assays were performed to study the involvement of ACTG1 in CRC. RESULTS: A signature including six DE-IRGs was developed. The overall survival (OS) rate was accurately estimated for TCGA and GSE38832 cohorts. The risk score (RS) of the signature was an independent factor for OS. Moreover, a nomogram encompassing age, RS, and pathological T stage accurately predicted the long-term OS probability of individuals with CRC. The high-risk group had an elevated proportion of patients treated with ICIs, including native B cells, relative to the low-risk group. Additionally, ACTG1 expression was upregulated, which supported the proliferation, migration, and invasion abilities of CRC cells. CONCLUSIONS: An immune-related prognostic signature was developed for predicting OS and for determining the immune status of individuals with CRC. The present study provides new insights into accurate immunotherapy for individuals with CRC. Moreover, ACTG1 may serve as a new immune biomarker.

Association between sagittal abdominal diameter-to-height ratio and arteriosclerotic cardiovascular disease among the United States adults: A cross-sectional study.

Objectives: Abdominal obesity is recognized as a significant determinant of Arteriosclerotic cardiovascular disease (ASCVD), with sagittal abdominal diameter (SAD) being considered a more precise indicator of visceral fat. Nevertheless, the association between SAD and ASCVD remains unexplored in large-scale general-population studies. Methods: The study included 11,211 participants aged 20 to 80 from the National Health and Nutrition Examination Survey. Logistic regression models were utilized to evaluate the association between the SAD-to-height ratio (SADHtR) and ASCVD. Subgroup analyses based on age categories, sex, diabetes, and hypertension were conducted to assess result robustness. Results: The median SADHtR value was 0.13 (0.12-0.15), and 1,006 cases (7.46 %) of ASCVD were recorded. Multivariable models showed that each standard deviation increase in SADHtR was positively associated with higher odds of ASCVD (OR 1.48, 95 % CI 1.36-1.62 in model 1; OR 1.41, 95 % CI 1.28-1.54 in model 2; OR 1.18, 95 % CI 1.08-1.30 in model 3). Comparing the first quartile of SADHtR to the second to fourth quartiles, positive associations with ASCVD were observed in models 1 and 2. However, in model 3, only the fourth quartile of SADHtR remained statistically significant (OR 1.58, 95 % CI 1.17-2.15), with all p-values for the trend being less than 0.05. No interactions were found in the subgroup analyses. Conclusion: This study demonstrates a positive association between SADHtR and ASCVD in the general adult population of the United States. Our findings indicate that SADHtR, especially when ≥ 0.155, could be a valuable metric for assessing the risk of ASCVD.

Association between visceral adipose tissue and total testosterone among the United States male adults: a cross-sectional study.

Visceral adipose tissue (VAT) is regarded as an important risk factor for obesity-related diseases. The results of the association between VAT and total testosterone (TT) are controversial and whether this association is nonlinear is still unknown. 3971 male participants who were aged 20-59 years from the National Health and Nutrition Examination Surveys 2011-2016 were included. VAT area was measured by dual-energy x-ray absorptiometry. TT in serum was assessed utilizing the isotope dilution liquid chromatography-tandem mass spectrometry technique. Linear regression models assessed the associations between VAT area and TT. A restricted cubic spline model was employed to investigate nonlinear relationships. A two-piecewise linear regression model was applied to determine the threshold effect. Subgroup analyses were conducted. The weighted methods were utilized in all analyses. VAT area was inversely associated with TT in the crude and adjusted models. In the fully adjusted model, VAT area was associated with TT (ß = -0.59, 95% confidence interval [CI] = -0.74, -0.43) and compared to the first tertile of VAT area, the second and the third tertile had a lower TT level, the ß and 95% CI = -65.49 (-83.72, -47.25) and -97.57 (-121.86, -73.27) respectively. We found these inverse associations were nonlinear. The cutoff point of the VAT area was 126 cm2. When the VAT area was <126 cm2, VAT area was significantly associated with a lower TT level (ß = -1.55, 95% CI = -1.93 to -1.17, p < 0.0001). However, when the VAT area was ≥126 cm2, this association was less apparent (ß = -0.26, 95% CI = -0.52 to 0.01, p = 0.06). No significant interactions among different ages (<50 or ≥50 years), marital, and physical activity status were found. These findings underscore the potential for VAT area as a modifiable indicator for improving testosterone deficiency.

LncRNA AC005165.1 Alleviates IL-1ß-Induced Osteoarthritis via miR-199a-3p/TXNIP Axis.

Osteoarthritis (OA) is a chronic musculoskeletal disease and often causes impaired joint mobility and disability. Long noncoding RNAs (lncRNAs) play pivotal roles in OA development. This study was done to explore the role and mechanism of the lncRNA AC005165.1 in the cell model of interleukin-1ß (IL)-1ß-treated chondrocytes. This study recruited 20 surgically treated OA patients and 12 age- and gender-matched controls. Real-time reverse transcription quantitative polymerase chain reaction was used to examine the expression levels of AC005165.1, miR-199a-3p, and thioredoxin-interacting protein (TXNIP) in articular cartilage of patients and IL-1ß-treated human chondrocytes. Cell viability and apoptosis were evaluated by cell counting kit-8 and flow cytometry assays, respectively. The protein levels of inflammatory cytokines were assessed by western blotting. Enzyme-linked immunosorbent assay was conducted to detect the concentrations of the inflammatory cytokines in chondrocytes. Luciferase reporter assay and Pearson's correlation analysis were used for analyzing the interaction and the correlation among AC005165.1, miR-199a-3p, and TXNIP. AC005165.1 expression was downregulated in cartilage of OA patients and chondrocytes treated with IL-1ß, compared to that in the control groups. AC005165.1 knockdown increased apoptosis and aggravated inflammatory response in IL-1ß-treated chondrocytes. AC005165.1 interacted with miR-199a-3p, and TXNIP was targeted by miR-199a-3p. In rescue assay, miR-199a-3p knockdown and TXNIP overexpression significantly reduced apoptosis and mitigated inflammatory response in IL-1ß-treated chondrocytes with AC005165.1 knockdown. AC005165.1 knockdown promoted apoptosis and inflammatory response in IL-1ß-treated chondrocytes via the miR-199a-3p/TXNIP axis.

Evodiamine ameliorates intervertebral disc degeneration through the Nrf2 and MAPK pathways.

Degradation of extracellular matrix (ECM), reactive oxygen species (ROS) production, and inflammation are critical players in the pathogenesis of intervertebral disc degeneration (IDD). Evodiamine exerts functions in inhibiting inflammation and maintaining mitochondrial antioxidant functions. However, the biological functions of evodiamine and its related mechanisms in IDD progression remain unknown. The IDD-like conditions in vivo were stimulated via needle puncture. Hematoxylin and eosin staining, Safranin O/Fast Green staining and Alcian staining were performed to determine the degenerative status. The primary nucleus pulposus cells (NPCs) were isolated from Sprague-Dawley rats and then treated with tert-butyl peroxide (TBHP) to induce cellular senescence and oxidative stress. The cell viability was assessed by cell counting kit-8 assays. The mitochondria-derived ROS in NPCs was evaluated by MitoSOX staining. The mitochondrial membrane potential in NPCs was identified by JC-1 staining and flow cytometry. The expression of collagen II in NPCs was measured by immunofluorescence staining. The levels of mRNAs and proteins were measured by RT-qPCR and western blotting. The Nrf2 expression in rat nucleus pulposus tissues was measured by immunohistochemistry staining. Evodiamine alleviated TBHP-induced mitochondrial dysfunctions in NPCs. The enhancing effect of TBHP on the ECM degradation was reversed by evodiamine. The TBHP-stimulated inflammatory response was ameliorated by evodiamine. Evodiamine alleviated the IDD process in the puncture-induced rat model. Evodiamine promoted the activation of Nrf2 pathway and inactivated the MAPK pathway in NPCs. In conclusion, evodiamine ameliorates the progression of IDD by inhibiting mitochondrial dysfunctions, ECM degradation and inflammation via the Nrf2/HO-1 and MAPK pathways.

Composite Dietary Antioxidant Index is inversely associated with visceral adipose tissue area among U.S. adults: A cross-sectional study.

Obesity is becoming a global health problem. Visceral adiposity is the main cause of metabolic and cardiovascular diseases. Dietary improvement is the key to controlling obesity. We hypothesized that a higher Composite Dietary Antioxidant Index (CDAI) was associated with a lower visceral adipose tissue (VAT) area. In this cross-sectional study, 10,389 adults were selected from the National Health and Nutrition Examination Survey 2011-2018. CDAI was calculated based on 6 micronutrients: zinc, selenium, total carotenoids, vitamin A, vitamin C, and vitamin E. VAT area was determined by the dual-energy X-ray absorptiometry scan. Linear regression models were constructed to evaluate the association between CDAI and VAT area. Subgroup analyses were also performed. The mean age of participants was 39.68 years, 5240 were male, and 3841 of those were non-Hispanic White. The inverse associations were observed in all models. In model 3, CDAI was inversely associated with VAT area as a continuous variable, ß (95% confidence interval), -0.56 (-0.85 to -0.27). When compared with the first tertile, the third tertile of CDAI was also inversely associated with VAT area, ß (95% confidence interval), -6.72 (-10.44 to -2.99). No interactions were found in the subgroup analyses. In conclusion, an inverse association between CDAI and VAT area was found among U.S. adults aged 20 to 59 years. These results suggest the possible benefit of an antioxidant diet in relieving visceral obesity. More prospective studies are needed to identify this dietary benefit.

Versatile Polymerization-Induced Emission Polymers from Barbier Polymerization of Cinnamic Esters with Tunable Emission.

Cinnamic ester is a common and abundant chemical substance, which can be extracted from natural plants. Compared with traditional esters, cinnamic ester contains α,ß-unsaturated carbonyl structure with multiple reactive sites, resulting in more abundant reactivities and chemical structures. Here, a versatile polymerization-induced emission (PIE) is successfully demonstrated through Barbier polymerization of cinnamic ester. Attributed to its abundant reactivities of α,ß-unsaturated carbonyl structure, Barbier polymerization of cinnamic esters with different organodihalides gives polyalcohol and polyketone via 1,2-addition and 1,4-addition, respectively, which is also confirmed by small molecular model reactions. Meanwhile, these organodihalides dependant polyalcohol and polyketone exhibit different non-traditional intrinsic luminescence (NTIL) from aggregation-induced emission (AIE) type to aggregation-caused quenching (ACQ) type, where novel PIE luminogens (PIEgens) are revealed. Further potential applications in explosive detection are carried out, where it achieves TNT detection sensitivity at ppm level in solution and ng level on the test paper. This work therefore expands the structure and functionality libraries of monomer, polymer and NTIL, which might cause inspirations to different fields including polymer chemistry, NTIL, AIE and PIE.

Identification of common stria vascularis cellular alteration in sensorineural hearing loss based on ScRNA-seq.

BACKGROUND: The stria vascularis (SV), located in the lateral wall of the cochlea, maintains cochlear fluid homeostasis and mechanoelectrical transduction (MET) activity required for sound wave conduction. The pathogenesis of a number of human inheritable deafness syndromes, age related hearing loss, drug-induced ototoxicity and noise-induced hearing loss results from the morphological changes and functional impairments in the development of the SV. In this study, we investigate the implications of intercellular communication within the SV in the pathogenesis of sensorineural hearing loss (SNHL). We aim to identify commonly regulated signaling pathways using publicly available single-cell transcriptomic sequencing (scRNA-seq) datasets. METHODS: We analyzed scRNA-seq data, which was derived from studying the cochlear SV in mice with SNHL compared to normal adult mice. After quality control and filtering, we obtained the major cellular components of the mouse cochlear SV and integrated the data. Using Seurat's FindAllMarkers and FindMarkers packages, we searched for novel conservative genes and differential genes. We employed KEGG and GSEA to identify molecular pathways that are commonly altered among different types of SNHL. We utilized pySCENIC to discover new specific regulatory factors in SV subpopulation cells. With the help of CellChat, we identified changes in subpopulation cells showing similar trends across different SNHL types and their alterations in intercellular communication pathways. RESULTS: Through the analysis of the integrated data, we discovered new conserved genes to SV specific cells and identified common downregulated pathways in three types of SNHL. The enriched genes for these pathways showing similar trends are primarily associated with the Electron Transport Chain, related to mitochondrial energy metabolism. Using the CellChat package, we further found that there are shared pathways in the incoming signaling of specific intermediate cells in SNHL, and these pathways have common upstream regulatory transcription factor of Nfe2l2. Combining the results from pySCENIC and CellChat, we predicted the transcription factor Nfe2l2 as an upstream regulatory factor for multiple shared cellular pathways in IC. Additionally, it serves as an upstream factor for several genes within the Electron Transport Chain. CONCLUSION: Our bioinformatics analysis has revealed that downregulation of the mitochondrial electron transport chain have been observed in various conditions of SNHL. E2f1, Esrrb, Runx1, Yy1, and Gata2 could serve as novel important common TFs regulating the electron transport chain. Adm has emerged as a potential new marker gene for intermediate cells, while Itgb5 and Tesc show promise as potential new marker genes for marginal cells in the SV. These findings offer a new perspective on SV lesions in SNHL and provide additional theoretical evidence for the same drug treatment and prevention of different pathologies of SNHL.

Case report: A lung squamous cell carcinoma patient with a rare EGFR G719X mutation and high PD-L1 expression showed a good response to anti-PD1 therapy.

Lung cancer treatment has transitioned fully into the era of immunotherapy, yielding substantial improvements in survival rate for patients with advanced non-small cell lung cancer (NSCLC). In this report, we present a case featuring a rare epidermal growth factor receptor (EGFR) mutation accompanied by high programmed death-ligand 1 (PD-L1) expression, demonstrating remarkable therapeutic efficacy through a combination of immunotherapy and chemotherapy. A 77-year-old male with no family history of cancer suffered from upper abdominal pain for more than half months in August 2020 and was diagnosed with stage IV (cT3N3M1c) lung squamous cell carcinoma (LUSC) harboring both a rare EGFR p.G719C mutation and high expression of PD-L1 (tumor proportion score [TPS] = 90%). Treatment with the second-generation targeted therapy drug Afatinib was initiated on September 25, 2020. However, resistance ensued after 1.5 months of treatment. On November 17, 2020, immunotherapy was combined with chemotherapy (Sintilimab + Albumin-bound paclitaxel + Cisplatin), and a CT scan conducted three months later revealed significant tumor regression with a favorable therapeutic effect. Subsequently, the patient received one year of maintenance therapy with Sintilimab, with follow-up CT scans demonstrating subtle tumor shrinkage (stable disease). This case provides evidence for the feasibility and efficacy of immunotherapy combined with chemotherapy in the treatment of EGFR-mutated and PD-L1 highly expressed LUSC.

Clickable Polymerization-Induced Emission Luminogens Toward Color-Tunable Modification of Non-Traditional Intrinsic Luminescent Polymers.

Non-traditional intrinsic luminescent (NTIL) polymer is an emerging field, and its color-tunable modification is highly desirable but still rarely investigated. Here, a click chemistry approach for the color-tunable modifications of NTIL polymers by introducing clickable polymerization-induced emission luminogen (PIEgen), is demonstrated. Through Cu-catalyzed azide-alkyne cycloaddition click chemistry, a series of PIEgens is successful prepared, which is further polymerized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Interestingly, after clickable modification, these monomers are nonemissive in both solution and aggregation states; while, the corresponding polymers exhibit intriguing aggregation-induced emission (AIE) characteristics, confirming their PIEgen characteristics. By varying alkynyl substitutions, color-tunable NTIL polymers are achieved with emission wavelength varying from 448 to 498 nm, revealing a series of PIEgens and verifying the importance of modification of NTIL polymers. Further luminescence energy transfer application is carried out as well. This work therefore designs a series of clickable PIEgens and opens a new avenue for the modification of NTIL polymers via click chemistry, which may cause inspirations to the research fields including luminescent polymer, NTIL, click chemistry, AIE and modification.

Identification and experimental validation of ferroptosis-related gene lactotransferrin in age-related hearing loss.

Objective: To reveal the relationship between ARHL and ferroptosis and screen ferroptosis-related genes (FRGs) in ARHL. Methods: Bioinformatics were used to analyze the hub genes and molecular mechanism of ferroptosis in the aging cochleae. Senescence ß-galactosidase staining, iron content detection, and micro malondialdehyde (MDA) assay kits were used to measure ß-galactosidase activity, and expression of Fe2+ and MDA, respectively. Fluorescence microscope was used for immunofluorescence assay of hub genes. Western blot was used to verify the expression of hub genes in HEI-OC1 cells, cochlear explants, and cochleae of C57BL/6J mice. Data were expressed as mean ± SD of at least three independent experiments. Results: The analysis of bioinformatics confirmed that lactotransferrin (LTF) is the hub gene and CEBPA-miR-130b-LTF network is the molecular mechanism for cochlear ferroptosis. Compared with the control group, the experiments proved that the indicators of ferroptosis, including Fe2+, MDA, and LTF were differentially expressed in aging HEI-OC1 cells, aging cochlear explants, and aging cochleae. Conclusion: These results demonstrate that ferroptosis plays an important role in ARHL, and LTF is a potential therapeutic target for ARHL via regulating cochlear ferroptosis.

Self-Lifting Droplet Driven by the Solidification-Induced Solutal Marangoni Flow.

Multicomponent droplets are pertinent to diverse applications ranging from 3D printing to fabrication of electronic devices to medical diagnostics and are typically inherent with the occurrence of the phase transition in the manifestation of evaporation and solidification. Indeed, the versatile transformations and fascinating morphologies of the droplets have been identified, which primarily arise from the evaporation-induced flow. Here, we report the self-lifting behavior of a frozen binary droplet, resulting in a nearly doubling in height, in a fashion that defies against the gravitational effect. This counterintuitive observation is attributed to an internal solutal Marangoni flow up to 1 mm/s, which is driven by the enriched solute concentration locally in the vicinity of the solidification front. Moreover, we perform theoretical analysis by incorporating the propagation of solidification front, and the calculated spatiotemporal evolution of droplet shape agrees with experiments excellently. The effects of several key physical parameters on self-lifting are elucidated quantitatively, providing guidance to control the self-lifting. These results will further advance our understanding of underlying physicochemical hydrodynamics in the multicomponent liquid systems subjected to heat transfer and phase change, consequently shedding light on the relevant technological applications.

Effects of neoadjuvant stereotactic body radiotherapy plus adebrelimab and chemotherapy for triple-negative breast cancer: A pilot study.

Background: Emerging data have supported the immunostimulatory role of radiotherapy, which could exert a synergistic effect with immune checkpoint inhibitors (ICIs). With proven effective but suboptimal effect of ICI and chemotherapy in triple-negative breast cancer (TNBC), we designed a pilot study to explore the efficacy and safety of neoadjuvant stereotactic body radiotherapy (SBRT) plus adebrelimab and chemotherapy in TNBC patients. Methods: Treatment-naïve TNBC patients received two cycles of intravenous adebrelimab (20 mg/kg, every 3 weeks), and SBRT (24 Gy/3 f, every other day) started at the second cycle, then followed by six cycles of adebrelimab plus nab-paclitaxel (125 mg/m² on days 1 and 8) and carboplatin (area under the curve 6 mg/mL per min on day 1) every 3 weeks. The surgery was performed within 3-5 weeks after the end of neoadjuvant therapy. Primary endpoint was pathological complete response (pCR, ypT0/is ypN0). Secondary endpoints included objective response rate (ORR), residual cancer burden (RCB) 0-I, and safety. Results: 13 patients were enrolled and received at least one dose of therapy. 10 (76.9%) patients completed SBRT and were included in efficacy analysis. 90% (9/10) of patients achieved pCR, both RCB 0-I and ORR reached 100% with three patients achieved complete remission. Adverse events (AEs) of all-grade and grade 3-4 occurred in 92.3% and 53.8%, respectively. One (7.7%) patient had treatment-related serious AEs. No radiation-related dermatitis or death occurred. Conclusions: Adding SBRT to adebrelimab and neoadjuvant chemotherapy led to a substantial proportion of pCR with acceptable toxicities, supporting further exploration of this combination in TNBC patients. Funding: None. Clinical trial number: NCT05132790.

Identification and validation of N6-methyladenosine (m6A)-related lncRNAs signature for predicting the prognosis of laryngeal carcinoma, especially for smoking patients.

Laryngeal cancer (LC), a highly fatal tumor in the head and neck region, has been the focus of research in recent years. The study of LC has primarily focused on the role of long non-coding RNAs (lncRNAs) in regulating gene expression, as they have emerged as pivotal factors in this biological process. Additionally, a reversible RNA modification called N6-methyladenosine (m6A) has been observed to have a significant impact on gene expression as well. The purpose of this research is to investigate the impact of m6A-related lncRNAs on the prognosis of laryngeal squamous cell carcinoma (LSCC). Specifically, this investigation analyzed the m6A-related regulators' patterns of expression and mutation, encompassing a total of 15 regulators. Drawing upon the expression levels of prognostic m6A-regulated lncRNAs, two distinct lncRNA clusters were identified. Further analysis revealed differentially expressed lncRNAs between these clusters. In addition to studying the expression of lncRNAs, the researchers also examined the distribution of clinical characteristics and the tumor microenvironment (TME) in relation to the identified lncRNA clusters. This provided valuable insights into potential associations between lncRNA expression patterns and the clinical features of LSCC. Through the establishment of a risk model associated with lncRNAs, we were able to further investigate their clinical features, prognosis, and immune status. Additionally, we conducted a separate analysis of LINC00528, a lncRNA associated with smoking, examining its expression, overall survival time, correlated mRNAs, and conducting enrichment of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), as well as determining the sensitivity of related drugs. RT-qPCR results also indicated an increase in LINC00528 expression among smoking LSCC patients. The findings suggest that a high expression level of LINC00528 in LSCC patients may lead to a more favorable prognosis, providing new insights for the management and treatment of LSCC patients, particularly those with high expression of LINC00528. Overall, this research sheds light on the prognostic impact of m6A-regulated lncRNAs in LSCC. The implications of these findings for the advancement of innovative therapeutic approaches for LSCC patients are noteworthy.

Ecological drought monitoring of Inner Mongolia vegetation growing season based on kernel temperature vegetation drought index (kTVDI).

Ecological drought monitoring is important for regional status assessment and protection of water resources. In this study, we constructed a new ecological drought index, the kernel temperature vegetation drought index (kTVDI), by using the kernel normalized vegetation index (kNDVI) to improve the temperature vegetation drought index (TVDI) in Inner Mongolia. We further analyzed the spatial and temporal distribution of ecological drought in Inner Mongolia during 2000-2022 and the future trend of ecological drought by using segmented linear regression model, Theil-Sen median, Mann-Kendall test, and Hurst index. The results showed that kTVDI performed better in monitoring ecological drought than TVDI. From 2000 to 2022, kTVDI showed a decreasing trend in the growing season in Inner Mongolia, but the change was not significant, and a sudden change occurred in 2016, and the wetting trend after the sudden change was more obvious. During the study period, ecological drought in 23.6% of the areas of Inner Mongolia showed an aggravating trend, and ecological drought was alleviated in 46.5% of the area. In the future, ecological drought would be exacerbated in the eastern part but alleviated in the central and western parts of Inner Mongolia.

Association between miR-365 polymorphism and ischemic stroke in a Chinese population.

Background: Ischemic stroke (IS) represents a major cause of morbidity and mortality across the globe. The aberrant expression of miR-365 has been found to be implicated in a wide array of human diseases, including atherosclerosis and cancer. Studies on single-nucleotide polymorphisms (SNPs) in miRNA genes can help gain insight into the susceptibility to the condition. This study aimed to examine the relationship between miR-365 SNPs and the risk of IS. Methods: The study recruited 215 IS patients and 220 controls. The SNPscans genotyping was employed to genotype three polymorphic loci (rs121224, rs30230, and rs178553) of miR-365. The relative expression of miR-365 in peripheral blood mononuclear cells of the patients and controls was determined by using real-time quantitative PCR. Results: The miR-365 rs30230 polymorphism exhibited a significant association with the risk of developing IS (TC vs. CC: adjusted OR = 0.55, 95% CI: 0.33-0.92, P = 0.022; TT vs. CC: adjusted OR = 0.34, 95% CI: 0.14-0.85, P = 0.021; TC +TT vs. CC: adjusted OR = 0.51, 95% CI: 0.31-0.83, P = 0.007; T vs. C: adjusted OR = 0.57, 95% CI: 0.39-0.83, P = 0.004). Haplotype analysis revealed that the C-T-G haplotype was associated with a decreased risk of IS (OR = 0.68, 95% CI: 0.46-1.00, P = 0.047). Furthermore, miR-365 expression was significantly higher in IS patients than in controls (P < 0.001). Interestingly, patients with rs30230 TC or TT genotypes had lower miR-365 levels compared to their counterparts with CC genotypes (P < 0.001). Conclusions: The miR-365 rs30230 polymorphism might bear an association with IS susceptibility in the Chinese population, and the rs30230 TC/TT genotype might be a protective factor against IS.

Neuroinflammation: The central enabler of postoperative cognitive dysfunction.

The proportion of advanced age patients undergoing surgical procedures is on the rise owing to advancements in surgical and anesthesia technologies as well as an overall aging population. As a complication of anesthesia and surgery, older patients frequently suffer from postoperative cognitive dysfunction (POCD), which may persist for weeks, months or even longer. POCD is a complex pathological process involving multiple pathogenic factors, and its mechanism is yet unclear. Potential theories include inflammation, deposition of pathogenic proteins, imbalance of neurotransmitters, and chronic stress. The identification, prevention, and treatment of POCD are still in the exploratory stages owing to the absence of standardized diagnostic criteria. Undoubtedly, comprehending the development of POCD remains crucial in overcoming the illness. Neuroinflammation is the leading hypothesis and a crucial component of the pathological network of POCD and may have complex interactions with other mechanisms. In this review, we discuss the possible ways in which surgery and anesthesia cause neuroinflammation and investigate the connection between neuroinflammation and the development of POCD. Understanding these mechanisms may likely ensure that future treatment options of POCD are more effective.

Discovery of potential novel TRPC5 inhibitors by virtual screening and bioassay.

The transient receptor potential canonical channel 5 (TRPC5), a member of the TRPC family, plays a crucial role in the regulation of various physiological activities and diseases, including those related to the central nervous system, cardiovascular system, kidney, and cancer. As a nonselective cation channel, TRPC5 mainly controls the influx of extracellular Ca2+ into cells, thereby modulating cellular depolarization and intracellular ion concentration. Inhibition of TRPC5 by small molecules presents a promising approach for the treatment of TRPC5-associated diseases. In this study, we conducted a comprehensive virtual screening of more than 1.5 million molecules from the Chemdiv database (https://www.chemdiv.com) to identify potential inhibitors of hTRPC5, utilizing the published structures and binding sites of hTRPC5 as a basis. Lipinski's rule, Veber's rule, PAINS filters, pharmacophore analysis, molecular docking, ADMET evaluation and cluster analysis methods were applied for the screening. From this rigorous screening process, 18 candidates exhibiting higher affinities to hTRPC5 were subsequently evaluated for their inhibitory effects on Ca2+ influx using a fluorescence-based assay. Notably, two molecules, namely SML-1 and SML-13, demonstrated significant inhibition of intracellular Ca2+ levels in hTRPC5-overexpressing HEK 293T cells, with IC50 values of 10.2 µM and 10.3 µM, respectively. These findings highlight SML-1 and SML-13 as potential lead molecules for the development of therapeutics targeting hTRPC5 and its associated physiological activities and diseases.

Identification of 3H-benzo[b] [1,4] diazepine derivatives as PPARα agonists by in silico studies and biochemical evaluation.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, whose pathologic features include dysregulated glucose homeostasis and lipid accumulation. Peroxisome proliferators-activated receptor α (PPARα) is a key regulator of fatty acid metabolism and ketogenesis due to its regulatory pathways involve activating fatty acid uptake, accelerating fatty acid oxidation, inhibiting gluconeogenesis, and suppressing inflammation and fibrosis. Therefore, PPARα is considered as a potential target for the treatment of NAFLD and some agonists have entered clinical trials, which drove us to discover more novel PPARα agonists. In current work, new 3H-benzo[b] [1,4] diazepine PPARα agonists were identified from the ChemDiv database by pharmacophore modeling, molecular docking, derivative structure search, and bioassays, where compound LY-2 and its derivatives (LY-10∼LY-19) were discovered to promote the expression of PPARα downstream gene, carnitine palmitoyl transterase-1 α (cpt1α). Among these active compounds, the EC50 value of LY-2 against increasing cpt1α was 2.169 µΜ. Furthermore, the effect of LY-2 on cpt1α was weakened when PPARα knock down, which confirmed that it is a PPARα agonist again. Finally, the results from molecular dynamics simulations and binding free energy calculations showed that π-π stacking and hydrogen bonding interactions played key roles in the binding of LY-2 and PPARα protein and their complex maintained a stable structure to facilitate LY-2 to have a better binding affinity with PPARα protein. Taken together, compound LY-2 might be a novel lead compound for the development of potent PPARα agonists.Communicated by Ramaswamy H. Sarma.