Sulforaphane decreases oxidative stress and inhibits NLRP3 inflammasome activation in a mouse model of ulcerative colitis.

Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes ameliorates clinical symptoms and morphological manifestations of IBD. Herein, we examined the roles of NLRP3 activation in IBD and modulation of NLRP3 by sulforaphane (SFN), a compound with multiple pharmacological activities that is extracted from cruciferous plants. To simulate human IBD, we established a mouse colitis model by administering dextran sodium sulfate in the drinking water. SFN (25, 50 mg·kg-1·d-1, ig) or the positive control sulfasalazine (500 mg/kg, ig) was administered to colitis-affected mice for 7 days. Model mice displayed pathological alterations in colon tissue as well as classic symptoms of colitis beyond substantial tissue inflammation. Expression of NLRP3, ASC, and caspase-1 was significantly elevated in the colonic epithelium. The expression of NLRP3 inflammasomes led to activation of downstream proteins and increases in the cytokines IL-18 and IL-1ß. SFN administration either fully or partially reversed these changes, thus restoring IL-18 and IL-1ß, substantially inhibiting NLRP3 activation, and decreasing inflammation. SFN alleviated the inflammation induced by LPS and NLRP3 agonists in RAW264.7 cells by decreasing the levels of reactive oxygen species. In summary, our results revealed the pathological roles of oxidative stress and NLRP3 in colitis, and indicated that SFN might serve as a natural NLRP3 inhibitor, thereby providing a new strategy for alternative colitis treatment.

tRF-33-P4R8YP9LON4VDP inhibits gastric cancer progression via modulating STAT3 signaling pathway in an AGO2-dependent manner.

It has been demonstrated that tRNA-derived small RNAs (tsRNAs) perform essential functions in the pathophysiology of cancer. In this study, we focused on the possible mechanisms of tRF-33-P4R8YP9LON4VDP (tRF-33) underlying the development of gastric malignancy. In total, 454 tissue samples with different gastric mucosal lesions were collected. The tRF-33 expression level in different cohorts was determined, and its value for diagnostic efficiency and prognosis evaluation were assessed. Cell proliferation assays, Transwell assay, flow cytometry, and xenotransplantation model were used to evaluate its effect on gastric cancer cells. The molecular mechanism was verified by fluorescence in situ hybridization, dual luciferase assay, Western blot, and RNA binding protein immunoprecipitation. The results showed that the expression of tRF-33 exhibited a gradual modification from normal control samples to gastritis tissues, early and latent stage of gastric cancer tissues. Consequently, tRF-33 holds significant potential as a predictive and diagnostic biomarker for gastric malignancy. Over-expression of tRF-33 inhibited gastric cancer cell progression and metastatic viability, and induced cell apoptosis. Tumorigenicity in nude mice showed the suppressive characteristics of tRF-33. Mechanistic investigation revealed that tRF-33 exerted silencing on STAT3 mRNA via binding to AGO2. In conclusion, tRF-33 exhibited values in diagnosing gastric cancer and evaluating its prognosis, and suppressed tumor cell viability by inhibiting STAT3 signaling pathway. The schematic mechanisms underlying tRF-33 regulating gastric cancer occurrence. tRF-33 binds to AGO2 proteins and then negatively regulates STAT3 expression through targeting its 3'UTR. The downregulated expression of STAT3 results in the decrease of STAT3 and p-STAT3 and further blocks the transcription of the downstream genes and finally inhibits the gastric cancer occurrence. MMP-9, matrix metalloproteinase-9; Bcl-2, B-cell lymphoma-2; STAT3, signal transducer and activator of transcription 3; UTR, untranslated region.

T7 peptide-mediated co-delivery platform overcoming multidrug-resistant breast cancer: In vitro and in vivo evaluation.

P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration based on P-gp-associated mechanism leads to severe toxic side effects. Here, we designed a T7 peptide-modified mixed liposome (T7-MLP@DTX/SchB) that, by active targeting co-delivering chemotherapeutic agents and P-gp inhibitors, harnessed synergistic effects to improve the treatment of MDR breast cancer. This study established drug-resistant cell models and animal models. Subsequently, comprehensive evaluations involving cell uptake, cell apoptosis, cellular toxicity assays, in vivo tumor-targeting capability, and anti-tumor activity assays were conducted to assess the drug resistance reversal effects of T7-MLP@DTX/SchB. Additionally, a systematic assessment of the biosafety profile of T7-MLP@DTX/SchB was executed, including blood profiles, biochemical markers, and histopathological examination. It was found that this co-delivery strategy successfully exerted the synergistic effects, since there was a significant tumor growth inhibitory effect on multidrug-resistant breast cancer. Targeted modification with T7 peptide enhanced the therapeutic efficacy remarkably, while vastly ameliorating the biocompatibility compared to free drugs. The intriguing results supported the promising potential use of T7-MLP@DTX/SchB in overcoming MDR breast cancer treatment.

Non-peptidic inhibitors targeting SARS-CoV-2 main protease: A review.

The COVID-19 pandemic continues to pose a threat to global health, and sounds the alarm for research & development of effective anti-coronavirus drugs, which are crucial for the patients and urgently needed for the current epidemic and future crisis. The main protease (Mpro) stands as an essential enzyme in the maturation process of SARS-CoV-2, playing an irreplaceable role in regulating viral RNA replication and transcription. It has emerged as an ideal target for developing antiviral agents against SARS-CoV-2 due to its high conservation and the absence of homologous proteases in the human body. Among the SARS-CoV-2 Mpro inhibitors, non-peptidic compounds hold promising prospects owing to their excellent antiviral activity and improved metabolic stability. In this review, we offer an overview of research progress concerning non-peptidic SARS-CoV-2 Mpro inhibitors since 2020. The efforts delved into molecular structures, structure-activity relationships (SARs), biological activity, and binding modes of these inhibitors with Mpro. This review aims to provide valuable clues and insights for the development of anti-SARS-CoV-2 agents as well as broad-spectrum coronavirus Mpro inhibitors.

Superb microvascular imaging for evaluating the activity of juvenile localised scleroderma: a preliminary study.

OBJECTIVES: To investigate microvascular changes in juvenile localised scleroderma (JLS) lesions using superb microvascular imaging (SMI) and assess SMI's utility in evaluating disease activity. METHODS: This prospective study enroled 16 children (7 males) with pathologically diagnosed JLS between January 2021 and June 2023. Lesions were assessed using Localised Scleroderma Cutaneous Assessment Tools, including the localised scleroderma skin activity index (LoSAI) and localised scleroderma skin damage index (LoSDI). Lesions with LoSAI scores > 0 were classified as active. The thickness and blood flow of the lesions and healthy skin layers of the contralateral site were evaluated using ultrasound. SMI was used to detect microvascular blood flow in the lesions and healthy skin, and the vascular index (VI) was calculated. The difference in VI between active lesions and healthy skin was correlated with LoSAI and total scores. RESULTS: Of 46 lesions, 23 were active and 23 inactive. The skin thickness of the lesion was 0.094 ± 0.024 cm, and that of the healthy site was 0.108 ± 0.026 cm (p < 0.001). The VI of the active lesions and healthy skin were 7.60 (3.60, 12.80)% and 1.10 (0.50, 2.10)%, respectively (p < 0.001). The VI of the inactive lesions and the healthy skin were 0.85 (0.00, 2.20)% and 1.60 (1.00, 3.10)%, respectively (p = 0.011). VI differences between active lesions and healthy skin positively correlated with the LoSAI clinical score (r = 0.625, p = 0.001) and total score (r = 0.842, p < 0.001). CONCLUSION: SMI can quantitatively detect microvascular blood flow changes in JLS skin, indicating lesion activity and severity. CLINICAL RELEVANCE STATEMENT: SMI is a convenient, non-invasive, technique for detecting active JLS lesions and can provide valuable information to guide treatment options. KEY POINTS: Current grading systems of juvenile localised scleroderma rely on subjective clinical information. Superb Microvascular Imaging identified that vascular indexes between active lesions and healthy skin positively correlated with clinical scores. Superb Microvascular Imaging effectively assesses microvascular blood flow, aiding juvenile localised scleroderma lesion activity evaluation.

Overexpression of AtMYB2 Promotes Tolerance to Salt Stress and Accumulations of Tanshinones and Phenolic Acid in Salvia miltiorrhiza.

Salvia miltiorrhiza is a prized traditional Chinese medicinal plant species. Its red storage roots are primarily used for the treatment of cardiovascular and cerebrovascular diseases. In this study, a transcription factor gene AtMYB2 was cloned and introduced into Salvia miltiorrhiza for ectopic expression. Overexpression of AtMYB2 enhanced salt stress resistance in S. miltiorrhiza, leading to a more resilient phenotype in transgenic plants exposed to high-salinity conditions. Physiological experiments have revealed that overexpression of AtMYB2 can decrease the accumulation of reactive oxygen species (ROS) during salt stress, boost the activity of antioxidant enzymes, and mitigate oxidative damage to cell membranes. In addition, overexpression of AtMYB2 promotes the synthesis of tanshinones and phenolic acids by upregulating the expression of biosynthetic pathway genes, resulting in increased levels of these secondary metabolites. In summary, our findings demonstrate that AtMYB2 not only enhances plant tolerance to salt stress, but also increases the accumulation of secondary metabolites in S. miltiorrhiza. Our study lays a solid foundation for uncovering the molecular mechanisms governed by AtMYB2 and holds significant implications for the molecular breeding of high-quality S. miltiorrhiza varieties.

Boron in the Second Coordination Sphere of Fe Single Atom Boosts the Oxygen Reduction Reaction.

Metal single atoms coordinated with four nitrogen atoms (M1N4) are regarded as tremendously promising catalysts for the electrocatalytic oxygen reduction reaction (ORR). Nevertheless, the strong bond intensity between the metal center and the O atom in oxygen-containing intermediates significantly limits the ORR activity of M1N4. Herein, the catalytically active B atom is successfully introduced into the second coordination sphere of the Fe single atom (Fe1N4-B-C) to realize the alternative binding of B and O atoms and thus facilitate the ORR activity. Compared with the pristine Fe1N4 catalyst, the synthesized Fe1N4-B-C catalyst exhibits improved ORR catalytic capability with a half-wave potential (E1/2) of 0.80 V and a kinetic current density (JK) of 5.32 mA cm-2 in acid electrolyte. Moreover, in an alkaline electrolyte, the Fe1N4-B-C catalyst displays remarkable ORR activity with E1/2 of 0.87 V and JK of 8.94 mA cm-2 at 0.85 V, outperforming commercial Pt/C. Notably, the mechanistic study has revealed that the active center is the B atom in the second coordination shell of the Fe1N4-B-C catalyst, which avoids the direct bonding of Fe-O. The B center has a moderate binding force to the ORR intermediate, which flattens the ORR energy diagram and thereby improves the ORR performance. Therefore, this study offers a novel strategy for tailoring catalytic performance by tuning the active center of single-atom catalyst.

Divergence of 10 satellite repeats in Artemisia (Asteraceae: Anthemideae) based on sequential fluorescence in situ hybridization analysis: evidence for species identification and evolution.

Artemisia is a large genus encompassing about 400 diverse species, many of which have considerable medicinal and ecological value. However, complex morphological information and variation in ploidy level and nuclear DNA content have presented challenges for evolution studies of this genus. Consequently, taxonomic inconsistencies within the genus persist, hindering the utilization of such large plant resources. Researchers have utilized satellite DNAs to aid in chromosome identification, species classification, and evolutionary studies due to their significant sequence and copy number variation between species and close relatives. In the present study, the RepeatExplorer2 pipeline was utilized to identify 10 satellite DNAs from three species (Artemisia annua, Artemisia vulgaris, Artemisia viridisquama), and fluorescence in situ hybridization confirmed their distribution on chromosomes in 24 species, including 19 Artemisia species with 5 outgroup species from Ajania and Chrysanthemum. Signals of satellite DNAs exhibited substantial differences between species. We obtained one genus-specific satellite from the sequences. Additionally, molecular cytogenetic maps were constructed for Artemisia vulgaris, Artemisia leucophylla, and Artemisia viridisquama. One species (Artemisia verbenacea) showed a FISH distribution pattern suggestive of an allotriploid origin. Heteromorphic FISH signals between homologous chromosomes in Artemisia plants were observed at a high level. Additionally, the relative relationships between species were discussed by comparing ideograms. The results of the present study provide new insights into the accurate identification and taxonomy of the Artemisia genus using molecular cytological methods.

Circular RNA CircSLC22A23 Promotes Gastric Cancer Progression by Activating HNRNPU Expression.

BACKGROUND: Circular RNAs (CircRNAs) play essential roles in cancer occurrence as regulatory RNAs. However, circRNA-mediated regulation of gastric cancer (GC) remains poorly understood. AIM: The purpose of this study was to investigate the molecular mechanism of circSLC22A23 (hsa_circ_0075504) underlying GC occurrence. METHODS: CircSLC22A23 levels were first quantified by quantitative real-time reverse transcription-polymerase chain reaction in GC cell lines, 80 paired GC tissues and adjacent normal tissues, and 27 pairs of plasma samples from preoperative and postoperative patients with GC. Then circSLC22A23 was knocked-down with short hairpin RNA to analyze its oncogenic effects on the proliferation, migration, and invasion of GC cells. Finally, circRNA-binding proteins and their downstream target genes were identified by RNA pulldown, mass spectrometry, RNA immunoprecipitation, quantitative real-time reverse transcription-polymerase chain reaction, and Western blot assays. RESULTS: CircSLC22A23 was found to be highly expressed in GC cells, GC tissues, and plasma from GC patients. Knockdown of circSLC22A23 inhibited GC cell proliferation, migration and invasion. RNA pulldown and RNA immunoprecipitation assays verified the interaction between circSLC22A23 and heterogeneous nuclear ribonucleoprotein U (HNRNPU). Knockdown of circSLC22A23 decreased HNRNPU protein levels. Moreover, rescue assays showed that the tumor suppressive effect of circSLC22A23 knockdown was reversed by HNRNPU overexpression. Finally, epidermal growth factor receptor (EGFR) was found to be one of the downstream target genes of HNRNPU that was up regulated by circSLC22A23. CONCLUSION: CircSLC22A23 regulated the transcription of EGFR through activation of HNRNPU in GC cells, suggesting that circSLC22A23 may serve as a potential therapeutic target for the treatment of GC.

The relationship between inflammatory cytokines and in-hospital complications of acute pancreatitis.

OBJECTIVE: Acute necrotic collection (ANC), acute peripancreatic fluid collection (APFC), pleural effusion, and ascites are common early complications of acute pancreatitis. This study aimed to investigate the relationship between 12 serum cytokines and the early complications and severity of acute pancreatitis (AP). METHODS: We retrospectively analyzed the clinical data of 307 patients with AP, and divided them into severe group and mild-to-moderate group according to the revised Atlanta classification. Propensity score matching was used to control for confounding factors. Binary logistic regression analysis was used to explore the relationship between cytokine levels and early complications of AP. RESULTS: Serum levels of interleukin (IL)-1ß, IL-5, IL-6, IL-8, IL-10, IL-17, and tumor necrosis factor-α were significantly higher in the severe acute pancreatitis (SAP) group than in the non-SAP group (p < .05). After adjusting for confounding factors, the upper quartiles of IL-6, IL-8, and IL-10 were associated with an increased risk of ANC compared with those in the lowest quartile (IL-6: quartile 3, odds ratio [OR] = 3.99, 95% confidence interval [CI] = 1.95-8.16; IL-8: quartile 4, OR = 2.47, 95% CI = 1.27-4.84; IL-10: quartile 2, OR = 2.22, 95% CI = 1.09-4.56). APFC was associated with high serum levels of IL-6 (quartile 3, OR = 1.32, 95% CI = 1.02-1.72), pleural effusions were associated with high serum levels of IL-1ß, IL-6, IL-8, and IL-10 (IL-1ß: quartile 4, OR = 2.36, 95% CI = 1.21-4.58; IL-6: quartile 3, OR = 4.67, 95% CI = 2.27-9.61; IL-8: quartile 3, OR = 2.95, 95% CI = 1.51-5.79; IL-10: quartile 4, OR = 3.20, 95% CI = 1.61-6.36), and high serum levels of IL-6 and IL-10 were associated with an increased risk of ascites (IL-6: quartile 3, OR = 3.01, 95% CI = 1.42-6.37; IL-10: quartile 3, OR = 2.57, 95% CI = 1.23-5.37). CONCLUSION: Serum cytokine levels, including IL-1ß, IL-6, IL-8, and IL-10 may be associated with the occurrence of early complications of AP. In daily clinical practice, IL-6 may be the most worthwhile cytokine to be detected.

The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7.

Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3ß, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1ß, IL-6, JAG2, KCNJ2, MALT1, ß-MHC, NF-κB, PCK1, PLCß1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.

Electromyographic biofeedback therapy for improving limb function after stroke: A systematic review and meta-analysis.

BACKGROUND: Upper and lower limb impairment is common after stroke. Electromyographic biofeedback therapy is a non-invasive treatment, and its effectiveness in functional rehabilitation of the limb after stroke still remains uncertain. OBJECTIVE: The objective of this study was to evaluate whether electromyographic biofeedback can improve upper and lower limb dysfunction in stroke patients. METHODS: PubMed, Embase, Cochrane Library, and Physiotherapy Evidence Database (PEDro) were searched from inception to 1st May 2022. Inclusion criteria were randomized controlled clinical trials of electromyographic biofeedback therapy interventions reporting changes in upper and lower limb function in post-stroke patients. Data were extracted by two independent reviewers and pooled in random-effects models using Review manager (RevMan) software. RESULTS: Our analyses included 10 studies enrolling a total of 303 participants. Electromyographic biofeedback therapy can effectively improve limb function after stroke (standardized mean difference [SMD], 0.44; 95% confidence interval [CI], 0.12-0.77; P = 0.008) and in subgroup analyses, the effect sizes of short-term effect (SMD, 0.33; 95% CI, 0.02-0.64; P = 0.04) was significant, but the long-term was not (SMD, 0.61; 95% CI, -0.11-1.33; P = 0.10). In addition, Electromyographic biofeedback therapy can improve the active range of motion of shoulder (SMD, 1.49; 95% CI, 2.22; P<0.0001) and wrist joints (SMD, 0.77; 95% CI, 0.13-1.42; P = 0.02) after stroke. CONCLUSION: In this meta-analysis, electromyographic biofeedback therapy intervention can improve upper and lower limb function in patients with stroke. Short-term (less than one month) improvement after electromyographic biofeedback therapy was supported, while evidence for long-term (more than one month) benefits was lacking. Range of motion in the glenohumeral and wrist joints were improved. Stronger evidence for individualized parameters, such as optimal treatment parameters and intervention period, is needed in the future. SYSTEMATIC REVIEW REGISTRATION: [https://www.crd.york.ac.uk/prospero/display_record.php?recordID=267596], identifier [CRD42022354363].

General Synthesis of High-Entropy Oxide Nanofibers.

The discovery of high-entropy oxides (HEOs) in 2015 has provided a family of potential solid catalysts, due to their tunable components, abundant defects or lattice distorts, excellent thermal stability (ΔG↓ = ΔH - TΔS↑), and so on. When facing the heterogeneous catalysis by HEOs, the micrometer bulky morphology and low surface areas (e.g., <10 m2 g-1) by traditional synthesis methods obstructed their way. In this work, an electrospinning method to fabricate HEO nanofibers with diameters of 50-100 nm was demonstrated. The key point lay in the formation of one-dimensional filamentous precursors, during which the uniform dispersion of five metal species with disordered configuration would help to crystallize into single-phase HEOs at lower temperatures: inverse spinel (Cr0.2Mn0.2Co0.2Ni0.2Fe0.2)3O4 (400 °C), perovskite La(Mn0.2Cu0.2Co0.2Ni0.2Fe0.2)O3 (500 °C), spinel Ni0.2Mg0.2Cu0.2Mn0.2Co0.2)Al2O4 (550 °C), and cubic Ni0.2Mg0.2Cu0.2Zn0.2Co0.2O (750 °C). As a proof-of-concept, (Ni3MoCoZn)Al12O24 nanofiber exhibited good activity (CH4 Conv. > 96%, CO2 Conv. > 99%, H2/CO ≈ 0.98), long-time stability (>100 h) for the dry reforming of methane (DRM) at 700 °C without coke deposition, better than control samples (Ni3MoCoZn)Al12O24-Coprecipitation-700 (CH4 Conv. < 3%, CO2 Conv. < 7%). The reaction mechanism of DRM was studied by in situ infrared spectroscopy, CO2-TPD, and CO2/CH4-TPSR. This electrospinning method provides a synthetic route for HEO nanofibers for target applications.

Effects of a mixture of glycerol monolaurate and cinnamaldehyde supplementation on laying performance, egg quality, and antioxidant status in laying hens.

BACKGROUND: This study aimed to determine the effects of a mixture of glycerol monolaurate and cinnamaldehyde (GCM) supplementation on the laying performance, egg quality, antioxidant capacity, and serum parameters of laying hens. A total of 1120 14-week-old Jingfen-1 strain laying hens with similar performance were randomly allocated to four dietary treatments: control, and GCM groups supplemented with 250, 500, or 1000 mg kg-1 for 12 weeks. RESULTS: Compared with the control group, GCM-supplemented groups significantly reduced (P < 0.05) the rate of unqualified eggs of laying hens aged 17-24 weeks. Supplementation of GCM significantly increased (P < 0.05) yolk color and serum glutathione peroxidase (GSH-Px) activity but decreased (P < 0.05) the hydrogen peroxide (H2 O2 ) content in the serum of laying hens at the age of 20 weeks. Furthermore, groups supplemented with GCM showed a significant increase (P < 0.05) in Haugh unit, yolk color, activities of total superoxide dismutase and GSH-Px, and the glucose content in serum, and a decrease (P < 0.05) in the content of urea nitrogen and H2 O2 and malondialdehyde in serum of laying hens at the age of 24 weeks. 500 mg kg-1 GCM supplementation significantly increased (P < 0.05) the number of large white follicles and 1000 mg kg-1 GCM supplementation decreased the number of large yellow follicles in 28-week-old laying hens. CONCLUSION: These results indicated that GCM supplementation has positive effects on reducing egg loss and improving egg quality in the early laying period of laying hens. © 2023 Society of Chemical Industry.

An updated review of YAP: A promising therapeutic target against cardiac aging?

The transcriptional co-activator Yes-associated protein (YAP) functions as a downstream effector of the Hippo signaling pathway and plays a crucial role in cardiomyocyte survival. In its non-phosphorylated activated state, YAP binds to transcription factors, activating the transcription of downstream target genes. It also regulates cell proliferation and survival by selectively binding to enhancers and activating target genes. However, the upregulation of the Hippo pathway in human heart failure inhibits cardiac regeneration and disrupts astrogenesis, thus preventing the nuclear translocation of YAP. Existing literature indicates that the Hippo/YAP axis contributes to inflammation and fibrosis, potentially playing a role in the development of cardiac, vascular and renal injuries. Moreover, it is a key mediator of myofibroblast differentiation and fibrosis in the infarcted heart. Given these insights, can we harness YAP's regenerative potential in a targeted manner? In this review, we provide a detailed discussion of the Hippo signaling pathway and consolidate concepts for the development and intervention of cardiac anti-aging drugs to leverage YAP signaling as a pivotal target.

Sleep Deprivation Impairs Intestinal Mucosal Barrier by Activating Endoplasmic Reticulum Stress in Goblet Cells.

Sleep deficiency is associated with intestinal inflammatory conditions and is increasingly recognized as a public health concern worldwide. However, the effects of sleep deficiency on intestinal goblet cells (GCs), which play a major role in intestinal barrier formation, remain elusive. Herein, the effects of sleep deprivation on intestinal GCs were determined using a sleep-deprivation mouse model. Sleep deprivation impaired the intestinal mucosal barrier and decreased the expression of tight junction proteins. According to single-cell RNA sequencing and histologic assessments, sleep deprivation significantly reduced GC numbers and mucin protein levels in intestinal tissues. Furthermore, sleep deprivation initiated endoplasmic reticulum stress by activating transcription factor 6 and binding Ig protein. Treatment with melatonin, an endoplasmic reticulum stress regulator, significantly alleviated endoplasmic reticulum stress responses in intestinal GCs. In addition, melatonin increased the villus length, reduced the crypt depth, and restored intestinal barrier function in mice with sleep deprivation. Overall, the findings revealed that sleep deprivation could impair intestinal mucosal barrier integrity and GC function. Targeting endoplasmic reticulum stress could represent an ideal strategy for treating sleep deficiency-induced gastrointestinal disorders.

Identification of a cancer associated fibroblasts-related index to predict prognosis and immune landscape in ovarian cancer.

Cancer-associated fibroblasts (CAFs) play a role in ovarian cancer (OV) evolution, immunosuppression and promotion of drug resistance. Exploring the value of CAFs-related biomarker in OV is of great importance. In the present work, we developed a CAFs-related index (CAFRI) based on an integrated analysis of single-cell and bulk RNA-sequencing and highlighted the value of CAFRI in predicting clinical outcomes in individuals with OV, tumour immune microenvironment (TIME) and response to immune checkpoint inhibitors (ICIs). The GSE151214 cohort was used for cell subpopulation localization and analysis, the TCGA-OV patients as a training set. Moreover, the ICGC-OV, GSE26193, GSE26712 and GSE19829 cohorts were used for the validation of CAFRI. The TIMER 2.0, CIBERSORT and ssGSEA algorithms were used for analysis of TIME characteristics based on the CAFRI. The GSVA, GSEA, GO, KEGG and tumour mutation burden (TMB) analyses were used for mechanistic exploration. Additionally, the IMvigor210 cohort was conducted to validate the predictive value of CAFRI on the efficacy of ICIs. Finally, CAFRI-based antitumour drug sensitivity was analysed. The findings demonstrate that the CAFRI can served as an excellent predictor of prognosis for individuals with OV, as well as identifying patients with different TIME characteristics, differentiating between immune 'hot' and 'cold' tumour populations, and providing new insights into the selection of ICIs and personalised treatment regimens. CAFRI provides new perspectives for the development of novel prognostic and immunotherapy efficacy predictive biomarkers for OV.

A deep learning model adjusting for infant gender, age, height, and weight to determine whether the individual infant suit ultrasound examination of developmental dysplasia of the hip (DDH).

Objective: To examine the correlation between specific indicators and the quality of hip joint ultrasound images in infants and determine whether the individual infant suit ultrasound examination for developmental dysplasia of the hip (DDH). Method: We retrospectively selected infants aged 0-6 months, undergone ultrasound imaging of the left hip joint between September 2021 and March 2022 at Shenzhen Children's Hospital. Using the entropy weighting method, weights were assigned to anatomical structures. Moreover, prospective data was collected from infants aged 5-11 months. The left hip joint was imaged, scored and weighted as before. The correlation between the weighted image quality scores and individual indicators were studied, with the last weighted image quality score used as the dependent variable and the individual indicators used as independent variables. A Long-short term memory (LSTM) model was used to fit the data and evaluate its effectiveness. Finally, The randomly selected images were manually measured and compared to measurements made using artificial intelligence (AI). Results: According to the entropy weight method, the weights of each anatomical structure as follows: bony rim point 0.29, lower iliac limb point 0.41, and glenoid labrum 0.30. The final weighted score for ultrasound image quality is calculated by multiplying each score by its respective weight. Infant gender, age, height, and weight were found to be significantly correlated with the final weighted score of image quality (P < 0.05). The LSTM fitting model had a coefficient of determination (R2) of 0.95. The intra-class correlation coefficient (ICC) for the α and ß angles between manual measurement and AI measurement was 0.98 and 0.93, respectively. Conclusion: The quality of ultrasound images for infants can be influenced by the individual indicators (gender, age, height, and weight). The LSTM model showed good fitting efficiency and can help clinicians select whether the individual infant suit ultrasound examination of DDH.

Simultaneous Promotion of Salt Tolerance and Phenolic Acid Biosynthesis in Salvia miltiorrhiza via Overexpression of Arabidopsis MYB12.

Transcription factors play crucial roles in regulating plant abiotic stress responses and physiological metabolic processes, which can be used for plant molecular breeding. In this study, an R2R3-MYB transcription factor gene, AtMYB12, was isolated from Arabidopsis thaliana and introduced into Salvia miltiorrhiza under the regulation of the CaMV35S promoter. The ectopic expression of AtMYB12 resulted in improved salt tolerance in S. miltiorrhiza; transgenic plants showed a more resistant phenotype under high-salinity conditions. Physiological experiments showed that transgenic plants exhibited higher chlorophyll contents, and decreased electrolyte leakage and O2- and H2O2 accumulation when subjected to salt stress. Moreover, the activity of reactive oxygen species (ROS)-scavenging enzymes was enhanced in S. miltiorrhiza via the overexpression of AtMYB12, and transgenic plants showed higher superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) activities compared with those of the wild type (WT) under salt stress, coupled with lower malondialdehyde (MDA) levels. In addition, the amount of salvianolic acid B was significantly elevated in all AtMYB12 transgenic hair roots and transgenic plants, and qRT-PCR analysis revealed that most genes in the phenolic acid biosynthetic pathway were up-regulated. In conclusion, these results demonstrated that AtMYB12 can significantly improve the resistance of plants to salt stress and promote the biosynthesis of phenolic acids by regulating genes involved in the biosynthetic pathway.