Multimodal evaluation of the effects of low-intensity ultrasound on cerebral blood flow after traumatic brain injury in mice.

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide, and destruction of the cerebrovascular system is a major factor in the cascade of secondary injuries caused by TBI. Laser speckle imaging (LSCI)has high sensitivity in detecting cerebral blood flow. LSCI can visually show that transcranial focused ultrasound stimulation (tFUS) treatment stimulates angiogenesis and increases blood flow. To study the effect of tFUS on promoting angiogenesis in Controlled Cortical impact (CCI) model. tFUS was administered daily for 10 min and for 14 consecutive days after TBI. Cerebral blood flow was measured by LSCI at 1, 3, 7 and 14 days after trauma. Functional outcomes were assessed using LSCI and neurological severity score (NSS). After the last test, Nissl staining and vascular endothelial growth factor (VEGF) were used to assess neuropathology. TBI can cause the destruction of cerebrovascular system. Blood flow was significantly increased in TBI treated with tFUS. LSCI, behavioral and histological findings suggest that tFUS treatment can promote angiogenesis after TBI.

Discovery and Potential Functional Characterization of Long Noncoding RNAs Associated with Familial Acne Inversa with NCSTN Mutation.

BACKGROUND: Long noncoding RNAs (lncRNAs) are associated with many dermatologic diseases. However, little is known about the regulatory function of lncRNAs in familial acne inversa (AI) patients with nicastrin (NCSTN) mutation. OBJECTIVES: The aim of this study was to explore the regulatory function of lncRNAs in familial AI patients with NCSTN mutation. METHODS: The expression profiles of lncRNAs and mRNAs in skin tissues from familial AI patients with NCSTN mutation and healthy individuals were analysed in this study via RNA sequencing (RNA-seq). RESULTS: In total, 359 lncRNAs and 1,863 mRNAs were differentially expressed between the two groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the dysregulated mRNAs targeted by lncRNAs were mainly associated with the immune regulation, Staphylococcus aureus infection and B cell receptor signalling pathways. The lncRNA-miRNA-mRNA coexpression network contained 265 network pairs comprising 55 dysregulated lncRNAs, 11 miRNAs, and 74 mRNAs. Conservation analysis of the differentially expressed lncRNAs between familial AI patients with NCSTN mutation and Ncstn keratinocyte-specific knockout (NcstnΔKC) mice identified 6 lncRNAs with sequence conservation; these lncRNAs may participate in apoptosis, proliferation, and skin barrier function. CONCLUSIONS: These findings provide a direction for exploring the regulatory mechanisms underlying the progression of familial AI patients with NCSTN mutation.

The Analgesic Effect of Ultrasound-guided Erector Spinae Plane Block in Median Sternotomy Cardiac Surgery in Adults: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVES: To assess the analgesic effect of erector spinae plane block in adults undergoing median sternotomy cardiac surgery. DESIGN AND SETTING: The Cochrane, Embase, and PubMed databases from inception to January 2024 were searched. The study has been registered in the International Prospective Register of Systematic Reviews (CRD42023470375). PARTICIPANTS: Eight randomized controlled trials involving 543 patients, comparing with no block or sham block, were included, whether it was a single injection or continuous. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were pain scores and opioid consumption. Erector spinae plane block reduced pain scores immediately after extubation (mean difference [MD], -1.19; 95% confidence interval [CI], -1.67 to -0.71; p for heterogeneity = 0.10), at 6 hours after extubation (MD, -1.96; 95% CI, -2.85 to -1.08; p for heterogeneity < 0.0001), and at 12 hours after extubation (MD, -0.98; 95% CI, -1.55 to -0.40; p for heterogeneity < 0.00001). The decrease in pain scores reached the minimal clinically important difference within 6 hours. Opioid consumption 24 hours after surgery decreased by 35.72 mg of oral morphine equivalents (95% CI, -50.88 to -20.57; p for heterogeneity < 0.0001). Sensitivity analysis confirmed the stability of results. The quality of primary outcomes was rated as very low to moderate. CONCLUSIONS: Erector spinae plane block decreased pain scores within 12 hours after extubation, reached the minimal clinically important difference within 6 hours, and decreased opioid consumption 24 hours after surgery, based on data of very low to moderate quality. However, high-quality randomized controlled trials are necessary to validate these findings.

Exosomes derived from EphB2-overexpressing bone marrow mesenchymal stem cells regulate immune balance and repair barrier function.

BACKGROUND: Disruption of intestinal barrier function and an imbalance in intestinal immunity are crucial for the occurrence and development of ulcerative colitis. Because of their important roles in regulating inflammation and immunity, exosomes (Exos) released from bone marrow mesenchymal stem cells (BMSCs) may be useful for treating ulcerative colitis. The EphB/EphrinB signaling pathway plays a crucial role in the inflammatory process and the development and function of immune cells, and can mediate long-distance intercellular communication through extracellular vesicles. This study was conducted to explore the effects of pre-modified BMSC-Exos expressing EphB2 (EphB2-Exos) on immunoregulation in vitro. METHODS: We transfected a lentivirus vector encoding EphB2 into BMSCs and isolated EphB2-Exos from the culture supernatant. Inflammation and oxidative damage in the human colon adenocarcinoma cell line (Caco-2) were induced by dextran sulfate sodium/hydrogen peroxide. In addition, spleen CD4+ T lymphocytes of rats were sorted in vitro. We conducted a series of experiments to explore the biological functions of EphB2-Exos. RESULTS: EphB2-Exos were successfully isolated and were found to significantly protect the activity, proliferation, and migration of Caco-2 cells that were inhibited by dextran sulfate sodium. EphB2-Exos alleviated inflammation and apoptosis and increased the activity of antioxidant enzymes while inhibiting oxidative stress in Caco-2 cells. EphB2-Exos restored intestinal barrier function by inhibiting the RhoA/ROCK pathway and regulated the polarization of CD4+T cells. CONCLUSION: EphB2-Exos enhanced intestinal barrier function and regulated the immune balance by inhibiting the RhoA/ROCK pathway in vitro. These findings suggest that EphB2-Exos can be applied as a cell-free therapy for ulcerative colitis.

Effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potentials in rats with global cerebral ischemia-reperfusion injury.

OBJECTIVE: To explore the effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potential in rats with global cerebral ischemia-reperfusion injury. METHODS: A total of 75 SPF Sprague-Dawley male rats were randomly divided into sham group (n=20), model group (n=20), pramipexole administration group (n=35). The rat model of global cerebral ischemia-reperfusion injury was prepared by the modified Pulsinelli's four-vessel occlusion method. Pramipexole administration group was administered intraperitoneally in rats with global cerebral ischemia-reperfusion injury at different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, once a day for 14 consecutive days. Based on the results of modified neurological severity scores, open field test and morphology by Nissl's staining to determine the optimal dose of pramipexole. Mitochondrial membrane potential in the optimal dose of pramipexole administration group were measured by the JC-1 fluorescent probe staining method. RESULTS: 1. Different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg, were used as drug administration in rats with global cerebral ischemia-reperfusion injury for 14 consecutive days, and we found that all four doses of pramipexole could improve the modified neurological severity scores of rats with global cerebral ischemia-reperfusion injury to varying degrees, but only 0.5 mg/kg pramipexole at 1, 3, 7 and 14 days consistently reduced modified neurological severity scores and improved neurological function in rats with global cerebral ischemia-reperfusion injury. In the open-field test, only 0.5 mg/kg pramipexole increased the number of entries into the central zone, duration spent in the central zone, total distance travelled in the open field and average velocity, which improved the spontaneous activities and reduced anxiety and depression of rats with global cerebral ischemia-reperfusion injury. 2. Different doses of pramipexole 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg for 14 consecutive days significantly increased the number of surviving neurons in the hippocampal CA1 subfield in rats with global cerebral ischemia-reperfusion injury to varying degrees. Based on these results, we tentatively found that 0.5 mg/kg pramipexole may be the optimal dose in all of the above. 3. We found that 0.5 mg/kg pramipexole significantly increased the mitochondrial membrane potential in rats after global cerebral ischemia-reperfusion injury. CONCLUSION: Different doses of dopamine receptor agonist pramipexole improved neurological function of rats with global cerebral ischemia-reperfusion injury to varying degrees, and 0.5 mg/kg pramipexole may be the optimal dose in all of the above. Pramipexole may produce neuroprotective effects by protecting neurons in the hippocampus and improving the mitochondrial membrane potential after global cerebral ischemia-reperfusion injury.

Optical and Photocatalytic Properties of Cobalt-Doped LuFeO3 Powders Prepared by Oxalic Acid Assistance.

B-site cobalt (Co)-doped rare-earth orthoferrites ReFeO3 have shown considerable enhancement in physical properties compared to their parent counterparts, and Co-doped LuFeO3 has rarely been reported. In this work, LuFe1-xCoxO3 (x = 0, 0.05, 0.1, 0.15) powders have been successfully prepared by a mechanochemical activation-assisted solid-state reaction (MAS) method at 1100 °C for 2 h. X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy studies demonstrated that a shrinkage in lattice parameters emerges when B-site Fe ions are substituted by Co ions. The morphology and elemental distribution were investigated by scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). The UV-visible absorbance spectra show that LuFe0.85Co0.15O3 powders have a narrower bandgap (1.75 eV) and higher absorbance than those of LuFeO3 (2.06 eV), obviously improving the light utilization efficiency. Additionally, LuFe0.85Co0.15O3 powders represent a higher photocatalytic capacity than LuFeO3 powders and can almost completely degrade MO in 5.5 h with the assistance of oxalic acid under visible irradiation. We believe that the present study will promote the application of orthorhombic LuFeO3 in photocatalysis.

Identification and expression analysis of BURP domain-containing genes in jujube and their involvement in low temperature and drought response.

BACKGROUND: Plant-specific BURP domain-containing genes are involved in plant development and stress responses. However, the role of BURP family in jujube (Ziziphus jujuba Mill.) has not been investigated. RESULTS: In this study, 17 BURP genes belonging to four subfamilies were identified in jujube based on homology analysis, gene structures, and conserved motif confirmation. Gene duplication analysis indicated both tandem duplication and segmental duplication had contributed to ZjBURP expansion. The ZjBURPs were extensively expressed in flowers, young fruits, and jujube leaves. Transcriptomic data and qRT-PCR analysis further revealed that ZjBURPs also significantly influence fruit development, and most genes could be induced by low temperature, salinity, and drought stresses. Notably, several BURP genes significantly altered expression in response to low temperature (ZjPG1) and drought stresses (ZjBNM7, ZjBNM8, and ZjBNM9). CONCLUSIONS: These results provided insights into the possible roles of ZjBURPs in jujube development and stress response. These findings would help selecting candidate ZjBURP genes for cold- and drought-tolerant jujube breeding.

Tfcancer: a manually curated database of transcription factors associated with human cancers.

SUMMARY: Transcription factors (TFs) are critical regulation elements and its dysregulation can lead to a variety of cancers. However, currently, there are no such online resources for large-scale collection, storage and analysis of TF-cancer associations in those cancers. To fill this gap, we present a database called TFcancer (http://lcbb.swjtu.edu.cn/tfcancer/), which contains 3136 experimentally supported associations between 364 TFs and 33 TCGA cancers by manually curating more than 1800 literature. TFcancer mainly concentrates on four aspects: TF expression, molecular alteration, regulatory relationships between TFs and target genes, and biological processes and signaling pathways of TFs in cancers. TFcancer not only provides a user-friendly interface for browsing and searching but also allows flexible data downloading and user data submitting. It is believed that TFcancer is a helpful and valuable resource for researchers who seek to understand the functions and molecular mechanisms of TFs involved in human cancers. AVAILABILITY AND IMPLEMENTATION: The TFcancer are freely available at http://lcbb.swjtu.edu.cn/tfcancer/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Effect of Dexmedetomidine on Tachyarrhythmias After Cardiac Surgery: A Systematic Review and Meta-Analysis.

ABSTRACT: Tachyarrhythmias after cardiac surgery is a common occurrence in clinical practice, which can be life threatening. We searched 6 databases, including Embase, PubMed, Cochrane, CNKI, Wanfang, and Sinomed, to evaluate the effect of dexmedetomidine on tachyarrhythmias after adult cardiac surgery. The primary end point was the number of patients with atrial fibrillation (AF) after cardiac surgery. The secondary end points included the number of patients with supraventricular tachycardia or with ventricular tachycardia or with ventricular fibrillation or with myocardial infarction or deceased patients, the duration of mechanical ventilation, the intensive care unit stay, hospital stay, and the number of patients with bradycardia and those with hypotension. Among the 1388 retrieved studies, 18 studies (n = 3171 participants) met our inclusion criteria. Dexmedetomidine reduced the incidence of AF by 17% [relative risk (RR) = 0.83; 95% confidence interval (CI), 0.73-0.93; P = 0.002]. Through subgroup analysis, we found that when the maintenance dose of dexmedetomidine was >0.7 µg·kg-1·h-1, the effect of preventing AF was obvious (RR = 0.58; 95%CI 0.43-0.78; P = 0.0003). Dexmedetomidine also reduced the incidence of supraventricular tachycardia by approximately 70% (RR = 0.29; 95% CI, 0.11-0.77; P = 0.01) and the incidence of ventricular tachycardia by approximately 80% (RR = 0.23; 95% CI, 0.08-0.63; P = 0.004) but had no effect on ventricular fibrillation (RR = 1.02; 95% CI, 0.14-7.31; P = 0.99). The major side effect of dexmedetomidine was bradycardia. Dexmedetomidine can reduce the incidence of AF (especially high dosages), supraventricular tachycardia, and ventricular tachycardia after cardiac surgery in adults, but it does not affect the occurrence of ventricular fibrillation.

CX3CR1 deficiency aggravates brain white matter injury and affects expression of the CD36/15LO/NR4A1 signal.

OBJECTIVE: To study the effects of CX3CR1 on white matter injury, neurofunction, recognition, and expression of the CD36/15LO/NR4A1 signal in mice with traumatic brain injury (TBI). METHODS: CX3CR1GFP/GFP, CX3CR1GFP/+ and C57BL/6 male mice were randomly divided into 3 groups. We used a controlled cortical impact (CCI) to establish a TBI model and T2wt MRI to detect the TBI lesion. FA and DTI allowed for quantitative evaluation of the structural integrity of white matter tracts. Several behavior tests were used to investigate nerve function; a computer-based tracing system was used to trace and analyze dendrites and cell bodies of microglia and astrocytes in the peri-lesional brain areas. We also used RT-PCR and western blot to detect the effect of CX3CL1/CX3CR1 axis on CD36/15LO/NR4A1 signal. RESULTS: The fractional anisotropy (FA) at the corpus callosum area of brain was decreased at 3 days post TBI, the average lesion volume CX3CR1GFP/GFP group was increased, and the neurologic deficit scores of mice of Cx3Cr1GFP/+ and wild-type groups were significantly increased compared to Cx3Cr1GFP/GFP group mice. In the Corner turn test, TBI induced impairments in forelimb function that were more severe than Cx3Cr11GFP/+ and wild-type TBI mice. We operated the Y-maze at 3 days post-TBI and the NOR test at 28 days after TBI. There was a significant TBI effect induced in decreased percentage entries into the novel arm in Cx3Cr1GFP/+ and wild-type TBI mice, compared with Cx3Cr1GFP/GFP; Cx3Cr1GFP/+. Wild-type mice showed decreased exploration time in new objects compared with Cx3Cr1GFP/GFP. Those two behavior tests demonstrated that Cx3Cr1 knock-out increased the damage caused by TBI to memory. In the tail suspension and force swimming tests, there was no significant difference between those three groups. CD36 increased in Cx3Cr1GFP/GFP compared with the other three groups at 3 days after TBI. TBI inhibited the expression of NR4A1 at 3 d after damage. Cx3Cr1 deficiency can induce high expression of 15LO, this was unaffected by TBI. CONCLUSION: CX3CR1 deletion can enhance white matter injury. It increased the expression of CD36 and 15LO and increased expression of NR4A1. The lack of CX3CR1 can affect the recovery of nerve function.

Effects of circadian rhythm disorder on the hippocampus of SHR and WKY rats.

The present study investigated the effects of circadian rhythm disorder (CRD) on the hippocampus of SHR and WKY rats. Male SHR rats (n = 27) and WKY rats (n = 27) were randomly divided into six groups: SHR and WKY normal (N)CR, SHR and WKY CRD 16/8 (CRD16/8), and SHR and WKY CRD 12/12 (CRD12/12). Activity patterns were adjusted using different photoperiods over 90 days and any changes were recorded. Rats were tested in the Morris water maze and in a novel object recognition experiment; serologic analysis, magnetic resonance imaging (diffusion tensor imaging + arterial spin labeling), hippocampal Nissl staining, Fluoro-Jade B staining, and immunohistochemistry were also performed. The results showed that both types of inverted photoperiod reduced CR amplitude and prolonged the circadian period. CRD and hypertension reduced memory performance and novel object recognition and preference. The decreases in memory and preference indices were greater in rats in the CRD12/12 group compared to the CRD16/8 group. CRD and hypertension decreased fractional anisotropy values, the number of neurons and astrocytes in the hippocampus, and the expression of brain-derived neurotrophic factor and synapsin 1; it also enhanced the degeneration of neurons and microglia and reduced blood flow in the hippocampus, and increased nuclear factor κB, caspase, neuron-specific enolase, and interleukin-6 levels. These findings reveal a biological basis for the link between CRD and cognitive decline, which has implications for CRD caused by shift work and other factors.

Influence of (ATP)-Binding Cassette Transporter Subfamily B Member 1 (ABCB1) Gene Polymorphism on the Efficacy of Remifentanil.

BACKGROUND The aim of this study was to investigate the influence of adenosine triphosphate (ATP)-binding cassette transporter subfamily B member 1 (ABCB1) gene polymorphism on the efficacy of Remifentanil. MATERIAL AND METHODS A total of 276 patients undergoing elective surgeries were included to collect general clinical information and detect the polymorphism of ABCB1 rs1045642 using the TaqMan-MGB probe, and they were divided into 3 groups - a genotype AA group, a genotype AG group, and a genotype GG group - based on different genotypes of ABCB1 rs1045642. RESULTS The comparisons showed that there were no differences in sex, age, body mass index (BMI), smoking, drinking status, or ASA class among the 3 groups (P˃0.05). The genotype GG group had higher consumption of Remifentanil than the genotype AA group (P˂0.05), but the genotype AG group was not different from the genotype AA and GG groups (P˃0.05). Comparison of the surgery duration revealed no difference among the 3 groups (P˃0.05). The analepsia time, autonomous respiratory recovery time, and orientation recovery time in the genotype GG group were longer than in the genotype AA group (P˂0.05), but the genotype AG group was not different from the genotype AA and GG groups (P˃0.05). There were no differences in adverse reactions among the 3 groups (P˃0.05). CONCLUSIONS ABCB1 gene polymorphism can affect the clinical efficacy of Remifentanil.

A Weld Position Recognition Method Based on Directional and Structured Light Information Fusion in Multi-Layer/Multi-Pass Welding.

Multi-layer/multi-pass welding (MLMPW) technology is widely used in the energy industry to join thick components. During automatic welding using robots or other actuators, it is very important to recognize the actual weld pass position using visual methods, which can then be used not only to perform reasonable path planning for actuators, but also to correct any deviations between the welding torch and the weld pass position in real time. However, due to the small geometrical differences between adjacent weld passes, existing weld position recognition technologies such as structured light methods are not suitable for weld position detection in MLMPW. This paper proposes a novel method for weld position detection, which fuses various kinds of information in MLMPW. First, a synchronous acquisition method is developed to obtain various kinds of visual information when directional light and structured light sources are on, respectively. Then, interferences are eliminated by fusing adjacent images. Finally, the information from directional and structured light images is fused to obtain the 3D positions of the weld passes. Experiment results show that each process can be done in 30 ms and the deviation is less than 0.6 mm. The proposed method can be used for automatic path planning and seam tracking in the robotic MLMPW process as well as electron beam freeform fabrication process.

Using functional and molecular MRI techniques to detect neuroinflammation and neuroprotection after traumatic brain injury.

This study was designed to investigate whether functional and molecular MRI techniques are sensitive biomarkers for assessment of neuroinflammation and drug efficacy after traumatic brain injury (TBI) in rats. We subjected rats to a controlled cortical impact model and used behavioral tests, histology, and immunofluorescence to assess whether flavonoid pinocembrin provides cerebral protection and improves functional recovery. Most importantly, we used multiple noninvasive structural, functional, and molecular MRI techniques to examine whether the pinocembrin-related neuroprotection and attenuation of neuroinflammation can be detected in vivo. Significant increases in cerebral blood flow (CBF) and amide proton transfer-weighted (APTw) MRI signals were observed in the perilesional areas in untreated TBI rats at 3days and could be attributed to increased glial response. In addition, increased apparent diffusion coefficient and decreased magnetization transfer ratio signals in untreated TBI rats over time were likely due to edema. Post-treatment with pinocembrin decreased microglial/macrophage activation at 3days, consistent with the recovery of CBF and APTw MRI signals in regions of secondary injury. These findings suggest that pinocembrin provides cerebral protection for TBI and that multiple MRI signals, CBF and APTw in particular, are sensitive biomarkers for identification and assessment of neuroinflammation and drug efficacy in the TBI model.

An ultra high performance liquid chromatography with tandem mass spectrometry method for plasma and cerebrospinal fluid pharmacokinetics of rhein in patients with traumatic brain injury after administration of rhubarb decoction.

Damage of blood-brain barrier is a common result of traumatic brain injury. This damage can open the blood-brain barrier and allow drug passage. An ultraperformance liquid chromatography with tandem mass spectrometry method was established to determine the concentration of rhein in the biofluids (plasma and cerebrospinal fluid) of patients with a compromised blood-brain barrier following traumatic brain injury after rhubarb administration. Furthermore, the pharmacokinetic profiles were analyzed. A triple-quadruple tandem mass spectrometer with electrospray ionization was used for rhein detection. The mass transition followed was m/z 283.06→239.0. The calibration curve was linear in the concentration range of 10-8000 ng/mL for the biofluids. The intra- and interday precisions were less than 10%. The relative standard deviation of recovery was less than 15% in biological matrices. The pharmacokinetic data showed that rhein was rapidly transported into biofluids, and exhibited a peak concentration 1 h after rhubarb administration. The elimination rate of rhein was slow. The AUCcerebrospinal fluid /AUCplasma (AUC is area under curve) of rhein was approximately 17%, indicating that portions of rhein could pass the impaired blood-brain barrier. The method was successfully applied to quantify rhein in the biofluids of all patients. The data presented can help to guide clinical applications of rhubarb for treating traumatic brain injury.

[Chemical constituents and cytotoxicity assay research in small polar substances from Vitis thunbergii var. taiwaniana].

This article studied the chemical constituents from the aerial part of Vitis thunbergii var. taiwaniana. The 60% ethanol extract was eluted with 95% ethanol though HP-20 macroporous adsorption resin column. 12 compounds, including (1) betulinic acid, (2)2, 2, 2'-bis (4-hydroxyphenyl) propane bis (2, 3-epoxypropyl) ether, (3) eriodictyol, (4) trans-ε-viniferin, (5) (+)-cis-ε-viniferin, (6) kobophenol A, (7) ampelopsin A, (8) nepalensinol B, (9) cis-miyabenol C, (10) cis-vitisin B, (11) cis-gnetin H and (12) (+)-hopeaphenol, were separated by using normal phase silica gel, ODS, Sephdadex LH-20 column chromatographies and semi-preparative or preparative HPLC. Compounds 2, 5, 6, 8, 9, 10, 11 were separated from the genus Vitis for the first time and compounds 3, 7, 12 were separated from Vitis thunbergii var. taiwaniana for the first time. At a concentration of 50 µmol · L(-1), compound 6, 7 and 11 showed strong cytotoxicity against MCF-7 cell lines with the inhibition rate of 66.58%, 57.16%, 52.84%, respectively.

miR-25-5p in exosomes derived from UVB-induced fibroblasts regulates melanogenesis via TSC2-dominated cellular organelle dysfunction.

BACKGROUND: Few reports have confirmed whether exosomes derived from fibroblasts can regulate the process of melanogenesis. We wondered whether exosomes derived from fibroblasts could have a potent regulatory effect on melanogenesis and explored the underlying mechanisms. OBJECTIVE: This study aimed to find the role of fibroblasts in melanocytes and revealed the related mechanisms. METHODS: RT-qPCR, Western blot analysis were conducted to measure the RNA and protein expression level of various related genes. miRNA sequencing, mass spectrum analysis and subsequent bioinformatics analysis were employed to find the underlying targets. Zebrafish were employed to measure the melanin synthesis related process in vivo. Furthermore, electron microscopy, ROS measurement and dual-luciferase reporter assay were adopted to investigate the relationship between these processes. RESULTS: We found that exosomes derived from human primary dermal fibroblasts were internalized by human primary melanocytes and MNT1 cells and that the melanin content and the expression of melanin synthesis-related proteins TYR and MITF was inhibited by exosomes derived from UVB-induced human primary dermal fibroblasts. The miRNA expression profile in secreted exosomes changed significantly, with miR-25-5p identified as capable of regulating TSC2 expression via the CDS region. The miR-25-5p-TSC2 axis could affect the melanin content through subsequent cellular organelle dysfunction, such as mitochondrial dysfunction, endoplasmic reticulum stress and dysregulation of lysosomal cysteine proteases. CONCLUSION: We unveiled a novel regulatory role of fibroblasts in melanocytes, facilitated by the secretion of exosomes. miR-25-5p within exosomes plays a pivotal role in regulating melanogenesis via TSC2-induced cellular organelle dysfunction.

Adaptive class augmented prototype network for few-shot relation extraction.

Relation extraction is one of the most essential tasks of knowledge construction, but it depends on a large amount of annotated data corpus. Few-shot relation extraction is proposed as a new paradigm, which is designed to learn new relationships between entities with merely a small number of annotated instances, effectively mitigating the cost of large-scale annotation and long-tail problems. To generalize to novel classes not included in the training set, existing approaches mainly focus on tuning pre-trained language models with relation instructions and developing class prototypes based on metric learning to extract relations. However, the learned representations are extremely sensitive to discrepancies in intra-class and inter-class relationships and hard to adaptively classify the relations due to biased class features and spurious correlations, such as similar relation classes having closer inter-class prototype representation. In this paper, we introduce an adaptive class augmented prototype network with instance-level and representation-level augmented mechanisms to strengthen the representation space. Specifically, we design the adaptive class augmentation mechanism to expand the representation of classes in instance-level augmentation, and class augmented representation learning with Bernoulli perturbation context attention to enhance the representation of class features in representation-level augmentation and explore adaptive debiased contrastive learning to train the model. Experimental results have been demonstrated on FewRel and NYT-25 under various few-shot settings, and the proposed model has improved accuracy and generalization, especially for cross-domain and different hard tasks.

Infliximab inhibits TNF-α-dependent activation of the NLRP3/IL-1ß pathway in acne inversa.

Background: Acne inversa (AI) is a refractory inflammatory skin disease, and TNF-α plays an important role in the pathogenesis of AI. By blocking TNF-α, infliximab (IFX) has been proven to be a promising method. Objectives: To explore the underlying mechanisms of IFX treatment in AI patients. Methods: In this research, we integrated transcriptome sequencing data from the samples of our patients with AI and the GEO database. Ex vivo skin culture of AI patients was conducted to evaluate the efficacy of IFX treatment. Animal studies and cell experiments were used to explore the therapeutic effect and mechanism of IFX treatment. Results: Both TNF-α and NLRP3 inflammasome-related pathways were enriched in skin lesions of AI patients and murine AI models. After IFX treatment, the NLRP3 inflammasome-related pathway was effectively blocked, and the IL-1ß level was normalized in ex vivo AI skin explants and murine AI models. Mechanistically, IFX suppressed the NF-κB signaling pathway to lower the expression of NLRP3 and IL-1ß in keratinocytes. Conclusions: IFX treatment alleviated skin lesions in murine AI models and downregulated NLRP3 and IL-1ß expression levels by inhibiting the NF-κB signaling pathway, which was helpful for understanding the mechanism of IFX therapy.

Tanshinone I improves TNBC chemosensitivity by suppressing late-phase autophagy through AKT/p38 MAPK signaling pathway.

The inhibition of autophagy is a potential therapeutic strategy to improve the chemosensitivity of triple-negative breast cancer (TNBC). In this study, we demonstrated that a natural terpenoid tanshinone I (TAN) enhanced the effectiveness of paclitaxel (PTX), at least in part, through an autophagy-dependent mechanism against TNBC. In vitro validation demonstrated that the combined therapy resulted in a synergistic decrease in the growth of TNBC cells. The chemosensitizing impact of TAN might be attributed to its inhibition of PTX-induced autophagy in the late phase by obstructing the fusion of autophagosomes and lysosomes, rather than by inhibiting lysosomal function. The findings from KEGG pathway analysis and molecular docking suggested that TAN might impact breast cancer chemoresistance primarily through the PI3K-Akt and MAPK signaling pathways. The non-canonical AKT/p38 MAPK signaling was further validated as the primary mechanism responsible for the inhibition of autophagy by TAN. In vivo study showed that the combined administration of TAN and PTX demonstrated a more significant suppression of tumor growth and autophagic activity compared to PTX monotherapy in the MDA-MB-231 xenograft nude mouse model. The safety evaluation of TAN in a zebrafish model, along with in vitro and in vivo validation, provided experimental and pre-clinical data supporting its potential as a natural adjunctive therapy in TNBC. Overall, this study suggests that the combination of TAN with PTX could provide an effective treatment option for advanced breast cancer, and targeting the AKT/p38 MAPK/late-autophagy signaling axis may be a promising approach for developing therapeutic interventions against TNBC.