CD4+CD8αα+ is the dominant phenotype of intraepithelial lymphocytes and regulated by ThPOK and Runx3 in Oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a common T cell-mediated oral mucosal immune inflammatory disease. Intraepithelial lymphocytes (IELs) are a unique subset of T cells that play an important role in regulating immune response. This study aims to investigate the phenotype and the differentiation mechanism of IELs in OLP. METHODS: The expression of CD4, CD8α, CD8ß, T-helper-inducing POZ/Krueppel-like factor (ThPOK), and RUNX family transcription factor 3 (Runx3) in the epithelium and peripheral blood mononuclear cells (PBMCs) of OLP was determined by immunofluorescence and immunohistochemistry. Then, the correlations among them were analyzed. Naïve CD4+ T cells were sorted from blood of OLP patients and stimulated with retinoic acid (RA) and transforming growth factor-ß1 (TGF-ß1). Then the expression of CD4, CD8α, CD8ß, ThPOK, and Runx3 was investigated by immunocytochemistry. RESULTS: CD8α expression and CD8αα+ cells were upregulated in the epithelium of OLP, whereas they were downregulated in PBMCs of OLP. CD8ß was not expressed in the epithelium of OLP. CD4, CD8α, and Runx3 expression and CD4+CD8α+ cells were increased, whereas ThPOK expression was decreased in the epithelium of OLP. CD8α expression was positively correlated with Runx3 expression, whereas ThPOK expression was negatively correlated with Runx3 expression. After RA and TGF-ß1 stimulation, CD8α and Runx3 expression was upregulated, and ThPOK expression was downregulated in naïve CD4+ T cells. CONCLUSION: CD4+CD8αα+ IELs may be the dominant phenotype of IELs in OLP, and the differentiation of CD4+CD8αα+ IELs in OLP is negatively regulated by ThPOK and positively regulated by Runx3.

MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis.

Posttraumatic osteoarthritis (PTOA) patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective. Early PTOA is characterized by overexpressed matrix metalloprotease 13 (MMP13). Herein, we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable, cyanine 5 (Cy5)-containing PEG, black hole quencher-3 (BHQ3), and cRGD ligands and loaded with siRNA silencing MMP13 (siM13), namely ERMs@siM13. ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell, causing cRGD exposure. Accordingly, the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surface αvß3 integrin, increasing intracellular siM13 delivery for on-demand MMP13 downregulation. Meanwhile, the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle, precisely reflecting the diseased cartilage state. In particular, the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity, enabling the physicians to adjust the therapeutic regimen. Finally, in the murine PTOA model, ERMs@siM13 could diagnose the early-stage PTOA, perform timely interventions, and monitor the OA progression level during treatment through a real-time detection of MMP13. Therefore, ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.

SiATG5-loaded cancer cell membrane-fused liposomes induced increased uptake of albumin-bound chemotherapeutics by pancreatic cancer cells.

Chemotherapeutic efficacy for pancreatic cancer is severely compromised by limited drug availability to tumor cells. Herein, we constructed a cancer cell membrane-fused liposome containing a siATG5-loaded calcium phosphate (CaP) core, termed CLip@siATG5. Through cancer cell membrane camouflage, the liposomes evaded immune clearance, actively infiltrated tumor tissues, and were preferentially taken up by homotypic tumor cells. Then, siATG5 escaped from the endosomes and was liberated in the cytoplasm, mainly benefiting from CaP dissolution-induced endosome rupture and liposome disassembly in acidic endosomes. The released siATG5 silenced autophagy protein 5 (ATG5) to inhibit autophagy, starving tumor cells. An alternative nutrient procurement pathway, macropinocytosis, was then upregulated in the cells, leading to increased uptake of the albumin-bound chemotherapeutic agent (nanoparticle albumin-bound paclitaxel (Nab-PTX)). Finally, in a murine pancreatic cancer model, CLip@siATG5 combined with Nab-PTX exerted superior efficacy to a twofold dose of Nab-PTX while avoiding its toxicity. Overall, we justified enhancing chemotherapeutic delivery by modulating the pancreatic cancer cell metabolism, which will enlighten the development of more effective chemotherapeutic adjuvants for pancreatic cancer in the future.

Chitinase-3 like-protein-1, matrix metalloproteinase -9 and positive intracranial arterial remodelling.

Introduction: Positive intracranial arterial remodelling is a dilated lesion of the large intracranial vessels; however, its pathogenesis is currently unknown. Some studies have identified chitinase-3 like-protein-1 (YKL-40) and matrix metalloproteinase (MMP)-9 as circulating inflammatory factors involved in positive vascular remodelling. Herein, we aimed to investigate the relationship between changes in serum YKL-40 and MMP-9 levels and positive intracranial arterial remodelling in patients with cerebral small vessel disease (CSVD). Methods: A total of 110 patients with CSVD were selected. Patients with brain arterial remodelling (BAR) scores >1 times the standard deviation were defined as the positive intracranial artery remodelling group (n = 21 cases), and those with BAR scores ≤1 times the standard deviation were defined as the non-positive intracranial artery remodelling group (n = 89 cases). Serum YKL-40 and MMP-9 levels were measured using an enzyme-linked immunosorbent assay kit. Factors influencing positive intracranial artery remodelling using binary logistic regression analysis and predictive value of YKL-40 and MMP-9 for positive intracranial arterial remodelling in patients with CSVD were assessed by a subject receiver operating characteristic curve. Results: Statistically significant differences in serum YKL-40 and MMP-9 levels were observed between the positive and non-positive remodelling groups (p < 0.05). The integrated indicator (OR = 9.410, 95% CI: 3.156 ~ 28.054, P<0.01) of YKL-40 and MMP-9 levels were independent risk factors for positive intracranial arterial remodelling. The integrated indicator (OR = 3.763, 95% CI: 1.884 ~ 7.517, p < 0.01) of YKL-40 and MMP-9 were independent risk factors for positive arterial remodelling in posterior circulation, but were not significantly associated with positive arterial remodelling in anterior circulation (p > 0.05). The area under the curve for YKL-40 and MMP-9 diagnostic positive remodelling was 0.778 (95% CI: 0.692-0.865, p < 0.01) and 0.736 (95% CI: 0.636-0.837, p < 0.01), respectively. Discussion: Elevated serum YKL-40 and MMP-9 levels are independent risk factors for positive intracranial arterial remodelling in patients with CSVD and may predict the presence of positive intracranial arterial remodelling, providing new ideas for the mechanism of its occurrence and development and the direction of treatment.

Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression.

Abnormal subchondral bone remodeling featured by overactivated osteoclastogenesis leads to articular cartilage degeneration and osteoarthritis (OA) progression, but the mechanism is unclear. We used lymphocyte cytosolic protein 1 (Lcp1) knockout mice to suppress subchondral osteoclasts in a mice OA model with anterior cruciate ligament transection (ACLT), and Lcp1-/- mice showed decreased bone remodeling in subchondral bone and retarded cartilage degeneration. For mechanisms, the activated osteoclasts in subchondral bone induced type-H vessels and elevated oxygen concentration, which ubiquitylated hypoxia-inducible factor 1 alpha subunit (HIF-1α) in chondrocytes and led to cartilage degeneration. Lcp1 knockout impeded angiogenesis, which maintained hypoxia environment in joints and delayed the OA progression. Stabilization of HIF-1α delayed cartilage degeneration, and knockdown of Hif1a abolished the protective effects of Lcp1 knockout. Last, we showed that Oroxylin A, an Lcp1-encoded protein l-plastin (LPL) inhibitor, could alleviate OA progression. In conclusion, maintaining hypoxic environment is an attractive strategy for OA treatment.

Intra-articular nanodrug delivery strategies for treating osteoarthritis.

Osteoarthritis (OA) is characterized by progressive cartilage degeneration. Pharmaceutical intervention remains a main treatment approach. However, drug delivery via intra-articular administration (IA) can be restricted by rapid clearance, the dense and highly negatively charged extracellular matrix (ECM) of cartilage, and uneven distribution of diseased chondrocytes. Nanodrug delivery systems, such as liposomes, micelles, and nanoparticles (NPs), have shown great potential to prolong intra-articular residence, penetrate the ECM, and achieve diseased chondrocyte-specific delivery. In this review, we discuss the challenges associated with intra-articular drug delivery in OA and the nanodrug delivery strategies developed to overcome these challenges. It is anticipated that these nanodrug delivery strategies will advance IA of drugs into broader applications in OA treatment.

Relationship between heart rate variability and cognitive function in patients with enlarged perivascular space.

Objective: To explore the relationship between heart rate variability (HRV), the brain distribution of enlarged perivascular space (EPVS), and cognitive impairment in patients with EPVS. Materials and methods: The clinical and imaging data of 199 patients with EPVS were retrospectively analyzed. EPVS load in the basal ganglia (BG) and centrum semiovale (CS) regions were assessed using the Potter's method. Cognitive function was evaluated using the Montreal Cognitive Assessment Scale. A logistic regression model was used to analyze the relationship between HRV, the brain distribution of EPVS and cognitive function in patients with EPVS. A receiver operating characteristic curve was used to assess the predictive value of HRV for cognitive function in patients with EPVS. Results: Of the 199 patients, 27 and 42 presented with severe BG-EPVS and cognitive impairment, respectively. Significant differences were observed in the root mean square of successive differences of normal-normal (NN) intervals for period of interest (rMSSD), the percentage of adjacent NN intervals greater than 50 ms (PNN50), and the ratio of low-frequency power (LF) to high-frequency power (HF) between the mild and severe BG-EPVS groups (P < 0.05). Patients who presented with and without cognitive impairment differed significantly in the standard deviation of NN intervals (SDNN), rMSSD, PNN50, total power, LF, and LF/HF (P < 0.05). rMSSD (odds ratio [OR] 0.871, 95% confidence interval [CI] 0.768-0.988) and LF/HF (OR 3.854, 95% CI 1.196-12.419) were independent influencing factors of BG-EPVS, and rMSSD (OR 0.936, 95% CI 0.898-0.976) was an independent influencing factor of cognitive impairment in patients with EPVS. The optimal cut-off point was 0.312, with an area under the curve of 0.795 (95% CI 0.719-0.872) for predicting cognitive impairment in patients with EPVS by rMSSD. Conclusion: Reduced HRV is involved in the pathophysiological mechanisms of the formation and development of BG-EPVS and is associated with cognitive impairment in patients with EPVS, independent of CS-EPVS. For patients with HRV changes but without autonomic nervous system symptoms, positive intervention may slow the occurrence or progression of EPVS and cognitive impairment in patients with EPVS.

Preparation and Characterization of Vancomycin Hydrochloride-Loaded Mesoporous Silica Composite Hydrogels.

This study aims to explore the feasibility of the novel temperature-sensitive hydrogel-based dual sustained-release system (Van/SBA-15/CS-GP-SA) in the repair and treatment of infectious jaw defects. Van/SBA-15 was prepared using the mesoporous silica (SBA-15) as a carrier for vancomycin hydrochloride (Van), and Van/SBA-15 was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive spectrometry (EDS), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR), Brunauer-Emmett-Teller (BET), and Barrett-Joyner-Halenda (BJH). The characterization results confirm that Van is loaded in SBA-15 successfully. Van/SBA-15/CS-GP-SA is constructed by encapsulating Van/SBA-15 in chitosan-sodium glycerophosphate-sodium alginate hydrogel (CS-GP-SA). The microstructures, sustained-release ability, biocompatibility, and antibacterial properties of Van/SBA-15/CS-GP-SA were systematically studied. Van/SBA-15/CS-GP-SA is found to have promising sustained-release ability, outstanding biocompatibility, and excellent antibacterial properties. This study provides new ideas for the management of infectious jaw defects.

A Deeply Supervised Convolutional Neural Network for Pavement Crack Detection With Multiscale Feature Fusion.

Automatic crack detection is vital for efficient and economical road maintenance. With the explosive development of convolutional neural networks (CNNs), recent crack detection methods are mostly based on CNNs. In this article, we propose a deeply supervised convolutional neural network for crack detection via a novel multiscale convolutional feature fusion module. Within this multiscale feature fusion module, the high-level features are introduced directly into the low-level features at different convolutional stages. Besides, deep supervision provides integrated direct supervision for convolutional feature fusion, which is helpful to improve model convergency and final performance of crack detection. Multiscale convolutional features learned at different convolution stages are fused together to robustly represent cracks, whose geometric structures are complicated and hardly captured by single-scale features. To demonstrate its superiority and generalizability, we evaluate the proposed network on three public crack data sets, respectively. Sufficient experimental results demonstrate that our method outperforms other state-of-the-art crack detection, edge detection, and image segmentation methods in terms of F1-score and mean IU.

[The effect of orthognathic surgery on speech function in patients with skeletal Class â ¢ malocclusion].

PURPOSE: To investigate the influence of the position of the upper and lower jaws on the anatomical structure of pharynx before and after orthognathic surgery in patients with skeletal Class Ⅲ malocclusion. METHODS: Craniofacial CT scan and speech data were collected from 31 patients with skeletal Class Ⅲ malocclusion before and 3 months after surgery. The collected CT data was imported into Dolphin imaging 11.95 software to establish a digital original model, and the anatomical structure of the pharynx was measured and analyzed. Speech data were analyzed objectively and subjectively by Computerized Speech Lab 4500b and professional speech specialists. Statistical analysis was performed using SPSS 24.0 software package. RESULTS: The distance from the lower edge of the soft palate to the posterior pharyngeal wall, the shortest distance from the posterior margin of the tongue to the posterior pharyngeal wall and its corresponding cross-sectional area were significantly different from those before surgery (P<0.05). The changes of SNA, SNB, ANB, OJ, and OBJ before and after surgery were significant in this series. Importantly, the speech intelligibility of orthognathic patients before and after surgery changed significantly subjectively (P<0.05). Objectively, the postoperative vowels /a/B2, B3, B4, /i/B1,B2, /u/B1,B2 and B4 of the patients were significantly different from those before surgery. There was no significant difference in the lower limit frequency of the consonants /x/, /zh/, /s/, the energy value of /zh/ and the grammatical form of /z/ before and after surgery. The maxillary advancement distance was highly correlated or significantly correlated with △S1, △VOP, and voice changes. CONCLUSIONS: Orthognathic surgery moves the upper and lower jaws to cause changes in the anatomy of the pharyngeal cavity, leading to changes of postoperative speech.

Safety Evaluation of Natural Drugs in Chronic Skeletal Disorders: A Literature Review of Clinical Trials in the Past 20 years.

Chronic skeletal disorders (CSDs), including degenerative diseases such as osteoporosis (OP) and autoimmune disorders, have become a leading cause of disability in an ageing society, with natural drugs being indispensable therapeutic options. The clinical safety evaluation (CSE) of natural drugs in CSDs has been given priority and has been intensively studied. To provide fundamental evidence for the clinical application of natural drugs in the elderly population, clinical studies of natural drugs in CSDs included in this review were selected from CNKI, Web of Science, PubMed, Science Direct and Google Scholar since 2001. Seventeen randomized controlled trials (RCTs) met our inclusion criteria: four articles were on OP, seven on osteoarthritis (OA), four on rheumatoid arthritis (RA) and two on gout. Common natural drugs used for the treatment of OP include Epimedium brevicornu Maxim [Berberidaceae], Dipsacus asper Wall ex DC [Caprifoliaceae] root, and Phalaenopsis cornu-cervi (Breda) Blume & Rchb. f[ Orchidaceae], which have been linked to several mild adverse reactions, such as skin rash, gastric dysfunction, abnormal urine, constipation and irritability. The safety of Hedera helix L [Araliaceae] extract, Boswellia serrata Roxb [Burseraceae] extract and extract from perna canaliculus was evaluated in OA and upper abdominal pain, and unstable movements were obsrerved as major side effects. Adverse events, including pneumonia, vomiting, diarrhoea and upper respiratory tract infection, were reported when RA was treated with Tripterygium wilfordii, Hook. F [Celastraceae][TwHF] polyglycosides and quercetin (Capsella bursa-pastoris (L.) Medik [Brassicaceae]). The present review aimed to summarize the CSE results of natural drugs in CSDs and could provide evidence-based information for clinicians.