Search

Background and aims: Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3) represents a type of severe fetal skeletal dysplasia (SD) characterized by shortened limbs, narrow thorax with or without polydactyly, which is caused by the homozygous or compound heterozygous mutations in the DYNC2H1 gene. SRTD3 is a recessive disorder, identification of the responsible genetic variation would be beneficial to an accurate prenatal diagnosis and well-grounded counseling for the affected families. Material and methods: Two families having experienced recurrent fetal SDs were recruited and submitted to a multiplatform genetic investigation. Whole-exome sequencing (WES) was performed with samples collected from the probands. Sanger sequencing and fluorescent quantitative PCR (qPCR) were conducted as validation assays for suspected variations. Results: WES identified two compound heterozygous variations in the DYNC 2H1(NM_001080463.2) gene, namely c.2386C>T (p.Arg796Trp) and c.7289T>C (p.Ile2430Thr) for one; and exon (64-83)del and c.8190G>T (p.Leu2730Phe) for the other, respectively. One variant in them, exon (64-83)del, was novelly identified. Conclusion: The study detected two compound heterozygous variation in DYNC2H1 including one novel deletion: exon (64-83) del. Our findings clarified the cause of fetal skeletal dysplasia in the subject families, provided guidance for their future pregnancies, and highlighted the value of WES in diagnosis of skeletal dysplasia with unclear prenatal indications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Li, Zhang, Yuan, Sun, Yuan, Yang, Liang and Guo.)

In rheumatoid arthritis (RA), insufficient apoptosis of macrophages and excessive generation of pro-inflammatory cytokines are intimately connected, accelerating the development of disease. Here, a fluorinated polyamidoamine dendrimer (FP) is used to deliver miR-23b to reduce inflammation by triggering the apoptosis of as well as inhibiting the inflammatory response in macrophages. Following the intravenous injection of FP/miR-23b nanoparticles in experimental RA models, the nanoparticles show therapeutic efficacy with inhibition of inflammatory response, reduced bone and cartilage erosion, suppression of synoviocyte infiltration and the recovery of mobility. Moreover, the nanoparticles accumulate in the inflamed joint and are non-specifically captured by synoviocytes, leading to the restoration of miR-23b expression in the synovium. The miR-23b nanoparticles target Tab2, Tab3 and Ikka to regulate the activation of NF-κB pathway in the hyperplastic synovium, thereby promoting anti-inflammatory and anti-proliferative responses. Additionally, the intravenous administration of FP/miR-23b nanoparticles do not induce obvious systemic toxicity. Overall, our work demonstrates that the combination of apoptosis induction and inflammatory inhibition could be a promising approach in the treatment of RA and possibly other autoimmune diseases., (© 2023. The Author(s).)

Background: The synergy between locoregional therapies and immune checkpoint inhibitors has not been investigated as conversion therapy for unresectable hepatocellular carcinoma. We aimed to investigate the activity of sequential transarterial chemoembolisation (TACE) and stereotactic body radiotherapy followed by avelumab (an anti-PD-L1 drug) for locally advanced, unresectable hepatocellular carcinoma., Methods: START-FIT was a single-arm, phase 2 trial in patients with locally advanced hepatocellular carcinoma who were not suitable for curative treatment, conducted in two hospitals in Hong Kong and one in Shenzhen, China. Eligible patients were those aged 18 years or older with an Eastern Cooperative Oncology Group performance status 0-1, Child-Pugh liver function score A5 to B7, tumour size of at least 5 cm, a maximum of three tumour lesions, and adequate hepatic, renal, and bone marrow function. Participants received TACE on day 1, followed by stereotactic body radiotherapy (27·5-40·0 Gy in five fractions) at day 28. Avelumab (10 mg/kg) was administered 14 days following stereotactic body radiotherapy and every 2 weeks thereafter. The primary endpoint was the proportion of patients deemed amenable to curative treatment, defined as those who had a sustained complete or partial treatment response for at least 2 months and if curative treatment could be performed (ie, resection, radiofrequency ablation, or transplantation), analysed by intention to treat. Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03817736) and has been completed., Findings: Between March 18, 2019, and Jan 27, 2021, 33 patients (32 [97%] men and one [3%] woman) were enrolled. The median sum of the largest diameters of lesions was 15·1 cm (IQR 8·3-14·9). 21 (64%) patients had macrovascular invasion (hepatic vein [n=13], branched portal vein [n=3], or both [n=5]). Median follow-up was 17·2 months (IQR 7·8-25·8). 18 (55%) patients were deemed amenable to curative treatment: four (12%) of 33 patients had curative treatment (resection [n=2] or radiofrequency ablation [n=2]), and 14 (42%) had a radiological complete response and opted for close surveillance. 11 (33%) of 33 patients had treatment-related adverse events that were grade 3 or worse. The most common treatment-related grade 3 or worse adverse event was transient increase in alanine aminotransferase or aspartate aminotransferase (five [15%]) after TACE. Five (15%) patients developed immune-related adverse events of grade 3 or worse (three had hepatitis, two had dermatitis)., Interpretation: To our knowledge, this is the first prospective trial using the combination of immunotherapy and locoregional treatment as conversion therapy for locally advanced unresectable hepatocellular carcinoma, with promising results. Future randomised trials with larger cohorts of patients are warranted., Funding: Merck., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hematopoietic stem and progenitor cells (HSPCs) are a heterogeneous group of cells with expansion, differentiation, and repopulation capacities. How HSPCs orchestrate the stemness state with diverse lineage differentiation at steady condition or acute stress remains largely unknown. Here, we show that zebrafish mutants that are deficient in an epigenetic regulator Atf7ip or Setdb1 methyltransferase undergo excessive myeloid differentiation with impaired HSPC expansion, manifesting a decline in T cells and erythroid lineage. We find that Atf7ip regulates hematopoiesis through Setdb1-mediated H3K9me3 modification and chromatin remodeling. During hematopoiesis, the interaction of Atf7ip and Setdb1 triggers H3K9me3 depositions in hematopoietic regulatory genes including cebpβ and cdkn1a , preventing HSPCs from loss of expansion and premature differentiation into myeloid lineage. Concomitantly, loss of Atf7ip or Setdb1 derepresses retrotransposons that instigate the viral sensor Mda5/Rig-I like receptor (RLR) signaling, leading to stress-driven myelopoiesis and inflammation. We find that ATF7IP or SETDB1 depletion represses human leukemic cell growth and induces myeloid differentiation with retrotransposon-triggered inflammation. These findings establish that Atf7ip/Setdb1-mediated H3K9me3 deposition constitutes a genome-wide checkpoint that impedes the myeloid potential and maintains HSPC stemness for diverse blood cell production, providing unique insights into potential intervention in hematological malignancy.

Background: Biomedical named entity recognition is one of the important tasks of biomedical literature mining. With the development of natural language processing technology, many deep learning models are used to extract valuable information from the biomedical literature, which promotes the development of effective BioNER models. However, for specialized domains with diverse and complex contexts and a richer set of semantically related entity types (e.g., drug molecules, targets, pathways, etc., in the biomedical domain), whether the dependencies of these drugs, diseases, and targets can be helpful still needs to be explored. Method: Providing additional dependency information beyond context, a method based on the graph attention network and BERT pre-training model named MKGAT is proposed to improve BioNER performance in the biomedical domain. To enhance BioNER by using external dependency knowledge, we integrate BERT-processed text embeddings and entity dependencies to construct better entity embedding representations for biomedical named entity recognition. Results: The proposed method obtains competitive accuracy and higher efficiency than the state-of-the-art method on three datasets, namely, NCBI-disease corpus, BC2GM, and BC5CDR-chem, with a precision of 90.71%, 88.19%, and 95.71%, recall of 92.52%, 88.05%, and 95.62%, and F1-scores of 91.61%, 88.12%, and 95.66%, respectively, which performs better than existing methods. Conclusion: Drug, disease, and protein dependencies can allow entities to be better represented in neural networks, thereby improving the performance of BioNER., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Han, Li, Wang, Wang, Gao and Chen.)

Identification of internal-rotation modes in the normal-mode analysis of complex molecules is important for accurately describing the thermodynamic properties and kinetics of complex molecules when it is necessary to treat the anharmonicity of torsions and the multiconformer anharmonicity caused by the internal rotations. However, identifying and distinguishing torsional modes are very challenging because they are coupled to one another. In this work, we present a new strategy to automatically identify torsional vibrations and separate them from the other vibrational modes. By combining a redundant-internal-coordinate auto-generation procedure with torsional projection techniques, we automate the procedure of identifying and separating the coupled torsions, and we show that we can obtain robust and consistent results with various reasonable definitions of redundant-internal-coordinate sets. This model has been implemented in a new development version of the MSTor program to reduce the user input needed for multistructural and torsional anharmonicity (MS-T) calculations. The new method is called multistructural and torsional anharmonicity with a coupled torsional potential and delocalized torsions ([MS-T(CD)]. As example applications, we consider MS-T(CD) calculations on three molecules (2-hexyl radical, n -propylbenzene, and 5-hydroperoxy-6-oxohexanoylperoxy radical) that have multiple rotors and that provide challenges to choosing good sets of nonredundant-internal coordinates, and we compare the performance of the new strategy to five other torsion identification methods. The new strategy is demonstrated to be efficient in separating the torsional and nontorsional elements in the Hessian matrix, as well as in providing reasonable projected nontorsional frequencies to be used for calculations of partition function and thermochemistry.

Objectives: To explore the value of an ultrasound contrast agent (Sonovue) as an interventional treatment for periappendiceal abscesses., Methods: From January 2019 to December 2020, 30 patients were recruited who were admitted to Jinan Central Hospital due to periappendiceal abscesses. Before the operation, 2.5 ml of SonoVue ® contrast agent was injected intravenously to determine the non-enhanced area of liquefaction and necrosis in the abscess cavity. The puncture sites were selected. Percutaneous catheterization and drainage (PCD) were performed under contrast-enhanced ultrasound guidance. After the operation, 1 ml of diluted SonoVue ® suspension was injected through the drainage tube to observe the position of the drainage tube, the degree of drainage and the development of the abscess., Results: An ultrasound contrast agent was used preoperatively to assess the extent of the abscess. Liquefaction and necrosis were observed in the abscess cavity. CEUS showed hyperenhancement in the wall of the abscess in the arterial phase and the liquefied necrotic area in the abscess cavity was not enhanced before PCD. CEUS allowed operators to confidently identify the puncture site. Amongst the 30 cases of PCD, 27 cases showed the clear positioning of the drainage tube. The head of the drainage tube was placed in the ideal position and development could be seen in the abscess cavity. The diffusion effect of the contrast agent was good with no spillover and the drainage was unobstructed. Abscess development was observed in 3 patients after puncture injection of the contrast agent but the head of the drainage tube was not in the predetermined position. After adjusting the position of the drainage tube, CEUS was repeated and showed a strong diffusion effect of the contrast agent., Conclusions: Intravenous injection of Sonovue before PCD of periappendiceal abscesses can evaluate the extent of the abscess, liquefaction and necrosis in the abscess cavity. The approach can also provide guidance for the placement of the drainage tube. After the operation, a diluted contrast agent was injected through the drainage tube. The position of the drainage tube and the flow direction of the contrast agent could be seen. This approach has good value for clinical applications to accurately judge the position of the drainage tube., (© 2022. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Urban waterbodies are one of the most pertinent issues involved in multiple aspects of Sustainable Development Goals (SDGs). However, waterbodies in large Chinese cities are highly vulnerable to urban-land expansion, which is mostly due to economic development, population growth, and rural-urban migration. In this work, we selected 159 Chinese cities of over one million in population to investigate the encroachment on waterbodies due to rapid urbanization from 1990 to 2018. Overall, 20.6% of natural waterbody area was lost during this period to urban expansion, and this fraction varied from city to city which was related to waterbody abundance. With the acceleration of urbanization, waterbody occupation is becoming more serious (P < 0.01). However, in all cities, this encroachment has eased since 2010, which justifies the effective implementation of national-scale policies to conserve urban waterbodies. Meanwhile, gains have occurred during urbanization, in addition to the loss of waterbodies. Especially, cities lacking waterbody placed a greater emphasis on ecological factors, whose urban waterbody areas showed an increasing trend. In the future, ecological resources, including waterbody, should be considered in urban planning to provide reasonable protection to waterbodies in the quest for urban sustainability., (© 2022. The Author(s).)

Background: Protein-protein interaction (PPI) is very important for many biochemical processes. Therefore, accurate prediction of PPI can help us better understand the role of proteins in biochemical processes. Although there are many methods to predict PPI in biology, they are time-consuming and lack accuracy, so it is necessary to build an efficiently and accurately computational model in the field of PPI prediction., Results: We present a novel sequence-based computational approach called DCSE (Double-Channel-Siamese-Ensemble) to predict potential PPI. In the encoding layer, we treat each amino acid as a word, and map it into an N-dimensional vector. In the feature extraction layer, we extract features from local and global perspectives by Multilayer Convolutional Neural Network (MCN) and Multilayer Bidirectional Gated Recurrent Unit with Convolutional Neural Networks (MBC). Finally, the output of the feature extraction layer is then fed into the prediction layer to output whether the input protein pair will interact each other. The MCN and MBC are siamese and ensemble based network, which can effectively improve the performance of the model. In order to demonstrate our model's performance, we compare it with four machine learning based and three deep learning based models. The results show that our method outperforms other models in all evaluation criteria. The Accuracy, Precision, [Formula: see text], Recall and MCC of our model are 0.9303, 0.9091, 0.9268, 0.9452, 0.8609. For the other seven models, the highest Accuracy, Precision, [Formula: see text], Recall and MCC are 0.9288, 0.9243, 0.9246, 0.9250, 0.8572. We also test our model in the imbalanced dataset and transfer our model to another species. The results show our model is excellent., Conclusion: Our model achieves the best performance by comparing it with seven other models. NLP-based coding method has a good effect on PPI prediction task. MCN and MBC extract protein sequence features from local and global perspectives and these two feature extraction layers are based on siamese and ensemble network structures. Siamese-based network structure can keep the features consistent and ensemble based network structure can effectively improve the accuracy of the model., (© 2022. The Author(s).)

Objectives: Joubert syndrome is a spectrum of rare genetic disorders, mainly characterized by a distinctive cerebellar and brain stem malformation called the "molar tooth sign" (MTS), hypotonia, and intellectual disability/developmental delay., Methods: In this study, 4 pediatric cases with developmental delay and oculomotor abnormities were recruited, and submitted to a clinical evaluation and magnetic resonance imaging (MRI) examination. Afterwards, genetic detection with whole exome sequencing (WES) was conducted on the 4 patients., Results: Imaging results demonstrated cerebellar dysplasia in all probands, yet the MTS findings varied in severity. WES detected diagnostic variations in all four probands, which were distributed in four genes, namely CC2D2A, NPHP1, AHI1 , and C5orf42 . Two variants were novelly identified, which were the CC2D2A : c.2444delC (p.P815fs*2) and the AIH1 : exon (15-17) del. In silico analysis supported the pathogenicity of the variations in this study., Conclusions: Our findings expanded the mutation spectrum of Joubert syndrome related disorders, and provided solid evidence to the affected families for further genetic counseling and pregnancy guidance., Competing Interests: None., (AJTR Copyright © 2022.)

Hepatocellular carcinoma (HCC) is a common malignancy with high mortality rates. While surgery can be curative in early-stage disease, 80% of patients cannot undergo surgical resection. Stereotactic body radiotherapy (SBRT), an emerging, non-invasive, precision treatment, has shown promising results across various stages of HCC and has thus been adopted in practice to varying degrees around the world. This article aims to review current guideline recommendations on SBRT, clinical evidence, and outcome comparisons with other local treatment modalities. Attempts are also made to compare the differences in clinical trials between Asian and Western countries., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Feng-Ming (Spring) Kong reported that the equipment, drugs, or supplies were provided by Shenzhen Science and Technology program and a Varian Medical Systems. Other authors declare that they have no conflict of interests., (© 2022 Chinese National Cancer Center. Published by Elsevier B.V.)

Sex determining region Y-box 2 (Sox2) is a transcription factor that is essential for maintaining self-renewal or pluripotency of undifferentiated embryonic stem cells. The expression and distribution of Sox2 in tumor tissues have been extensively recorded, which are related to the progression and metastasis of tumor. However, a complete mechanistic understanding of Sox2 regulation and function remains to be studied. Herein, we show new potential properties of Sox2 regulation and functions from bioinformatics analysis. We use numerous algorithms to characterize the Sox2 gene promoter elements and the Sox2 protein structure, physio-chemical, localization properties and its evolutionary relationships. The expression of Sox2 is regulated by a diverse set of transcription factors and associated with the levels of methylation of CpG Islands in promoters. The structural properties of Sox2 indicate that Sox2 expresses as a stem cell marker in a variety of stem cells. Sox2 together with other transcription factors or proteins regulate the expression of downstream target genes, which makes a great difference to the biological function of stem cells. Not only stem cells, Sox2 also play an important role in tumor cells. In conclusion, this information from bioinformatics analysis will help to understand Sox2 regulation and functions better in future attempts.

Objective: The genetic aberrations that underlie chromatin remodeling in sporadic nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) remain largely unknown. Here, we investigated the dysregulation of the switch/sucrose nonfermentable (SWI/SNF) component ARID1A and its correlation with clinicopathological features and prognosis., Methods: We sequenced the exomes of sporadic NF-pNETs. Quantitative real-time polymerase chain reaction and immunohistochemistry were used to determine messenger RNA level and protein expression., Results: The sporadic NF-pNETs harbored 264 somatic mutations in 228 different genes, most commonly affecting the SWI/SNF components ARID1B (57.1%) and ARID1A (42.9%). The expression of ARID1A was remarkably downregulated in NF-pNETs and corresponding liver metastases compared with that in normal pancreatic islet tissue. Reduced expression of ARID1A was associated with malignant clinicopathological features (P < 0.05). The loss of ARID1A was related to a high Ki-67 index (P < 0.05). Patients with ARID1A-negative expression had a significantly worse overall survival rate than those with ARID1A-positive expression (P < 0.05). The ARID1A status was an independent predictor of overall survival, and a nomogram integrating ARID1A with clinicopathological features was proposed., Conclusions: The loss of SWI/SNF components ARID1A may be associated with malignant behaviors and an unfavorable prognosis. Aberrations of ARID1A may contribute to tumorigenesis and metastasis in sporadic NF-pNETs.

Angiogenesis is a critical, fine-tuned, multi-staged biological process. Tip-stalk cell selection and shuffling are the building blocks of sprouting angiogenesis. Accumulated evidences show that tip-stalk cell selection and shuffling are regulated by a variety of physical, chemical and biological factors, especially the interaction among multiple genes, their products and environments. The classic Notch-VEGFR, Slit-Robo, ECM-binding integrin, semaphorin and CCN family play important roles in tip-stalk cell selection and shuffling. In this review, we outline the progress and prospect in the mechanism and the roles of the various molecules and related signaling pathways in endothelial tip-stalk cell selection and shuffling. In the future, the regulators of tip-stalk cell selection and shuffling would be the potential markers and targets for angiogenesis.

The histone acetylation modifications (HAMs) influence a large number of cellular functions. They are mediated through histone acetyltransferase (HAT) and histone deacetylase (HDAC). Nowadays, people have realized that HAMs are crucial for development and prognosis of breast cancer. Investigations about abnormal HAMs in breast cancer focus on initiating molecular mechanisms in breast cancer development, identification of new biomarkers to predict breast cancer aggressiveness and the therapeutic potential. As HAMs are reversible, breast cancer may be treated by restoring HAMs to normal levels. Indeed, some HDAC inhibitors have been approved by the US Food and Drug Administration to treat certain cancers. Furthermore, HAT inhibitors, HAT activators and HDAC activators may also be used as drugs to treat breast cancer.

Aim: We aim to investigate the clinical characteristics of the rectal NECs and the prognosis-related factors and construct a nomogram for prognosis prediction., Methods: The data of 41 patients and 1028 patients with rectal NEC were retrieved respectively from our institution and SEER database. OS or PFS were defined as the major study outcome. Variables were compared by Chi2 test, t-test when appropriate. Kaplan-Meier analysis with log-rank test was used for survival analysis and the cox regression analysis were applied. The nomogram integrating risk factors for predicting OS was constructed by R to achieve superior discriminatory ability. Predictive utility of the nomogram was determined by concordance index (C-index) and calibration curve., Results: In the univariate and multivariate analysis, tumor differentiation, N stage, M stage and resection of primary site were identified as independent prognostic indicators. The linear regression relationship was found between the value of Ki-67 index and the duration of OS (P<0.05). Furthermore, the independent prognostic factors were added to formulate prognostic nomogram. The constructed nomogram showed good performance according to the C-index., Conclusions: Contrary to WHO classification guideline, we found that the rectal NEC disease are heterogeneous and should be divided as different categories according to the pathological differentiation. Besides, the nomogram formulated in this study showed excellent discriminative capability to predict OS for those patients. More advanced predictive model for this disease is required to assist risk stratification via the formulated nomogram.

Objective: To investigate clinicopathological features and prognostic factors of appendiceal neuroendocrine neoplasms(a-NEN)., Methods: Clinical data of 20 patients diagnosed with a-NEN at Zhongshan Hospital of Fudan University between January 2000 and December 2016 were retrospectively analyzed. Pathological diagnosis was based on the WHO classification criteria of digestive system tumors (2010 edition). Based on the mitotic count and Ki-67 index, a-NENs were divided into grade 1 neuroendocrine tumor (NET G1), grade 2(G2) NET G2) and grade 3 (neuroendocrine carcinoma, NEC). Some special types of a-NEN (e.g. goblet cell carcinoid) and mixed adenoneuroendocrine neoplasms were classified as mixed adenoneuroendocrine carcinoma (MANEC). Follow-up was conducted by telephone or return visits. Univariate analysis was carried out using the Kaplan-Meier method, and the log-rank test was used to draw survival curves., Results: Of 20 patients, 14 were male and 6 were female with median age of 54 years. Seventeen cases presented acute right lower quadrant abdominal pain, 1 chronic right lower quadrant abdominal pain, 1 persistent abdominal discomfort with outburst whole abdominal pain and 1 was found during body check without symptoms. Twenty cases comprised 8 G1 patients, 4 G2 patients, 3 G3 patients, and 5 MANEC patients. When diagnosed, there was 1 patient with liver metastasis, 1 patient with abdominal and pelvic metastases, and 2 patients with postoperative pathological findings of lymph node metastasis. Six patients underwent appendectomy, 12 underwent right hemicolectomy, 1 underwent right hemicolectomy plus small intestine resection, and 1 underwent partial hepatectomy plus right hemicolectomy. The follow-up time was 7-187 months(average, 36 months). The total 1- and 3-year survival rates were 94.7% and 60.2%, respectively. Univariate analysis showed that age >50 years (χ 2 =7.036, P=0.008), pathology grade as MANEC (χ 2 =5.297, P=0.021), and metastasis (χ 2 =6.558, P=0.010) indicated lower 5-year survival rate., Conclusions: Most a-NEN patients have no typical symptoms, and the main complaint at consultation is acute right lower quadrant abdominal pain. Prognosis is poor for patients with age >50 years, MANEC pathology grade and metastasis.

MicroRNAs (miRNAs) are key regulators of diverse biological processes in tumor progression including melanoma. LRIG2 is reported as an oncogene in cancer, however, little is known regarding the molecular and functions of LRIG2 in melanoma. In this study, we reported that LRIG2 expression was higher in melanoma tissues and cell lines and was regulated by miR-149-5p. Furthermore, a luciferase reporter assay and rescue experiment indicated that miR-149-5p directly targeted LRIG2 by binding its 3'UTR. The overexpression of miR-149-5p significantly suppressed melanoma cell proliferation, colony formation, and promoted cell apoptosis. These results suggest that miR-149-5p acts as a suppressing molecule and may be a good method for melanoma therapy., Competing Interests: None.

A scaffold fabricated with lysine/nerve growth factor (NGF)/poly (lactic acid coglycolic acid) copolymer (PLGA) and acellular pigskin was evaluated in vitro as a potential artificial nerve scaffold. Properties of the scaffold such as microstructure, mechanical property, degradation behavior in PBS and water, Schwann cell adhesion property, and release of NGF were investigated. Results showed PLGA had permeated into the porous structure of acellular pigskin; its breaking strength was 8.308 MPa, breaking extensibility was 38.98%, elastic modulus was 97.27 MPa. The porosities of the scaffold ranged from 68.3% to 81.2% with densities from 0.62 g/cm3 to 0.68 g/cm3. At 4 weeks of degradation in vitro, maximum mass loss ratio was 43.3%. The release of NGF could still be detected on the 30th day, and its accumulative release rate was 38%. Lysine added into the scaffold neutralized the acidoid preventing degradation of PLGA to maintain a solution pH value. Schwann cells had grown across the scaffold after co-cultivation for 15 days. These in vitro properties of the pigskin based composite might indicate its potentiality to be an artificial nerve scaffold.

Ultraviolet (UV) irradiation induces the expression of matrix metalloproteinases (MMPs), disturbing the metabolism of extracellular matrix (ECM), and causes the characteristic changes of photoaging in skin. Inhibition of induction of MMPs is suggested to alleviate photoaging induced by UV irradiation. Zeatin, purified from Zea mays, is a member of the cytokinin group of plant growth factors, the activity of which is attributed to its more stable trans form. In this study, we investigated the effect of trans-Zeatin on UVB-induced matrix metalloproteinase-1 (MMP-1) expression in cultured human skin fibroblasts (HSFs) and studied the mechanisms of its actions. We found that pretreatment with trans-Zeatin significantly inhibits UVB-induced MMP-1 expression and c-Jun activation in a dose-dependent manner. We also observed that trans-Zeatin inhibits UVB-induced phosphorylation of ERK, JNK and p38 MAP kinases (MAPKs) dose-dependently. As expected, PD98059, an ERK inhibitor, SP600125, a JNK inhibitor and SB203580, a p38 MAPK inhibitor effectively inhibit UVB-induced phosphorylation of ERK, JNK and p38 MAPKs, respectively. Moreover, the inhibitory mechanism of trans-Zeatin was further demonstrated in MMP-1 secretion using MAPK-specific inhibitors. PD98059, SP600125 and SB203580 suppressed UVB-induced MMP-1 secretion, which is consistent with the above results. Collectively, our results suggest that trans-Zeatin inhibits UVB-induced MMP-1 expression, which may be mediated by inhibition of ERK, JNK and p38 MAPKs signaling pathways in HSFs. Trans-Zeatin is a potential agent for the management of skin photoaging.