Carnosic acid: an effective phenolic diterpenoid for prevention and management of cancers via targeting multiple signaling pathways.

Cancer is a serious global public health issue, and a great deal of research has been made to treat cancer. Of these, discovery of promising compounds that effectively fight cancer always has been the main point of interest in pharmaceutical research. Carnosic acid (CA) is a phenolic diterpenoid compound widely present in Lamiaceae plants such as Rosemary (Rosmarinus officinalis L.). In recent years, there has been increasing evidence that CA has significant anti-cancer activity, such as leukaemia, colorectal cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, stomach cancer, lymphoma, prostate cancer, oral cancer, etc. The potential mechanisms involved by CA, including inhibiting cell proliferation, inhibiting metastasis, inducing cell apoptosis, stimulating autophagy, regulating the immune system, reducing inflammation, regulating the gut microbiota, and enhancing the effects of other anti-cancer drugs. This article reviews the biosynthesis, pharmacokinetics and metabolism, safety and toxicity, as well as the molecular mechanisms and signaling pathways of the anticancer activity of CA. This will contribute to the development of CA or CA-containing functional foods for the prevention and treatment of cancer, providing important advances in the advancement of cancer treatment strategies.

Advanced Strategies for Strengthening the Immune Activation Effect of Traditional Antitumor Therapies.

The utilization of traditional therapies (TTS), such as chemotherapy, reactive oxygen species-based therapy, and thermotherapy, to induce immunogenic cell death (ICD) in tumor cells has emerged as a promising strategy for the activation of the antitumor immune response. However, the limited effectiveness of most TTS in inducing the ICD effect of tumors hinders their applications in combination with immunotherapy. To address this challenge, various intelligent strategies have been proposed to strengthen the immune activation effect of these TTS, and then achieve synergistic antitumor efficacy with immunotherapy. These strategies primarily focus on augmenting the tumor ICD effect or facilitating the antigen (released by the ICD tumor cells) presentation process during TTS, and they are systematically summarized in this review. Finally, the existing bottlenecks and prospects of TTS in the application of tumor immune regulation are also discussed.

Nanoplatform-based strategies for enhancing the lethality of current antitumor PDT.

Photodynamic therapy (PDT) exhibits great application prospects in future clinical oncology due to its spatiotemporal controllability and good biosafety. However, the antitumor efficacy of PDT is seriously hindered by many factors, including tumor hypoxia, limited light penetration ability, and strong defense mechanisms of tumors. Considering that it is difficult to completely solve the first two problems, enhancing the lethality of antitumor PDT has become a good idea to extend its clinical application. Herein, we summarize the nanoplatform-involved strategies to effectively amplify the tumoricidal capability of current PDT and then discuss the present bottlenecks and prospects of the nanoplatform-based PDT sensitization strategies in tumor therapy. We hope this review will provide some references for others to design high-performance PDT nanoplatforms for tumor therapy.

Tumor-Targeting Multiple Metabolic Regulations for Bursting Antitumor Efficacy of Chemodynamic Therapy.

Interfering with intratumoral metabolic processes is proven to effectively sensitize different antitumor treatments. Here, a tumor-targeting catalytic nanoplatform (CQ@MIL-GOX@PB) loading with autophagy inhibitor (chloroquine, CQ) and glucose oxidase (GOX) is fabricated to interfere with the metabolisms of tumor cells and tumor-associated macrophages (TAMs), then realizing effective antitumor chemodynamic therapy (CDT). Once accumulating in the tumor site with the navigation of external biotin, CQ@MIL-GOX@PB will release Fe ions and CQ in the acid lysosomes of tumor cells, the latter can sensitize Fe ions-involved antitumor CDT by blocking the autophagy-dependent cell repair. Meanwhile, the GOX component will consume glucose, which not only generates many H2O2 for CDT but also once again decelerates the tumor repair process by reducing energy metabolism. What is more, the release of CQ can also drive the NO anabolism of TAMs to further sensitize CDT. This strategy of multiple metabolic regulations is evidenced to significantly improve the antitumor effect of traditional CDT nanoagents and might provide a new sight to overcome the bottlenecks of different antitumor treatments.

Extraction, purification, structural characteristics and biological properties of the polysaccharides from Armillaria mellea (Vahl) P. Kumm.: A review.

Armillaria mellea (Vahl) P. Kumm. is a well-known homoeopathic plant with medicinal and culinary uses. Modern phytochemical researchers have successfully extracted and purified over 40 types of A. mellea polysaccharides (AMPs) from the fruiting bodies, hyphae and fermentation broth of A. mellea, and some of them have been analyzed and identified by their chemical structures. The impressive biological activity of these polysaccharides has been recognized by scientists worldwide. Many studies show that AMPs have remarkable antioxidant, anti-diabetic, anti-tumor, anti-inflammatory, immunoregulatory, hypolipidemic, thrombectomy, anti-aging, pulmonary protective, hepatic protective, anti-Alzheimer's properties, etc. However, the current understanding of the relationships between their chemical structure and biological activity, toxicological effects and pharmacokinetics remains limited. This article provides a systematic review of the research conducted over the past decades on the extraction and purification methods, structural characteristics, biological activity and mechanism of action of AMPs. The aim is to provide a research base that will benefit the future application of AMPs as therapeutic drugs and functional foods, and also provide insights for the further development of AMPs.

Tumor Microenvironment-Induced Drug Depository for Persistent Antitumor Chemotherapy and Immune Activation.

Herein, a drug-loading nanosystem that can in situ form drug depository for persistent antitumor chemotherapy and immune regulation is designed and built. The system (DOX@MIL-LOX@AL) is fabricated by packaging alginate on the surface of Doxorubicin (DOX) and lactate oxidase (LOX) loaded MIL-101(Fe)-NH2 nanoparticle, which can easily aggregate in the tumor microenvironment through the cross-linking with intratumoral Ca2+. Benefiting from the tumor retention ability, the fast-formed drug depository will continuously release DOX and Fe ions through the ATP-triggered slow degradation, thus realizing persistent antitumor chemotherapy and immune regulation. Meanwhile, LOX in the non-aggregated nanoparticles is able to convert the lactic acid to H2O2, which will be subsequently decomposed into ·OH by Fe ions to further enhance the DOX-induced immunogenic death effect of tumor cells. Together, with the effective consumption of immunosuppressive lactic acid, long-term chemotherapy, and oxidation therapy, DOX@MIL-LOX@AL can execute high-performance antitumor chemotherapy and immune activation with only one subcutaneous administration.

Immune landscape in rejection of renal transplantation revealed by high-throughput single-cell RNA sequencing.

Background: The role of the cellular level in kidney transplant rejection is unclear, and single-cell RNA sequencing (scRNA-seq) can reveal the single-cell landscape behind rejection of human kidney allografts at the single-cell level. Methods: High-quality transcriptomes were generated from scRNA-seq data from five human kidney transplantation biopsy cores. Cluster analysis was performed on the scRNA-seq data by known cell marker genes in order to identify different cell types. In addition, pathways, pseudotime developmental trajectories and transcriptional regulatory networks involved in different cell subpopulations were explored. Next, we systematically analyzed the scoring of gene sets regarding single-cell expression profiles based on biological processes associated with oxidative stress. Results: We obtained 81,139 single cells by scRNA-seq from kidney transplant tissue biopsies of three antibody-mediated rejection (ABMR) patients and two acute kidney injury (AKI) patients with non-rejection causes and identified 11 cell types, including immune cells, renal cells and several stromal cells. Immune cells such as macrophages showed inflammatory activation and antigen presentation and complement signaling, especially in rejection where some subpopulations of cells specifically expressed in rejection showed specific pro-inflammatory responses. In addition, patients with rejection are characterized by an increased number of fibroblasts, and further analysis of subpopulations of fibroblasts revealed their involvement in inflammatory and fibrosis-related pathways leading to increased renal rejection and fibrosis. Notably, the gene set score for response to oxidative stress was higher in patients with rejection. Conclusion: Insight into histological differences in kidney transplant patients with or without rejection was gained by assessing differences in cellular levels at single-cell resolution. In conclusion, we applied scRNA-seq to rejection after renal transplantation to deconstruct its heterogeneity and identify new targets for personalized therapeutic approaches.

[Nonradiological methods for implant surgical guide accuracy measurement].

PURPOSE: To evaluate the accuracy of static computer-navigated implantation with surgical guides, based on a non-radiological method. Traditional measurements with a second cone-beam CT (CBCT) were applied to verify the accuracy. METHODS: A total of thirty template-guided implantations were designed and performed on 15 resin models. Two paralleled bone-level implants were planned in the edentulous space of each model, between which the distance was 4 mm. Postoperative implant positions were detected with both CAD/CAM-based measurements applying an intraoral scanner (3Shape TRIOS) and traditional ways via CBCT. Both methods were conducted with a CAD quality-control, reverse engineering software, Geomagic Studio 2013, comparing the positions with the virtual ones. Statistical analysis was processed with SPSS 23.0 software package. RESULTS: Measurements using CBCT (control group) showed a trend toward greater deviations when the results were directly compared(P<0.05). In the CAD/CAM-based evaluation of the 30 samples, the mean deviation of the insertion axis from the planned implant axis was 1.134°. The mean deviations of the implant shoulders in the horizontal direction and at the implant apices were 0.447 mm and 0.557 mm, respectively. No significant difference was observed when measuring distance deviation with the two assessment ways. CONCLUSIONS: Compared with evaluation based on radiology, CAD/CAM based evaluation system is able to evaluate implant accuracy precisely, effectively reduce radiological exposure of patients, being suitable for clinical evaluation.

Proteomic analysis of differentially expressed proteins in the serum of patients with acute renal allograft rejection using iTRAQ labelling technology.

Transplantation is currently the best treatment for patients with end­stage renal disease. However, acute rejection (AR) is the major source of failure in renal transplantation. The current best practice for the diagnosis of AR involves renal biopsy, but it is invasive, time­consuming, costly and inconvenient. Sensitive and less invasive detection of AR episodes in renal transplant patients is essential to preserve allograft function. The present study applied isobaric tags for relative and absolute quantitation (iTRAQ) mass spectrometry to analyze serum protein expression in patients with AR and healthy controls. Overall, 1,399 proteins were identified. Using a cut­off of Q<0.05 and a fold change of >1.2 for the variation in expression, 109 proteins were identified to be differentially expressed between the AR and control groups, 72 of which were upregulated and 37 were downregulated. Several proteins, including properdin, keratin 1, lipoprotein(a) and vitamin D­binding protein, may have roles in the pathogenesis of AR. The present study focused on iTRAQ­based proteomic profiling of serum samples in AR. Insight from the present study may help advance the understanding of the molecular mechanisms of AR and identify potential novel biomarkers of AR for further characterization.

Evaluation and application of donors with primary central nervous system tumors.

BACKGROUND: This study aimed to explore the safety of donors with primary central nervous system tumors for kidney and liver transplantations. METHODOLOGY: Clinical data of 29 donors with primary CNS tumors in January 2007 to December 2017, as well as the follow-up data of 16 liver transplant recipients and 46 kidney transplant recipients, were analyzed. According to the risk factors, the high-risk group was classified as Group 1, the low-risk factors were classified as Group 2, and the unknown risk group was classified as Group 3. The incidence of donor-transmitted CNS tumors was calculated and compared. RESULTS: The duration from the diagnosis of 29 donors to donation was 5.67 ± 6.36 months. None of the liver and kidney transplant recipients who were followed up had tumor metastasis. Although the mean survival time of Group 1 was lower than that of Group 2 and Group 3, the Kaplan-Meier curve showed no significant difference in survival time. CONCLUSION: No obvious difference was observed between high-risk and low-risk and unknown risk CNS tumors in terms of the survival rate of transplants and tumor metastasis rate. High-risk CNS tumor donors can be used with the informed consent of recipients after a full evaluation.

Development of a monoclonal antibody against swine leukocyte antigen (SLA)-DR α chain and evaluation of SLA-DR expression in bone marrow-derived dendritic cells after PRRSV infection.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most common diseases in the global swine industry. PRRSV infection is highly restricted to cells of the monocyte-macrophage lineage. However, the lack of antibodies to swine monocyte-macrophage lineage markers significantly hampers PRRSV research. In this study, we have developed a monoclonal antibody against the swine leukocyte antigen (SLA)-DRα chain and confirmed its reactivity with endogenous expressed SLA-DR in a variety of cell lines and primary swine antigen-presenting cells (PAMs, PBMC and BM-DCs). Moreover, the level of SLA-DR expression after PRRSV infection were evaluated by our homemade Mab and a commercial anti-SLA-DR antibody. Based on our result, the protein level of SLA-DRα expression is increased after PRRSV infection in DC, while the mRNA of both SLA-DRα and SLA-DRß were significantly inhibited by PRRSV replication. In conclusion, we successfully developed a MAb reactive with endogenous SLA-DR in western blotting, and this MAb could be a useful tool for further research and analysis. Moreover, the inconsistency of SLA-DR expression between protein and mRNA levels may suggest a novel role of DC played during the immune response after PRRSV infection.

Comparative proteomic analysis of human serum before and after liver transplantation using quantitative proteomics.

Liver cancer is the second leading cause of cancer mortality worldwide. Safer and more effective diagnostic methods for liver cancer are desirable, and biomarkers represent a potentially alternative method for diagnosis. The present study was designed to identify liver cancer biomarkers. We quantified the changes in serum protein levels between liver transplantation and healthy (control) females using isobaric tags for relative and absolute quantitation (iTRAQ) as well as proteomic analysis. A total of 1399 proteins were identified; of these, three proteins showed significantly different concentrations between the before transplantation group and the control group. These proteins may thus be relevant to liver cancer and constitute potential liver cancer biomarkers.

[Effects of dimethylamine tetracycline combined with tea polyphenols on the levels of IL-1ß and IL-17F in patients with early peri-implant soft tissue inflammation].

PURPOSE: Using impact test to study energy absorption ability of mouthguard splints of different thickness and materials. METHODS: In this experiment, group 1 was BIOPLAST 5 mm splint, group 2 was BIOPLAST 4 mm splint, group 3 was BIOPLAST 3 mm splint，group 4 was BIOPLAST 2 mm splint and group 7 was BIOPLAST 1 mm splint. Group 5 was ERKOLOC-PRO 2 mm splint, group 6 was DURAN 2 mm splint. Mouthguard splints were clashed by impact head from different heights. Digital Image Correlation System was used to record the process of the test. Images were transferred to data processing software, to analyze incident speed, incident depth and rebound height of the impact head. Absorbed energy and energy absorption ratio were calculated to analyze energy absorption ability of mouthguard splints of different thickness and materials. The data were analyzed using SPSS 22.0 software package for one-way analysis of variance and LSD. RESULTS: The higher impact head fell, the larger energy absorption ratio was. There was significant difference among group 1, 2, 3, 4, 7 in average energy absorption ratio（P<0.05）, and group 7 was the largest. There was significant difference among group 4, 5, 6 in average energy absorption ratio（P<0.05）, among which group 4 and group 5 were larger. CONCLUSIONS: 3 mm splint is good enough to be used to make mouthguard, which is also thinner and more comfortable. Splint of soft material is more suitable for mouthguard than splint of hard material.

Circadian Rhythm Regulates Development of Enamel in Mouse Mandibular First Molar.

Rhythmic incremental growth lines and the presence of melatonin receptors were discovered in tooth enamel, suggesting possible role of circadian rhythm. We therefore hypothesized that circadian rhythm may regulate enamel formation through melatonin receptors. To test this hypothesis, we examined expression of melatonin receptors (MTs) and amelogenin (AMELX), a maker of enamel formation, during tooth germ development in mouse. Using qRT-PCR and immunocytochemistry, we found that mRNA and protein levels of both MTs and AMELX in normal mandibular first molar tooth germs increased gradually after birth, peaked at 3 or 4 day postnatal, and then decreased. Expression of MTs and AMELX by immunocytochemistry was significantly delayed in neonatal mice raised in all-dark or all-light environment as well as the enamel development. Furthermore, development of tooth enamel was also delayed showing significant immature histology in those animals, especially for newborn mice raised in all daylight condition. Interestingly, disruption in circadian rhythm in pregnant mice also resulted in delayed enamel development in their babies. Treatment with melatonin receptor antagonist 4P-PDOT in pregnant mice caused underexpression of MTs and AMELX associated with long-lasting deficiency in baby enamel tissue. Electromicroscopic evidence demonstrated increased necrosis and poor enamel mineralization in ameloblasts. The above results suggest that circadian rhythm is important for normal enamel development at both pre- and postnatal stages. Melatonin receptors were partly responsible for the regulation.

Single-center study on transplantation of livers donated after cardiac death: A report of 6 cases.

Effective use of all available donated organs is critical, in order to meet the increasing demand for transplants. The present study explored liver transplantation with livers that were donated following cardiac death (DCD). According to the guidelines established by The Red Cross Society of China, 42 DCD organs were procured. Selected donors were treated with extracorporeal membrane oxygenation (ECMO) prior to the organ retrieval. The present single-center study included 6 liver transplantations of DCD organs (5 liver transplants and 1 liver-kidney combined transplant). All 6 recipients had a successful recovery without significant complications. The serum alanine transaminase, total bilirubin and international normalized ratio returned to the normal levels within a short period of time following transplantation, and the liver function remained normal during the follow-up period, which lasted up to 24 months. The present report demonstrated the feasibility of orthotopic liver transplantation using DCD livers. The pre-conditioning DCD donors and optimization of the recipient's condition using ECMO, played a crucial role in ensuring the success of transplantation.

[Post-transplant kidney from C-III donation after cardiac death of children: a clinicopathologic study of 20 cases].

OBJECTIVE: To study the clinical and histopathologic features of post-transplant kidney biopsy tissues from pediatric C-III donors. METHODS: The clinical and pathologic features of 20 cases (22 case-times) of renal transplant biopsies from pediatric cadaveric donors were analyzed by light microscopy and immunohistochemistry according to the Banff system of working classification of renal allograft pathology. Biopsies were compared to those from adult C-III donors and adult cadaveric donors. RESULTS: Sixteen cases (72.7%) showed renal allograft drug toxicity damage by Tacrolimus, seven cases (31.8%) showed degeneration and necrosis of renal tubular epithelial cells, four cases (18.2%) showed T cell-mediated acute rejection and six cases (27.3%) showed renal interstitial inflammation. There were two cases (9.1%) of renal dysplasia and one case (4.5%) of renal infarction. There was insufficient evidence for diagnosis of renal allograft nephropathy. Compared to post-transplant kidney from adult C-III donors, the proportion of drug toxicity damage was higher (P<0.05). Compared to post-transplant kidney from adult cadavers, the proportions of drug toxicity damage, degeneration and necrosis of renal tubular epithelial cells were higher (P<0.05) while the proportion of acute rejection was lower (P<0.05). CONCLUSIONS: The pathologic changes in the post-transplant kidneys from pediatric donors are different from those from adult donors. Optimal long-term outcome can be accomplished by effective treatment based on timely or procedural biopsy.

Cold-induced modulation and functional analyses of the DRE-binding transcription factor gene, GmDREB3, in soybean (Glycine max L.).

DREB (dehydration-responsive element-binding protein) transcription factors have important roles in the stress-related regulation network in plants. A DREB orthologue, GmDREB3, belonging to the A-5 subgroup of the DREB subfamily, was isolated from soybean using the RACE (rapid amplification of cDNA ends) method. Northern blot analysis showed that expression of GmDREB3 in soybean seedlings was induced following cold stress treatment for 0.5 h and was not detected after 3 h. However, it was not induced by drought and high salt stresses or by abscisic acid (ABA) treatment. This response was similar to those of members in the A-1 subgroup and different from those of other members in the A-5 subgroup, suggesting that the GmDREB3 gene was involved in an ABA-independent cold stress-responsive signal pathway. Furthermore, analysis of the GmDREB3 promoter elucidated its cold-induced modulation. A promoter fragment containing bases -1058 to -664 was involved in response to cold stress, and its effect was detected for 1 h after treatment, but a transcriptional repressor appeared to impair this response by binding to a cis-element in the region -1403 to -1058 at 24 h after the beginning of cold stress. Moreover, the GmDREB3 protein could specifically bind to the DRE element in vitro, and activated expression of downstream reporter genes in yeast cells. In addition, overexpression of GmDREB3 enhanced tolerance to cold, drought, and high salt stresses in transgenic Arabidopsis. Physiological analyses indicated that the fresh weight and osmolality of GmDREB3 transgenic Arabidopsis under cold stress were higher than those of wild-type controls. GmDREB3 transgenic tobacco accumulated higher levels of free proline under drought stress and retained higher leaf chlorophyll levels under high salt stress than wild-type tobacco. In addition, constitutive expression of GmDREB3 in transgenic Arabidopsis caused growth retardation, whereas its expression under control of the stress-inducible Rd29A promoter minimized negative effects on plant growth under normal growth conditions, indicating that a combination of the Rd29A promoter and GmDREB3 might be useful for improving tolerance to environmental stresses in crop plants.