Serum Cell Division Cycle 42 before and after Programmed Death-1 Inhibitor Therapy in Advanced Melanoma Patients: Correlation with Tumor Features, Clinical Response, and Survival.

Cell division cycle 42 (CDC42) mediates immune escape in cancers. This study aimed to investigate linkages of CDC42 with tumor features, treatment response, and survival in advanced melanoma patients receiving programmed death-1 (PD-1) inhibitors. Pre-treatment and post-treatment (after 2 cycles) serum CDC42 of 35 advanced melanoma patients receiving PD-1 inhibitor was assessed by enzyme-linked immunosorbent assay. Patients with tumor-node-metastasis (TNM) stage IV (vs. III) (P = 0.050) and abnormal (vs. normal) lactate dehydrogenase (LDH) (P = 0.022) had higher pre-treatment CDC42. After 2-cycle therapy, CDC42 was declined (P < 0.001). Objective response and disease control rates were 34.3% and 62.9%, respectively. Additionally, pre-treatment and post-treatment CDC42 was reduced in patients with objective response and disease control than those without (all P < 0.050). Concerning survival, pre-treatment with CDC42 > 700 pg/mL was associated with shorter progression-free survival (PFS) (P = 0.013), but not overall survival (OS) (P = 0.060). Specifically, the 12-month PFS rate was 26.7% and 66.2%, and the 12-month OS rate was 61.1% and 82.5% in patients with pre-treatment with CDC42 > 700 pg/mL and ≤ 700 pg/mL, respectively. Post-treatment with CDC42 > 700 pg/mL was correlated with shortened PFS (P = 0.010) and OS (P = 0.006). The 12-month PFS rate was 12.5% and 62.0%, and the 12-month OS rate was 42.3% and 88.0% in patients with post-treatment with CDC42 > 700 pg/mL and ≤ 700 pg/mL, accordingly. Furthermore, post-treatment with CDC42 > 700 pg/mL was independently related to PFS [hazard ratio (HR): 2.704, P = 0.029 and OS (HR: 7.749, P = 0.005)]. Elevated CDC42 correlates with advanced TNM, abnormal LDH, worse clinical response, and dismal survival in advanced melanoma patients receiving PD-1 inhibitors.

Regulation of Circulating miR-342-3p Alleviates the Radiation-Induced Immune System Injury.

Ionizing radiation in space, radiation devices or nuclear disasters are major threats to human health and public security. Expanding countermeasures for dealing with accidental or occupational radiation exposure is crucial for the protection of radiation injuries. Circulating microRNAs (miRNAs) have emerged as promising radiation biomarkers in recent years. However, the origin, distribution and functions of radiosensitive circulating miRNAs remain unclear, which obstructs their clinical applications in the future. In this study, we found that mmu-miR-342-3p (miR-342) in mouse serum presents a stable and significant decrease after X-ray total-body irradiation (TBI). Focusing on this miRNA, we investigated the influences of circulating miR-342 on the radiation-induced injury. Through tail vein injection of Cy5-labeled synthetic miR-342, we found the exogenous miR-342-Cy5 was mainly enriched in metabolic and immune organs. Besides, the bioinformatic analysis predicted that miR-342 might involve in immune-related processes or pathways. Further, mice were tail vein injected with synthetic miR-342 mimetics (Ago-miR-342) after irradiation to upregulate the level of miR-342 in circulating blood. The results showed that the upregulation of circulating miR-342 alleviated the radiation-induced depletion of CD3+CD4+ T lymphocytes and influenced the levels of IL-2 and IL-6 in irradiated mice. Moreover, the injection of Ago-miR-342 improved the survival rates of mice with acute radiation injury. Our findings demonstrate that upregulation of circulating miR-342 alleviates the radiation-induced immune system injury, which provides us new insights into the functions of circulating miRNAs and the prospect as the targets for mitigation of radiation injuries.

Identification of the Kupffer cell-derived circulating IGFBP-3 as a universal radiation biomarker for heavy ion, proton, and X-ray exposure.

The minimally invasive biomarkers that can facilitate a rapid dose assessment are valuable for the early medical treatment when accidental or occupational radiation exposure happens. Our previous proteomic research identified one kind of circulating protein, Insulin-like Growth Factor Binding Protein 3 (IGFBP-3), which showed a significant increase after total body exposure of mice to carbon ions and X-rays. However, several critical issues such as the responses to diverse radiation, the origin and underlying mechanism in radiation response obstruct the utilization of circulating IGFBP-3 as a reliable radiation biomarker. In this study, mice were subjected to total or partial body irradiation with carbon ions, protons or X-rays, or treated with chloroform as a comparison. The level of IGFBP-3 in serum and different organs were measured via Enzyme Linked Immunosorbent Assay (ELISA), Western blot (WB) and Immunohistochemistry (IHC). A significant increase of IGFBP-3 was discovered in serum and liver tissue post-irradiation with three kinds of radiation, but absent when challenged with chloroform. Likewise, a similar response was also observed in blood samples from patients receiving radiotherapy. Moreover, the effect of radiation on three main hepatic cells was investigated, the findings indicated that IGFBP-3 could be detected in the culture medium of Kupffer cells (MKC) alone and was elevated in cells and cultured medium of MKC post-irradiation. Additionally, we observed a co-expression effect between P53 and IGFBP-3 in liver tissues and MKC post-irradiation. Along with down-regulation of Trp53 by siRNA, the response of IGFBP-3 to radiation was attenuated. The present study demonstrated that circulating IGFBP-3 could be a promising universal biomarker for complex environmental radiation exposure, and the upregulation of IGFBP-3 is attributed to the MKC in a P53-dependent manner. Circulating IGFBP-3 assays would offer rapid, convenient and effective dose and toxicity assessment methods in occupational exposure or radiation disaster management.

Application of a linear interpolation algorithm in radiation therapy dosimetry for 3D dose point acquisition.

Air-vented ion chambers are generally used in radiation therapy dosimetry to determine the absorbed radiation dose with superior precision. However, in ion chamber detector arrays, the number of array elements and their spacing do not provide sufficient spatial sampling, which can be overcome by interpolating measured data. Herein, we investigated the potential principle of the linear interpolation algorithm in volumetric dose reconstruction based on computed tomography images in the volumetric modulated arc therapy (VMAT) technique and evaluated how the ion chamber spacing and anatomical mass density affect the accuracy of interpolating new data points. Plane measurement doses on 83 VMAT treatment plans at different anatomical sites were acquired using Octavius 729, Octavius1500, and MatriXX ion chamber detector arrays, followed by the linear interpolation to reconstruct volumetric doses. Dosimetric differences in planning target volumes (PTVs) and organs at risk (OARs) between treatment planning system and reconstruction were evaluated by dose volume histogram metrics. The average percentage dose deviations in the mean dose (Dmean) of PTVs reconstructed by 729 and 1500 arrays ranged from 4.7 to 7.3% and from 1.5 to 2.3%, while the maximum dose (Dmax) counterparts ranged from 2.3 to 5.5% and from 1.6 to 7.6%, respectively. The average percentage dose/volume deviations of mixed PTVs and OARs in the abdomen/gastric and pelvic sites were 7.6%, 3.5%, and 7.2%, while mediastinum and lung plans showed slightly larger values of 8.7%, 5.1%, and 8.9% for 729, 1500, and MatriXX detector arrays, respectively. Our findings indicated that the smaller the spacing between neighbouring detectors and the more ion chambers present, the smaller the error in interpolating new data points. Anatomical regions with small local mass density inhomogeneity were associated with superior dose reconstruction. Given a large mass density difference in the various human anatomical structures and the characteristics of the linear interpolation algorithm, we suggest that an alternative data interpolation method should be used in radiotherapy dosimetry.

Exploring the Role and Mechanism of Adipose Derived Mesenchymal Stem Cells on Reversal of Pigmentation Model Effects.

Interventions for extrinsic aging can be implemented, but these must address photoaging, which is the primary cause of extrinsic aging. Pigmentation due to photoaging depends on the duration and intensity of sun exposure. This study investigated the relationship between adipose-derived mesenchymal stem cells (ASCs) and photoaging pigmentation, and the underlying mechanism of action by establishing a photoaging pigmentation model using various treatments and exposure options in a guinea pigs. The energy dose of each UVB irradiation was 120 mJ/cm2 and the total dose of irradiation was 360 mJ/cm2. After successfully establishing the photoaging model, ASCs (1×106) in an balanced salt solution (0.9 ml), balanced salt solution (0.9 ml), and bFGF (9 µg) mixed with an balanced salt solution (0.9 ml) were injected intradermally in ten guinea pigs. ELISA, macroscopic skin and histological observations, and Masson-Fontana staining were done. At 2 and 4 weeks post-injection, noticeable changes were observed. Guinea pigs receiving ASCs injections displayed significantly lower visible skin scores while the melanin content continued to decrease. Somewhat improved histopathological morphology, including epidermal thinning, dermal thickening, and little inflammatory cell infiltration was observed immediately after and up to 4 weeks of ASCs injection. Melanocortin 1 receptor (MC1R) and alpha-melanocyte test hormone (alpha-MSH) levels reduced significantly, and basic fibroblast growth factor (bFGF) levels increased significantly immediately after and up to 4 weeks of ASCs injection. The MC1R and alpha-MSH levels reduced significantly immediately after and up to 4 weeks of bFGF injection. Briefly, intradermal ASCs injection can notably eliminate pigmentation in a guinea pig photoaging pigmentation model. This may be related to the fact that bFGF secreted by ASCs lowers MC1R and alpha-MSH levels, blocks the cAMP signalling pathway, and inhibits melanin synthesis. This finding may present new options for treating photoaging pigmentation.Level of Evidence: N/A.

Tazarotene/Betamethasone Dipropionate Cream in Patients with Plaque Psoriasis: Results of a Prospective, Multicenter, Observational Study.

BACKGROUND: Topical agents are still the mainstay for the treatment of mild-to-moderate plaque psoriasis, in which fixed combinations play an important role. Tazarotene/betamethasone dipropionate (Taz/BD) cream is a novel fixed combination approved for treating plaque psoriasis in China, but its efficacy and safety have not been verified in a real-world environment. OBJECTIVES: The primary objective was to investigate the efficacy and safety of Taz/BD cream in treating plaque psoriasis. The secondary objectives were to assess its relapse after discontinuation and the efficacy and safety profiles during retreatment. METHODS: A prospective, multicenter, large-scale observational study was conducted. Adult patients with chronic plaque psoriasis involving <20% of the body surface area were enrolled. Taz/BD cream was applied once daily for 4 weeks. Patients who achieved ≥90% improvement in the Psoriasis Area and Severity Index (PASI) from baseline to week 4 were followed up to investigate relapse after drug withdrawal. Relapsed patients underwent another 4-week treatment. RESULTS: In total, 2,299 eligible patients were enrolled, and 2,095 patients (91.1%) completed the 4-week study. The mean PASI improvement at week 4 was 53.7%, and the PASI 50/75 response rates were 62.5 and 26.8%, respectively. The mean PASI reduction in plaque induration, desquamation and erythema were 58.3, 61.0 and 40.0%, respectively (p < 0.001). Adverse reactions occurred in 445 patients (20.8%) at week 4. The most frequently reported adverse reactions were local skin irritation, including pruritus (10%), pain (6.7%), erythema (6.1%) and desquamation (1.8%). During the post-treatment period, 47 patients (24.0%) relapsed within 8 weeks after drug discontinuation. Forty-five patients were retreated for another 4 weeks, and the PASI 50/75 response rates were 72.7 and 40.9%, respectively. There were no unexpected safety signals during retreatment. CONCLUSION: Taz/BD cream is effective and well tolerated in treating mild-to-moderate plaque psoriasis under near real-world conditions and demonstrates efficacy and safety during retreatment.

Dysfunction of regulatory T cells mediated by AKT-FOXO1 signaling pathway occurs during the development of psoriasis.

Psoriasis is an immune-mediated skin disease with abnormal T cells. Regulatory T cells (Treg) are a kind of cell group with immunosuppressive effects. This study aimed to explore the role of Treg cells in the pathogenesis of psoriasis and its possible mechanism. Imiquimod induced psoriasis mice model was conducted. The skin lesions were evaluated according to the psoriasis area and severity index (PASI). Skin biopsies were taken for HE staining and immunohistochemical staining of IL-23, IL-17, IL-33 and TNF-α. CD4+CD25+ Treg cells were isolated. The proportions of Treg cells, cell proliferation, and immunosuppressive activity were analyzed by flow cytometry. The expression of AKT, Foxo1, pAKT, pFoxo1 protein, and the localization of Foxo1 protein in Treg cells were detected by western blot and immunofluorescence. The results showed that the psoriasis mice model was established successfully. There was no significant difference in the proportion of Treg cells between the two groups (P > 0.05). The cell proliferation abilities were decreased, and the immunosuppressive functions of Treg cells were weakened in the psoriatic group (P < 0.05). Western blot showed that pAKT and pFoxo1 levels of Treg cells were significantly increased in the psoriatic group (P < 0.05). Immunofluorescence showed that Foxo1 was mainly expressed in the nucleus of Treg cells in the control group, whereas expressed in the cytoplasm in the psoriasis group. Therefore, we concluded that the cell proliferation and immunosuppressive dysfunction of Treg cells mediated by AKT-FOXO1 signaling pathway may occurs during the development of psoriasis.

MicroRNA-125b exerts antitumor functions in cutaneous squamous cell carcinoma by targeting the STAT3 pathway.

BACKGROUND: MicroRNA-125b (miR-125b) is downregulated in human cutaneous squamous cell carcinoma (CSCC). However, its function in CSCC has yet to be extensively explored. Here, we analyze the relationship between signal transducer and activator of transcription 3 (STAT3) and miR-125b in CSCC. METHODS: Western blotting and quantitative RT-PCR were used to determine the expression of the miR-125b-STAT3 axis in human CSCC tissues and cell lines. The direct regulatory effect of miR-125b on STAT3 expression was assessed using a luciferase reporter gene assay and RNA immunoprecipitation assay. The MTT assay and flow cytometry were used to determine the role of the miR-125b-STAT3 axis in CSCC cell proliferation and apoptosis. RESULTS: MiR-125b expression levels were significantly lower in CSCC cell lines and tissues than in normal cell lines and tissues. STAT3 was identified as the direct target of miR-125b. Upregulation of miR-125b and downregulation of STAT3 suppressed cell proliferation and promoted cell apoptosis. Cyclin D1 and Bcl2 were identified as the downstream targets of the miR-125-STAT3 axis. CONCLUSIONS: Our findings indicate that miR-125b acts as a tumor suppressor in CSCC by targeting the STAT3 pathway. This observation increases our understanding of the molecular mechanisms of CSCC. Therapies aimed at activating miR-125b or inhibiting STAT3 signaling should be explored as potential treatments for CSCC.

Upregulated long-non-coding RNA DLEU2 exon 9 expression was an independent indicator of unfavorable overall survival in patients with esophageal adenocarcinoma.

In this study, we aimed to explore the expression profiles of some known functional lncRNAs in esophageal adenocarcinoma (EAD) and to screening the potential prognostic makers, using data from The Cancer Genome Atlas (TCGA)-esophageal carcinoma (ESCA). Results showed that DLEU2 is a high potential OS related marker among 73 functional lncRNAs. DLEU2 and its intronic miR-15a and miR-16-1 expression were significantly upregulated in EAD compared with adjacent normal tissues. However, miR-15a and miR-16-1 expression were only weakly correlated with DLEU2 expression. Univariate and multivariate analysis confirmed that DLEU2 expression, but not miR-15a or miR-16-1 expression is an independent prognostic marker in terms of OS (HR:1.688, 95%CI: 1.085-2.627, p = 0.020) in EAD patients. The exon 9 of DLEU2 is very strongly co-expressed with DLEU2 (Pearson's r = 0.96) and showed better predictive value than total DLEU2 expression in predicting the OS of EAD patients. Multivariate analysis confirmed its independent prognostic value (HR:1.970, 95%CI: 1.266-3.067, p = 0.003), after adjustment of histologic grade, pathological stages and the presence of residual tumor. By checking the methylation status of DLEU2 gene, we excluded the possibility of the influence of two CpG sites near the DLEU2 exon 9 locus on its expression. In addition, although copy number alterations (CNAs) were observed DLEU2 gene, heterozygous loss (-1), low-level copy gain (+1) and high-level amplification (+2) had no significant association with DLEU2 transcription. Based on these findings, we infer that DLEU2 exon 9 expression might serve as a valuable biomarker of unfavorable OS in EAD patients.

Analysis of Immunologic Function Changes in Lichen Planus After Clinical Treatment.

BACKGROUND Lichen planus (LP) is a common chronic superficial skin lesion that causes chronic or sub-acute inflammatory disorders. LP can affect the oral cavity, skin, mucous membrane, and other body parts, and features include repeat attacks and long duration, leading to lower quality of life. This study aimed to analyze the changes of immunologic function before and after treatment of LP. MATERIAL AND METHODS Thirty cutaneous LP patients were selected. Peripheral blood was collected in the morning before and after treatment. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient method. Flow cytometry was used to detect T cell subpopulation CD4⁺ T cells and CD8⁺ T to calculate CD4⁺ T/CD8⁺ T ratio. Enzyme-linked immunosorbent assay (ELISA) was adopted to detect the helper T-cell (Th) factor IL-2, IFN-γ, IL-4, IL-6, IL-17, and IL-22 levels. RESULTS Compared with before treatment, the expressions of CD4⁺ T cells and CD8⁺ T cells were decreased, while the proportion of CD4⁺ T/CD8⁺ T were significantly elevated after treatment. IL-2 and IFN-γ secretion were markedly increased, whereas IL-4, IL-6, IL-17, and IL-22 were significantly reduced after treatment (P<0.05). CONCLUSIONS LP treatment reduces the distribution of CD4⁺ T cells and CD8⁺ T cells, and promotes the changes of Th1, Th2, and Th17 cytokines secretion.

MFAP2 promotes epithelial-mesenchymal transition in gastric cancer cells by activating TGF-ß/SMAD2/3 signaling pathway.

INTRODUCTION: Microfibril-associated protein 2 (MFAP2) is an extracellular matrix protein that interacts with fibrillin to modulate the function of microfibrils. MFAP2 has been reported to play a significant role in obesity, diabetes, and osteopenia, and has been shown to be upregulated in head and neck squamous cell carcinoma. However, the molecular function and prognostic value of MFAP2 have never been reported in gastric cancer (GC) or any other tumors. METHODS: The current study investigated the expression patterns, prognostic significance, functional role, and possible mechanisms of MFAP2 in GC. RESULTS: We demonstrated that MFAP2 was overexpressed in GC tissues, and its overexpression was significantly correlated with poor overall and disease-free survival in patients with GC. Moreover, we found that MFAP2 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) phenotype in GC cells. MFAP2 might modulate EMT of GC cells by activating the TGF-ß/SMAD2/3 signaling pathway. CONCLUSION: These findings provide novel evidence that MFAP2 plays a crucial role in the progression of GC. Therefore, MFAP2 may be a promising prognostic marker and a potent anticancer agent.

MACC1 facilitates chemoresistance and cancer stem cell­like properties of colon cancer cells through the PI3K/AKT signaling pathway.

With regards to colon cancer, resistance to 5­fluorouracil (5­FU)­based chemotherapy and cancer stem cells (CSCs) are considered important factors underlying therapy failure. Metastasis­associated colon cancer 1 (MACC1) has been associated with poor prognosis and the promotion of metastasis within several types of cancer. However, the biological behavior of MACC1 in chemoresistance and CSC­like properties remains unclear. In the present study, various methods including gene knockdown, gene overexpression, western blotting, quantitative polymerase chain reaction and MTT assay, have been adopted. According to the results of the present study, MACC1 was depleted in two colon cancer cell lines resistant to 5­FU; subsequently, CSC­like properties and 5­FU sensitivity were investigated. Within 5­FU­resistant cells, cell death was facilitated by MACC1 knockdown. Furthermore, sphere formation and the expression levels of pluripotent markers, including cluster of differentiation (CD) 44, CD133 and Nanog were reduced due to MACC1 depletion. Additionally, it was indicated that the phosphoinositide 3­kinase/protein kinase B signaling pathway may be associated with 5­FU resistance and CSC­like properties via MACC1.

NADPH Oxidase Activation Contributes to Heavy Ion Irradiation-Induced Cell Death.

Increased oxidative stress plays an important role in heavy ion radiation-induced cell death. The mechanism involved in the generation of elevated reactive oxygen species (ROS) is not fully illustrated. Here we show that NADPH oxidase activation is closely related to heavy ion radiation-induced cell death via excessive ROS generation. Cell death and cellular ROS can be greatly reduced in irradiated cancer cells with the preincubation of diphenyleneiodium, an inhibitor of NADPH oxidase. Most of the NADPH oxidase (NOX) family proteins (NOX1, NOX2, NOX3, NOX4, and NOX5) showed increased expression after heavy ion irradiation. Meanwhile, the cytoplasmic subunit p47phox was translocated to the cell membrane and localized with NOX2 to form reactive NADPH oxidase. Our data suggest for the first time that ROS generation, as mediated by NADPH oxidase activation, could be an important contributor to heavy ion irradiation-induced cell death.

Modulation of mesenchymal stem cells with miR-375 to improve their therapeutic outcome during scar formation.

Understanding of the mechanism of cutaneous scar formation with the goal of developing potential therapies to promote scar-less wound healing appears to be extremely critical. Mesenchymal stem cells (MSCs) have a demonstrate role in promoting scar-less wound healing. However, recent studies have shown that the function of MSCs may be attenuated due to insufficient activation in vivo. Here, we aimed to increase the activity and functions of MSCs to improve their effects during scar formation. We found that overexpression of microRNA-375 (miR-375) in MSCs significantly decreased the levels of tissue inhibitor of metalloproteinases 1 (TIMP-1) protein, but not mRNA. Mechanistically, miR-375 inhibited TIMP-1 protein translation through binding to the 3'-UTR of the TIMP-1 mRNA in MSCs. Transplantation of miR-375-expressing MSCs significantly reduced the fibrosis in the scar region of the mice, possibly through reduction of reactive oxygen species (ROS), suppression of transition of myofibroblasts from fibroblasts, and increases in hepatic growth factor (HGF). Together, these data suggest that overexpression of miR-375 in MSCs may substantially improve the effects of MSCs on reduction of scar during wound healing. Our study sheds new light on a scar-less wound healing.

Telomere-Mitochondrion Links Contribute to Induction of Senescence in MCF-7 Cells after Carbon-Ion Irradiation.

The effects of carbon-ion irradiation on cancer cell telomere function have not been comprehensively studied. In our previous report cancer cells with telomere dysfunction were more sensitive to carbon-ion irradiation, but the underlying mechanisms remained unclear. Here we found that telomerase activity was suppressed by carbon-ion irradiation via hTERT down-regulation. Inhibition of telomere activity by MST-312 further increased cancer cell radiosensitivity to carbon-ion radiation. hTERT suppression caused by either carbon-ion irradiation or MST-312 impaired mitochondrial function, as indicated by decreased membrane potential, mtDNA copy number, mitochondrial mass, total ATP levels and elevated reactive oxygen species (ROS). PGC-1α expression was repressed after carbion-ion irradiation, and hTERT inhibition by MST-312 could further exacerbate this effect. Lowering the mitochondrial ROS level by MitoTEMPO could partially counteract the induction of cellular senescence induced by carbon-ion radiation and MST-312 incubation. Taken together, the current data suggest that telomere-mitochondrion links play a role in the induction of senescence in MCF-7 cells after carbon-ion irradiation.

Characterization and functional analysis of two inhibitor of apoptosis genes in Zhikong scallop Chlamys farreri.

The proteins of inhibitor of apoptosis (IAP) family play important roles in regulation of apoptosis, immunological response and cell proliferation. Here we reported two IAP genes (named CfIAP1 and CfIAP2) in Zhikong scallop Chlamys farreri. The full-length CfIAP1 cDNA contained 1552 nucleotides, encoding a predicted protein of 251 amino acids with two BIR domains. The full-length CfIAP2 cDNA contained 1243 nt, encoding a 356-aa protein with one BIR domain and one RING domain. The two genes are ubiquitously expressed in six types of tissue of C. farreri. The expression levels of CfIAP1 and CfIAP2 were significantly up-regulated after challenged with acute viral necrobiotic disease virus, lipopolysaccharide and exposure to air. Subcellular localization assay showed that CfIAP1 was mainly distributed in cytoplasm and CfIAP2 was in cytoplasm and nucleus. As assessed using a kit designed to test Caspase3 function in mammalian cells, the activity of CfCaspase3 was enhanced as a result of the down-regulation of CfIAP2 expression by dsRNA-mediated gene silencing. Our study indicated that CfIAP1 and CfIAP2 may participate in the innate immunity and stress responses and that CfIAP2 might block apoptosis via inhibiting CfCaspase3 indirectly through an unexplored mechanism in C. farreri.

In Vivo Biodistribution and Toxicity of Highly Soluble PEG-Coated Boron Nitride in Mice.

The boron nitride (BN) nanoparticles, as the structural analogues of graphene, are the potential biomedicine materials because of the excellent biocompatibility, but their solubility and biosafety are the biggest obstacle for the clinic application. Here, we first synthesized the highly soluble BN nanoparticles coated by PEG (BN-PEG) with smaller size (~10 nm), then studied their biodistribution in vivo through radioisotope (Tc(99m)O4 (-)) labeling, and the results showed that BN-PEG nanoparticles mainly accumulated in the liver, lung, and spleen with the less uptake by the brain. Moreover, the pathological changes induced by BN-PEG could be significantly observed in the sections of the liver, lung, spleen, and heart, which can be also supported by the test of biochemical indexes in serum. More importantly, we first observed the biodistribution of BN-PEG in the heart tissues with high toxicity, which would give a warning about the cardiovascular disease, and provide some opportunities for the drug delivery and treatment.

Diallyl disulfide attenuated carbon ion irradiation-induced apoptosis in mouse testis through changing the ratio of Tap73/ΔNp73 via mitochondrial pathway.

Diallyl disulfide (DADS), a major organosulfur compound derived from garlic, has various biological properties, including anti-cancer effects. However, the protective mechanism of DADS against radiation-induced mouse testis cell apoptosis has not been elucidated. In this study, the magnitude of radiation effects evoked by carbon ion irradiation was marked by morphology changes, significant rise in apoptotic cells, activation expression of p53, up regulation the ratio of pro-apoptotic Tap73/anti-apoptotic ΔNp73, as well as alterations of crucial mediator of the mitochondrial pathway. Interestingly, pretreatment with DADS attenuated carbon ion irradiation-induced morphology damages and apoptotic cells. Additionally, DADS elevated radiation-induced p53 and p21 expression, suggesting that p53 might be involved in the inhibition of cell cycle progression through up regulation of p21. Furthermore, administration with DADS prevented radiation-induced Tap73/ΔNp73 expression and consequently down regulated Bax/Bcl-2 ratio, cytochrome c release and caspase-3 expression, indicating that the balance between Tap73 and ΔNp73 had potential to activate p53 responsive genes. Thus, our results showed that radio protection effect of DADS on mouse testis is mediated by blocking apoptosis through changing the ratio of Tap73/ΔNp73 via mitochondrial pathway, suggesting that DADS could be used as a potential radio protection agent for the testis against heavy-ion radiation.

Diallyl disulfide enhances carbon ion beams-induced apoptotic cell death in cervical cancer cells through regulating Tap73 /ΔNp73.

Diallyl disulfide (DADS), extracted from crushed garlic by steam-distillation, has been reported to provide the anticancer activity in several cancer types. However, the effect of DADS on high-LET carbon beams - induced cell death remains unknown. Therefore, we used human cervical cancer cells to elucidate the molecular effects of this diallyl sulfide. Radiotherapy remains the mainstay of treatment, especially in advanced cervical cancer and there is still space to improve the radiosensitivity to reduce radiation dosage. In this study, we found that radiation effects evoked by high-LET carbon beam was marked by inhibition of cell viability, cell cycle arrest, significant rise of apoptotic cells, regulation of transcription factor, such as p73, as well as alterations of crucial mediator of the apoptosis pathway. We further demonstrated that pretreatment of 10 µM DADS in HeLa cells exposed to radiation resulted in decrease in cell viability and increased radiosensitivity. Additionally, cells pretreated with DADS obviously inhibited the radiation-induced G2/M phase arrest, but promoted radiation-induced apoptosis. Moreover, combination DADS and the radiation exacerbated the activation of apoptosis pathways through up-regulated ration of pro-apoptotic Tap73 to anti-apoptotic ΔNp73, and its downstream proteins, such as FASLG, and APAF1. Taken together, these results suggest that DADS is a potential candidate as radio sensitive agent for cervical cancer.