A New Dy(III) Complex: Fluorescence Performances, Loading with Resveratrol-Hydrogels Against Skin Aging and Molecular Docking.

In the present research, novel lanthanide coordination compounds [DyL(PhCOO)(CH3OH)](ClO4)2·(CH3OH)2 (1) were characterized by the compression of 2,6-diformyl-4-methyl-phenol (dmp) and 1,3-diamino-2-propanol using benzoate as the secondary ligand, where L indicates the deprotonated macrocyclic ligand. Through the high structural rigidity driven by the coordination of the macrocyclic ligand formed by condensation in methanol solution and sodium benzoate with Dy(ClO4)3·6H2O, compound 1 exhibits outstanding cyan-emitting fluorescence performance and potential applications as a fluorescent material. Additionally, hyaluronic acid (HA)/ carboxymethyl chitosan (CMCS) hydrogels were prepared with loaded resveratrol metal-organic complexes according to the synthetic chemical approach. In biological study, we evaluated the effect of hydrogels on oxidative stress on human dermal fibroblasts. Examined by molecular docking simulation, the results showed that the binding interactions were from the phenol group, the carboxyl group and also the "-N=" group, indicating Dy metal complex has excellent biological capability.

Platinum (IV) drugs with cannabidiol inducing mitochondrial dysfunction and synergistically enhancing anti-tumor effects.

Chemotherapy resistance is an insurmountable problem in clinical anticancer therapy. Although Oxaliplatin is an effective chemotherapeutic agent for the treatment of colorectal cancer (CRC), it still suffers from serious toxicities as well as drug resistance. In this work, three Oxaliplatin tetravalent platinum prodrugs(O1-O3) and three novel mixed ammine/amine analogs(C1-C3) were constructed, introducing cannabidiol with anti-tumor activity in their axial position. All Pt(IV) prodrugs exhibited potent antitumor effects in a variety of tumor cell lines, especially in HCT-116 cells, where complex O3 showed strong inhibitory effects with the half maximal inhibitory concentrations (IC50) value of 6.02 ± 0.69 µM and about 2.6 times higher than that of Oxaliplatin. Further studies revealed that complex O3 decreased cellular mitochondrial membrane potential in a concentration-dependent manner and enhanced reactive oxygen species (ROS) accumulation by decreasing the expression of catalase, superoxide dismutase 2 (SOD2) and superoxide dismutase 3 (SOD3). Complex O3 induces mitochondrial dysfunction and upregulates the pro-apoptotic protein Noxa, ultimately leading to severe DNA damage. The upregulation of Phosphorylated histone protein H2AX (γ-H2AX) expression is clear evidence. In addition, O3 inhibits the expression of RAD51 protein and prevents DNA damage repair, thus overcoming drug resistance. This strategy of combining bioactive molecules cannabidiol with platinum drugs to improve therapeutic efficacy and overcome drug resistance has been proven to be very effective and deserves further investigation.

Copper-Catalyzed Oxygenative Skeletal Rearrangement of Tetrahydro-ß-carbolines Using H2 O and O2 as Oxygen Sources.

Herein, we report an unprecedented skeletal rearrangement reaction of tetrahydro-ß-carbolines enabled by copper-catalyzed single-electron oxidative oxygenation, in which H2 O and O2 act as oxygen sources to generate a unique 2-hydroxyl-3-peroxide indoline intermediate. The synthetic reactivity of 2-hydroxyl-3-peroxide indoline species was demonstrated by a unique multi-step bond cleavage and formation cascade. Using a readily available copper catalyst under open-air conditions, highly important yet synthetically difficult spiro[pyrrolidone-(3,1-benzoxazine)] products were obtained in a single operation. The synthetic utility of this methodology is demonstrated by the efficient synthesis of the natural products donaxanine and chimonamidine, as well as the 3-hydroxyl-pyrroloindoline scaffold, in just one or two steps.

Inhibition of TMEM16A improves cisplatin-induced acute kidney injury via preventing DRP1-mediated mitochondrial fission.

Acute kidney injury (AKI) is associated with high morbidity and mortality. Our previous study has demonstrated that TMEM16A, a Ca2+-activated chloride channel, contributes to renal fibrosis progression in chronic kidney disease. However, whether TMEM16A is involved in AKI is still unknown. In this study, we established cisplatin AKI mice model and found that TMEM16A expression was upregulated in the injured kidney. In vivo knockdown of TMEM16A effectively prevented cisplatin-induced tubular cell apoptosis, inflammation and kidney function loss. Western blot and transmission electron microscopy (TEM) revealed that TMEM16A knockdown inhibited Drp1 translocation from the cytoplasm to mitochondria and prevented mitochondrial fission in tubular cells. Consistently, in cultured HK2 cells, knockdown or inhibition of TMEM16A by shRNA or its specific inhibitor suppressed cisplatin-induced mitochondrial fission and its associated energy dysfunction, ROS accumulation, and cell apoptosis via inhibiting Drp1 activation. Further investigation showed that genetic knockdown or pharmacological inhibition of TMEM16A inhibited cisplatin-induced Drp1 Ser-616 site phosphorylation through ERK1/2 signaling pathway, whereas overexpression of TMEM16A promoted this effect. Treatment with Drp1 or ERK1/2 inhibitor could efficiently prevent cisplatin-induced mitochondrial fission. Collectively, our data suggest that TMEM16A inhibition alleviated cisplatin-induced AKI by preventing tubular cell mitochondrial fission through the ERK1/2 / Drp1 pathway. Inhibition of TMEM16A may be a novel therapeutic strategy for AKI.

In Silico Exploration of the Molecular Mechanism of Cassane Diterpenoids on Anti-inflammatory and Immunomodulatory Activity.

Cassane diterpenoids (CAs), recognized as main constituents of many medical plants of the genus Caesalpinia, exhibit diverse bioactivities, including anti-inflammatory and immunomodulatory activity, and also showed a therapeutic effect on rheumatoid arthritis (RA) according to previous work, including ours. In this study, 102 CA compounds were selected to explore the possible molecular mechanism of this class of natural products on anti-inflammatory and immunomodulatory activity using RA as a disease model through a series of in silico methods: chemical-similarity-based target prediction, molecular docking, and molecular dynamics (MD) simulation. As a consequence, four signaling pathways (TCR signaling pathway, TLR signaling pathway, VEGF signaling pathway, and osteoclast differentiation pathway) by which CAs exert their effect on inflammation and immunomodulation were identified. Furthermore, the binding modes of CAs complexing with several crucial targets, which were picked out by credible docking results and took part in these signaling pathways, were explored by MD simulations. This is the first time that the molecular mechanism of the anti-RA activity of natural CAs has been investigated with in silico methods, and these findings might explain the activity of CAs on anti-inflammation and immunomodulation, which could supply a valuable reference for drug design research on CAs.

Peroxisome proliferator-activated receptor-γ agonist-mediated inhibition of cell growth is independent of apoptosis in human epidermoid carcinoma A431 cells.

Evidence suggests that peroxisome proliferator activated receptor-γ (PPAR-γ) acts as a tumor suppressor in multiple types of cancer; however, the role of action of PPAR-γ on human epidermoid carcinoma is unclear. The present study investigated the effects of a PPAR-γ agonist, rosiglitazone, on human epidermoid carcinoma cell growth using the A431 cell line. The effects of rosiglitazone on cell viability and proliferation were evaluated with MTS and [3H] thymidine incorporation assays. The effects of rosiglitazone on the cell cycle and apoptosis were analyzed by flow cytometry, and western blotting. It was identified that rosiglitazone inhibited A431 cell proliferation in a dose-dependent manner, increased the proportion of cells in the G1 phase, but did not affect apoptosis. Consistently, there was a significant decrease in the expression of cell proliferation-associated proteins, including cyclin D1, cyclin-dependent kinase (Cdk)2 and Cdk4 in A431 cells treated with rosiglitazone. This decrease was rescued by a selective antagonist of PPAR-γ or specific PPAR-γ small interfering RNAs. However, the ratio of B-cell lymphoma 2 (Bcl-2) to Bcl-2 associated X protein, which is associated with cell apoptosis, was not affected by these treatments. The data of the present study suggest that the PPAR-γ agonist rosiglitazone inhibits human epidermoid carcinoma cell growth through regulating the expression of the cell cycle-associated proteins, and that this effect is independent of apoptosis.

MicroRNA­24­1­5p promotes malignant melanoma cell autophagy and apoptosis via regulating ubiquitin D.

The present study aimed to investigate the key roles and possible regulatory mechanism of microRNA (miR)­24­1­5p in regulating the autophagy, and apoptosis of malignant melanoma cells. The expression levels of miR­24­1­5p in malignant melanoma tissues were determined. Human melanoma A375 cells were transfected with miR­24­1­5p mimic and control. The effects of miR­24­1­5p overexpression on regulating the expressions of autophagy­related proteins [microtubule­associated protein 1A/1B­light chain 3 (LC3)­II, LC3­I and Beclin­1] and apoptosis­related proteins [apoptosis regulator Bcl­2 (Bcl­2) and (BCL2 like 1) Bcl­xL] were investigated. The percentage of apoptotic cells in different transfected cells was detected. In addition, luciferase reporter assays were performed to confirm whether ubiquitin D (UBD) was a target of miR­24­1­5p. The effects of UBD silencing on autophagy and apoptosis were also investigated. The expression levels of janus kinase (JNK), phosphorylated (P)­JNK, Jun proto­oncogene AP­1 transcription factor subunit (c­Jun) and p­c­Jun were determined following the overexpression of miR­24­1­5p, and UBD. In comparison with adjacent normal tissues, miR­24­1­5p was significantly downregulated in malignant melanoma tissues. Overexpression of miR­24­1­5p significantly increased the levels of LC3­II/I ratio and Beclin­1 expression, and decreased the expression levels of Bcl­2 and Bcl­xL. Flow cytometry also showed that miR­24­1­5p overexpression promoted cell apoptosis. Moreover, UBD was confirmed as a direct target of miR­24­1­5p. Silencing of UBD promoted melanoma cell autophagy and apoptosis via regulating the expression levels of related proteins. Besides, the levels of the p­JNK/JNK and p­c­Jun/Jun ratios were significantly increased following miR­24­1­5p overexpression, which were reversed following co­overexpression of miR­24­1­5p, and UBD. Overexpression of miR­24­1­5p may target UBD, and subsequently promote the autophagy and apoptosis of malignant melanoma cells through activation of the JNK signaling pathway.

Autologous peripheral blood haematopoietic stem cell transplantation for systemic lupus erythematosus: the observation of long-term outcomes in a Chinese centre.

OBJECTIVES: We aimed to evaluate the safety and long-term efficacy of autologous peripheral blood haematopoietic stem cell transplantation (APHSCT). METHODS: We did not want to evaluate the efficacy of antibodies but rather the clinical response by investigating progression-free survival and serologic response by assessing autoantibody titres and complement levels. RESULTS: Overall, 22 patients with SLE (17 females; median age, 23 years) undergoing APHSCT were included. The 3-year progression-free survival (PFS) was 77.27% at our centre. We found that all the patients survived over three years. The 5-year PFS and overall survival (OS) rate was 67.90% and 95.20%. The titres of antinuclear antibody (ANA), anti-double-stranded deoxyribonucleic acid antibody (anti-dsDNA), anti-Sm antibody, and 24-h urinary protein significantly decreased, while complements 3 (C3) and C4 normalised at 100 days after transplantation (p<0.05). Kidney re-biopsy revealed a decrease in immune complex deposits in patients with remission. The incidence of CMV reactivation was 59.09% after transplantation in 3 years. Pregnancy and childbirth were reported in three female patients after transplantation. The risk of post-transplantation complications persisted for many years. CONCLUSIONS: Immunoablation followed by APHSCT has the potential to induce long-term clinical and serologic remissions despite withdrawal of immunosuppressive maintenance therapy. While relapses may occur, in our small cohort of patients we found no predictive markers for relapse development by analysing antibody and complement levels and urinary proteinuria.

Increased miR-424-5p expression in peripheral blood mononuclear cells from patients with pemphigus.

Pemphigus is an autoimmune disease that causes blisters and erosions in the skin and mucous membranes. The development of pemphigus is associated with the imbalance of T­cell and humoral responses. MicroRNAs (miRNAs) can regulate many cell functions. However, whether miRNA expression is altered in peripheral blood mononuclear cells (PBMCs) during the pathogenesis of pemphigus has not been clarified. The aim of the present study was to examine the miRNA expression profiles of PBMCs from patients with pemphigus. The expression profiles of miRNAs in PBMCs from patients with active pemphigus (n=3) and healthy subjects (n=3) were analyzed by microarray. The relative levels of miR-424-5p expression in PBMCs from 9 patients and controls were validated by RT-qPCR. The functional and biological processes of the differentially expressed miRNAs were analyzed by bioinformatics. There were 124 differentially expressed miRNAs in PBMCs from the patients with pemphigus, compared with healthy controls, including 71 that were upregulated (P<0.05, fold change >2), and 53 that were downregulated (P<0.05, fold change <0.5). miR-424-5p was highly expressed in patients with pemphigus. Bioinformatics analysis indicated that the genes targeted by miR-424-5p were involved in intracellular signaling cascades, phosphate metabolism and regulation of kinase activity. The predicted target genes were associated with the T-cell receptor and mitogen-activated protein kinase signaling pathways as well as others. In conclusion, the results have demonstrated the miRNA expression profile, and verified that miR-424-5p was upregulated in PBMCs from patients with pemphigus. The biological function and potential pathways of miR-424-5p in pemphigus were predicted. Thus, miR-424-5p may contribute to the pathogenesis of pemphigus.

Application of autologous hematopoietic stem cell transplantation for pemphigus.

BACKGROUND: Pemphigus is a rare and fatal autoimmune disease for which the treatment options are limited. This study aimed to evaluate the efficacy of autologous peripheral hematopoietic stem cell transplantation (APHSCT) for pemphigus. METHODS: We conducted APHSCT for 12 pemphigus patients (seven males and five females, mean age 23.8 years) with life-threatening complications or who responded poorly to conventional therapy. Peripheral blood stem cells were mobilized with cyclophosphamide, granulocyte colony-stimulating factor, and rituximab, and purified autologous CD34+ stem cells were infused. Overall survival rate, progression-free survival, and adverse events were recorded. RESULTS: With a mean follow-up period of 80.3 months, overall survival and complete clinical remission rates were 92% (11/12) and 75% (9/12), respectively. Adverse effects included pyrexia, allergy, infection, and elevation of enzymes. Only one patient died of severe sepsis and multiple organ failure 2 months after APHSCT. CONCLUSION: Overall APHSCT is a promising therapeutic option for pemphigus.

Suppression of interleukin 17 contributes to the immunomodulatory effects of adipose-derived stem cells in a murine model of systemic lupus erythematosus.

Due to roles in immunoregulation and low immunogenicity, mesenchymal stem cells have been suggested to be potent regulators of the immune response and may represent promising treatments for autoimmune disease. Adipose-derived stem cells (ADSCs), stromal cells derived from adipose tissue, were investigated with allogeneic ADSCs in B6.MRL/lpr mice, a murine model of systemic lupus erythematosus (SLE). We intravenously injected allogeneic ADSCs into SLE mice after disease onset and report that ADSCs reduced anti-ds DNA antibodies in serum and proteinuria in SLE mice. Also, ADSCs decreased IL-17 and IL-6 expression in serum of SLE mice. ADSCs alleviated renal damage and inflammatory cell infiltration and edema of the renal interstitium. Furthermore, ADSCs significantly downregulated renal IL-17 and CD68 expression, suggesting that ADSCs suppressed renal inflammation. ADSCs also decreased IL-17 mRNA expression and increased Foxp3, ROR-γt and miR-23b mRNA expression in renal tissue in SLE mice. ADSCs reduced renal protein expression of TAB 2 and IKK-α in SLE mice. Thus, ADSCs may be a novel potential therapy for treating SLE.

Primary cutaneous anaplastic large-cell lymphoma: a case report.

Primary cutaneous anaplastic large-cell lymphoma (PCALCL) is a part of the spectrum of CD30+ lymphoproliferative cutaneous processes. The characteristics include single or multifocal nodules that ulcerate as skin lesion, slow disease progression, autoregressive, and recurrent in few years. The present study report the case of a 16-year-old boy presenting PCALCL with single nodules, ulcer, keloid, and scab in his right-side face. He showed a good response to the treatment with systemic chemotherapy and dermatoplasty, and regained confidence after the appearance of recovery. There is no relapse of the primary lesion and organs involved till now. The chemotherapy combining with surgical excision and dermatoplasty is a good method for PCALCL, per the lesion biopsy and positron emission tomography-computed tomography before and after treatment.

[Expression of BATF, a member of the activator protein-1 family, in renal tissues of MRL/lpr mice].

OBJECTIVE: To investigate the expression of BATF, a member of the activator protein-1 family, in the renal tissues of mice with lupus nephritis. METHODS: The renal tissues from 24-week-old female MRL/lpr mice and age- and sex-matched C57BL/6 mice were examined for BATF protein expressions using Western blotting and for expressions of BATF, RORγt and IL-17A mRNA using quantitative real-time PCR. The results of laboratory examinations were analyzed in relation with the histopathology of the mice. RESULTS: The urinary protein and ds-DNA levels were significantly higher in MRL/lpr mice than in the control mice (P<0.05). Compared to normal control mice, MRL/lpr mice showed obvious glomerular fibrosis and inflammatory cell infiltrating with significantly increased BATF protein and mRNA expressions (P<0.05) and RORγt and IL-17 mRNA expressions in the renal tissues (P<0.05). In MRL/lpr mice, the expression of BATF mRNA was positively correlated with the RORγt and IL-17A mRNA expressions in the renal tissues. CONCLUSION: The renal expressions of BATF protein and mRNA is increased in MRL/lpr mice. BATF may participate in the immunopathogenesis of lupus nephritis by enhancing Thl7 cell response.

Migration and vascular lumen formation of endothelial cells in cancer cell spheroids of various sizes.

We developed a microfluidic device to culture cellular spheroids of controlled sizes and suitable for live cell imaging by selective plane illumination microscopy (SPIM). We cocultured human umbilical vein endothelial cells (HUVECs) within the spheroids formed by hepatocellular carcinoma cells, and studied the distributions of the HUVECs over time. We observed that the migration of HUVECs depended on the size of spheroids. In the spheroids of ∼200 µm diameters, HUVECs migrated outwards to the edges within 48 h; while in the spheroids of ∼250 µm diameters, there was no outward migration of the HUVECs up to 72 h. In addition, we studied the effects of pro-angiogenic factors, namely, vascular endothelial growth factor (VEGF) and fibroblast growth factor (ß-FGF), on the migration of HUVECs in the carcinoma cell spheroid. The outward migration of HUVECs in 200 µm spheroids was hindered by the treatment with VEGF and ß-FGF. Moreover, some of the HUVECs formed hollow lumen within 72 h under VEGF and ß-FGF treatment. The combination of SPIM and microfluidic devices gives high resolution in both spatial and temporal domains. The observation of HUVECs in spheroids provides us insight on tumor vascularization, an ideal disease model for drug screening and fundamental studies.

When formal laws and informal norms collide: lineage networks versus birth control policy in China.

Ancestor worship and bloodline continuation are the core norms of lineage in China. Beginning in the late 1970s, these cultural norms came into direct confrontation with the state birth control policy. Pitched against each other are the antinatalist laws backed by the powerful and unyielding state apparatus on the one side and the ancient pronatalist norms backed by revived lineage networks on the other. Even though the draconian state policies did succeed in dramatically reducing the overall birthrates, data analyses show that villages with strong kinship networks tend to have higher birthrates. The findings demonstrate the normative capacity of social networks to bend the iron bars of formal institutions. A general framework is developed for analyzing the roles of social networks in four ideal-typical juxtapositions of formal and informal institutions: normativism, legalism, congruence, and conflict.