Traumatic brain injury is one of the leading causes of mortality and morbidity worldwide. At present there is no effective treatment. Previous studies have demonstrated that topical application of ...adipose tissue-derived mesenchymal stem cells can improve functional recovery in experimental traumatic brain injury. In this study, we evaluated whether hypoxic preconditioned mesenchymal stem cells could enhance the recovery from traumatic brain injury. Traumatic brain injury was induced with an electromagnetically controlled cortical impact device. Two million mesenchymal stem cells derived from the adipose tissue of transgenic green fluorescent protein Sprague-Dawley rats were cultured under either hypoxic (2.5% O2 for 18 hours) (N = 30) or normoxic (18% O2) (N = 30) conditions, then topically applied to the exposed cerebral cortex within 1 hour after traumatic brain injury. A thin layer of fibrin was used to fix the cells in position. No treatment was given to the animals with traumatic brain injury (N = 30). Animals that underwent craniectomy without traumatic brain injury were treated as the sham group (N = 15). Neurological functions were evaluated with water maze, Roto-rod and gait analysis. Animals were sacrificed at days 3, 7, and 14 for microscopic examinations and real-time polymerase chain reaction analysis. The rats treated with hypoxic mesenchymal stem cells showed the greatest improvement in neurological function recovery. More green fluorescent protein-positive cells were found in the injured brain parenchyma treated with hypoxic mesenchymal stem cells that co-expressed glial fibrillary acidic protein, Nestin, and NeuN. Moreover, there was early astrocytosis triggered by the infiltration of more glial fibrillary acidic protein-positive cells and microgliosis was suppressed with fewer ionized calcium binding adapter molecule 1-positive cells in the penumbra region of hypoxic mesenchymal stem cells group at day 3. Compared with normoxic mesenchymal stem cells and traumatic brain injury only groups, there was significantly (p < 0.05) less neuronal death in both the hippocampus and penumbral regions in sections treated with hypoxic mesenchymal stem cells as determined by Cresyl violet and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining respectively. The expression of pro-inflammatory genes (interleukin 6, interleukin 1a, interleukin 1b, tumor necrosis factor α) was upregulated and apoptotic gene (Caspase-3) expression was suppressed at day 3. Anti-inflammatory (interleukin 10) and anti-apoptotic (BCL2 associated agonist of cell death) gene expression was upregulated at days 7 and 14. Our study showed that a hypoxic precondition enhanced the beneficial effects of mesenchymal stem cells on neurological recovery after traumatic brain injury.
Clinicians need reliable outcome predictors to improve the prognosis of septic patients. Mouse models are widely used in sepsis research. We aimed to review how mouse models were used to search for ...novel prognostic biomarkers of sepsis in order to optimize their use for future biomarker discovery.
We searched PubMed from 2012 to July 2022 using “((sepsis) AND (mice)) AND ((prognosis) OR (prognostic biomarker))”.
A total of 412 publications were retrieved. We selected those studies in which mouse sepsis was used to demonstrate prognostic potential of biomarker candidates and/or assist the subsequent evaluation in human sepsis for further appraisal. The most frequent models were lipopolysaccharide (LPS) injection and caecal ligation and puncture (CLP) using young male mice. Discovery technologies applied on mice include setting survival and nonsurvivable groups, detecting changes of biomarker levels and measuring physiological parameters during sepsis. None of the biomarkers achieved sufficient clinical performance for clinical use.
The number of studies and strategies using mouse models to discover prognostic biomarkers of sepsis are limited. Current mouse models need to be further optimized to better conform to human sepsis. Current biomarker platforms do not achieve predictive performance for clinical use.
Blood biomarkers hold potential for the early diagnosis of ischaemic stroke (IS). We aimed to evaluate the current weight of evidence and identify potential biomarkers and biological pathways for ...further investigation. We searched PubMed, EMBASE, the Cochrane Library and Web of Science, used R package meta4diag for diagnostic meta-analysis and applied Gene Ontology (GO) analysis to identify vital biological processes (BPs). Among 8544 studies, we included 182 articles with a total of 30,446 participants: 15675 IS, 2317 haemorrhagic stroke (HS), 1798 stroke mimics, 846 transient ischaemic attack and 9810 control subjects. There were 518 pooled biomarkers including 203 proteins, 114 genes, 108 metabolites and 88 transcripts. Our study generated two shortlists of biomarkers for future research: one with optimal diagnostic performance and another with low selection bias. Glial fibrillary acidic protein was eligible for diagnostic meta-analysis, with summary sensitivities and specificities for differentiating HS from IS between 3 h and 24 h after stroke onset ranging from 73% to 80% and 77% to 97%, respectively. GO analysis revealed the top five BPs associated with IS. This study provides a holistic view of early diagnostic biomarkers in IS. Two shortlists of biomarkers and five BPs warrant future investigation.
Highlights • Cryostored skull bone flaps at −75 to −80 °C beyond four months showed no viable osteoblasts. • Bacterial contamination rate of cryostored skull bone flaps was 27.8% in this study. • ...Bacterial culture yielded Pasteurella multocida and Methicillin-resistant Staphylococcus aureus in this study.
The biological role of mesenchymal stem cells (MSCs) in wound healing has been demonstrated. However, there were limited studies on the healing effect of secretome which consists of many biological ...factors secreted by MSCs. In this study, we aimed to compare the therapeutic effects of secretome with MSCs on facilitating wound healing.
Green fluorescent protein labelled adipose-derived MSCs (GFP-ADMSCs) or secretome was injected in the full-thickness skin excision model on SD rats. The wound healing process was evaluated by calculating the healing rate and the histological examinations on skin biopsy. The cell viability, proliferation and mobility of the rat dermal fibroblasts were compared after different treatments. The inflammatory response in macrophages was indicated by the level of nitric oxide (NO) and inflammatory cytokines through NO assay and ELISA.
On day 5 and day 14, both MSCs and secretome accelerated the wound healing, secretome further enhanced the process. GFP-MSCs were detected 10 days after transplantation. The level of IL-6 and TNF-α in blood was reduced after MSCs and secretome treatments. The expressions of VEGF and PCNA were increased after treatment, higher intensity of VEGF was observed in secretome-injected tissue. The concentrations of total protein and VEGF in secretome were 2.2 ± 0.5 mg/mL and 882.0 ± 72.7 pg/mL, respectively. The cell viability and proliferation of FR were promoted significantly after the treatment. The scratch test showed that secretome accelerated the wound healing speed. Secretome reduced the metabolism of macrophages remarkably, but it did not decrease the level of macrophage-secreted NO. The expression of the pro-inflammatory cytokines (IL-6, MCP-1 and TNF-α) was downregulated significantly.
Our study indicated both MSCs and MSCs-derived secretome enhanced the wound healing process in early phase. Secretome further promoted the healing effects through promoting the fibroblast proliferation and migration and suppressing the inflammatory response.
End-capping the diethynylfluorene unit with gold(I) moieties could significantly strengthen its cytotoxic activity on human cancer cells. Further study of the gold(I) derivative demonstrated its in ...vivo antitumor activity using Hep3B human hepatocellular carcinoma model with limited adverse effects on vital organs including liver and kidney.
A list of diethynylfluorenes and their gold(I) derivatives have been studied for their antitumor activity as a function of their structure–activity relationships. End-capping the fluoren-9-one unit with gold(I) moieties could significantly strengthen the cytotoxic activity in vitro on three human cancer cell lines with induction of reactive oxygen species generation on Hep3B hepatocellular carcinoma cells and exhibit attractive antitumor activity from in vivo nude mice Hep3B xenograft model with limited adverse effects on vital organs including liver and kidney.
2-Formyl-8-hydroxy-quinolinium chloride was prepared as Galipea longiflora alkaloid analogue and its anticancer activity was evaluated. Representative histopathological sections showed (a) ...significant tumour necrosis could be identified in 2-Formyl-8-hydroxy-quinolinium chloride-treated group while (b) good cellular integrity could be observed in vehicle treated group on day 23 (10 days after stopping the treatment).
The quinolinium chloride salt of 8-hydroxyqinolinecarbaldehyde (2-Formyl-8-hydroxy-quinolinium chloride) was prepared as Galipea longiflora alkaloid analogue and its anticancer activity was evaluated both in vitro and in vivo. This chloride salt was found to show certain degree of selectivity between hepatoma cells and normal hepatocytes in vitro. Athymic nude mice Hep3B xenograft model further demonstrated that this 2-Formyl-8-hydroxy-quinolinium chloride could execute strong anti-tumour activity with the identification of extensive necrotic feature from the tumour xenograft and limited adverse toxicological effect.
Following our previously reported pyridinyl phosphine oxides as antitumor agents, we targeted the commercially available C
2-axial chiral organophosphine ligand catalysts, such as ...2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (
BINAP)
1 and 2,2′,6,6′-tetramethoxy-4,4′-bis(diphenylphosphino)-3,3′-bipyridine (
P-Phos)
2 as a convenient source for producing organophosphine oxides as antitumor leads. Their corresponding chiral and racemic bi-phosphine oxides
3 and
4 can be obtained easily through a simple oxidation step with hydrogen peroxide, and their antitumor activities towards human hepatocellular carcinoma Hep3B cell line were reported. We found out that compound
3 shows stronger antitumor activity than that of
4, where axial chirality cannot improve their activity. Further athymic nude mice Hep3B xenograft model demonstrates the attractive
in vivo antitumor potential of
3.
Compound
rac-
3 (derived from
BINAP) shows preliminary
in vitro anti-cancer activity for human hepatocellular carcinoma Hep3B cell line, and showed retardation of Hep3B xenograft tumor growth
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The preparation of enantioselective tetrahydroquinolines using Ir-catalysed asymmetric hydrogenation and their possible cytotoxic potential towards the human carcinoma cell lines were presented. Of ...which, 1,2,3,4-tetrahydroquin-8-ol (2l) shows its anti-cancer activity both in vitro and in vivo.
The preparation of chiral tetrahydroquinolines using Ir-catalysed asymmetric hydrogenation and their possible cytotoxic potential anti-cancer activity were reported. Both of the in vitro cytotoxicity assay on a series of human cancer cell lines including A549 small cell lung cancer, MDA-MB-231 breast cancer, SaoS2 sacroma, SKHep-1 hepatoma and Hep3B hepatocellular carcinoma as well as in vivo animal model using Hep3B hepatocellular tumour xenograft on athymic nude mice suggest that 1,2,3,4-tetrahydroquin-8-ol is a potential anti-tumour alkaloid which may be further developed as a novel cancer chemotherapeutic agent.
A homologous set of 9,9‐dialkyl‐4,5‐diazafluorene compounds were prepared by alkylation of 4,5‐diazafluorene with the appropriate alkyl bromide and under basic conditions. The structures of these ...simple organic compounds were confirmed by spectroscopic techniques (FTIR, NMR, and FABMS). Their biological effects toward a panel of human carcinoma cells, including Hep3B hepatocellular carcinoma, MDAMB‐231 breast carcinoma, and SKHep‐1 hepatoma cells, were investigated; a structure–activity correlation was established with respect to the length of the alkyl chain and the fluorene ring structure. The relationship between the mean potency log(1/IC50) and alkyl chain length was systematically studied. The results show that compounds with butyl, hexyl, and octyl chains exhibit good growth inhibitory effects toward these three human carcinoma cell lines, and the 9,9‐dihexyl‐4,5‐diazafluorene further exhibits antitumor activity in athymic nude mice Hep3B xenograft models. For the structurally related dialkylfluorenes that lack the diaza functionality, in vitro cytotoxicity was not observed at clinically relevant concentrations.
A homologous series of 9,9‐dialkyl‐4,5‐diazafluorenes were prepared. Their spectroscopic properties and biological activities toward three human cancer cell lines, including Hep3B hepatocellular carcinoma, MDAMB‐231 breast carcinoma, and SKHep‐1 hepatoma, were investigated to understand their structure–activity relationships.