Intermittent hypoxia protects against hypoxic-ischemic brain damage by inducing functional angiogenesis.

Ischemic stroke (IS) induces neurological damage due to cerebrovascular occlusion. Restoring blood perfusion to the ischemic brain area in a timely fashion is the most effective treatment strategy. Hypoxia is an effective way of restoring blood perfusion by improving cerebrovascular microcirculation, while the effect varies greatly depending on hypoxic mode. This study aimed to screen for the optimal hypoxic mode to improve cerebrovascular microcirculation and prevent IS. Here, we found that compared with continuous hypoxia (CH), intermittent hypoxia (IH) significantly improved cerebral blood flow and oxygen saturation in mice without causing neurological impairment. By analyzing cerebrovascular microcirculation from mice, we found that the IH mode (13%, 5*10) with 13% O2, 5 min interval, and 10 cycles per day significantly improved the cerebrovascular microcirculation by promoting angiogenesis without affecting the integrity of the blood-brain barrier. In addition, IH (13%, 5*10) treatment of distal middle cerebral artery occlusion (dMCAO) mice significantly alleviated neurological dysfunction and reduced cerebral infarct volume by improving cerebrovascular microcirculation. CH had none of these positive effects. In summary, our study screened for an appropriate intermittent hypoxic mode that could improve cerebrovascular microcirculation, laying a theoretical foundation for the prevention and treatment of IS in clinical practice.

Higher serum occludin after successful reperfusion Is associated with early neurological deterioration.

AIMS: Early neurological deterioration (END) is an important factor that affects prognosis in patients with acute ischemic stroke. We explored the relationship between serum occludin levels after successful reperfusion and END in patients treated with endovascular thrombectomy (EVT). METHODS: We prospectively enrolled 120 stroke patients who underwent EVT with successful reperfusion. Enzyme-linked immunosorbent assay was used to detect the serum occludin levels on admission and within 1 h after successful reperfusion. Receiver operating characteristic curves (ROC) and regression analysis were used to compare the relationship between serum occludin and END after thrombectomy. RESULTS: Among the 120 patients, 36 (30%) experienced END. The END group had higher serum occludin levels than the non-END group after successful reperfusion [4.31 (3.71-5.38) vs 6.32 (5.88-6.99), p < 0.001]. The ROC curve showed that postoperative serum occludin levels had a significant prediction value for END (AUC: 0.86, p < 0.001). Regression analysis showed that serum occludin was an independent risk factor for END in EVT patients (adjusted odds ratio: 4.46, 95% confidence interval: 1.92-10.32; p < 0.001). CONCLUSIONS: The higher serum occludin levels were strongly related to END after successful reperfusion. Serum occludin may be an independent risk factor for END in EVT patients.

UPLC/MS-based untargeted metabolomics reveals the changes in muscle metabolism of electron beam irradiated Solenocera melantho during refrigerated storage.

Shrimp meat is an extremely perishable product; however, refrigeration can slow down spoilage. In this study, we used electron beam irradiation (EBI) to pre-treat shrimp meat and analyzed the metabolites of the treated shrimp meat during refrigerated storage using metabonomic analysis methods. In total, 4865 metabolites were identified, of which, 103 differential metabolites had KEGG (Kyoto Encyclopedia of Genes and Genomes) IDs. Further, two potential biomarkers were obtained. Based on the results, l-lysine was downregulated, while 2'-deoxyguanosine 5'-monophosphate and dihydroxyacetone phosphate acyl ester were upregulated during the refrigerated storage. The metabolic activity began to weaken gradually after 9 days. However, the different metabolites related to EBI were not identified herein. Nonetheless, the study findings revealed the metabolic changes in Solenocera melantho at the molecular level during refrigerated storage after EBI.

Engineering bacterial outer membrane vesicles as transdermal nanoplatforms for photo-TRAIL-programmed therapy against melanoma.

Melanoma is an aggressive cancer with rapid progression, relapse, and metastasis. Systemic therapies for melanoma exhibit limited anticancer potential and high toxicity. Here, we developed the outer membrane vesicles derived from transgenic Escherichia coli, modified with αvß3 integrin peptide targeting ligand and indocyanine green (named as I-P-OMVs), to induce the transdermal photo-TRAIL-programmed treatment in skin melanoma.-OMVs, which are outer membrane vesicles derived from transgenic Escherichia coli, modified with αvß3 integrin targeting ligand and indocyanine green (named as I-P-OMVs), to induce the transdermal photo-TRAIL-programmed treatment in skin melanoma. I-P-OMVs exhibited excellent stratum corneum penetration and specificity to melanoma. Upon near-infrared irritation, I-P-OMVs not only induced photothermal-photodynamic responses against primary melanoma spheroids but also activated TRAIL-induced apoptosis in disseminated tumor cells, resulting in a complete eradication of melanoma. I-P-OMVs are the first nanoplatforms to induce transdermal photo-TRAIL-programmed therapy in melanoma with enhanced antitumor performance and high safety, having great potential in cancer therapy.

Transdermal siRNA delivery by pH-switchable micelles with targeting effect suppress skin melanoma progression.

Melanoma is an aggressive disease with rapid progression and fast relapse, representing one of the formidable challenges in clinic. Current systemic therapies for melanoma exhibit limited anticancer potential due to the lack of specificity and limited efficacy. Herein, we design a cationic polymer (SCP-HA-PAE) by conjugating skin/cell penetrating peptide (SCP) and hyaluronic acid (HA) to the amphipathic polymer (poly ß-amino esters, PAE), then fabricate the nanocarriers (SHP) composed by SCP-HA-PAE for delivering siRNA to skin melanoma by transdermal application. SHP not only manifests the excellent ability in penetrating through skin stratum corneum (SC), targeting melanoma and being sensitive to pH, but also expresses the advantages in compacting the vector/siRNAs nanocomplexes and stimulating their endosome escape inside cells, which ensure the enhanced siRNA delivery efficiency. SHP/siRNA induce the strong efficacy in retarding the progression and relapse of skin melanoma through the enhanced apoptosis effect both in vitro & in vivo. This study provides a proof-of-concept design of pH-switchable cationic micelles as transdermal gene delivery nanoplatforms with targeting effect for melanoma therapy, which may be adapted widely in the treatment of various superficial tumors and skin genetic diseases.

Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti-nuclear antibody production in Lyn-deficient mice.

The intracellular tyrosine kinase Lyn mediates inhibitory receptor function in B cells and myeloid cells, and Lyn(-/-) mice spontaneously develop an autoimmune and inflammatory disease that closely resembles human systemic lupus erythematosus. TLR-signaling pathways have been implicated in the production of anti-nuclear Abs in systemic lupus erythematosus and mouse models of it. We used a conditional allele of Myd88 to determine whether the autoimmunity of Lyn(-/-) mice is dependent on TLR/MyD88 signaling in B cells and/or in dendritic cells (DCs). The production of IgG anti-nuclear Abs, as well as the deposition of these Abs in the glomeruli of the kidneys, leading to glomerulonephritis in Lyn(-/-) mice, were completely abolished by selective deletion of Myd88 in B cells, and autoantibody production and glomerulonephritis were delayed or decreased by deletion of Myd88 in DCs. The reduced autoantibody production in mice lacking MyD88 in B cells or DCs was accompanied by a dramatic decrease in the spontaneous germinal center (GC) response, suggesting that autoantibodies in Lyn(-/-) mice may depend on GC responses. Consistent with this view, IgG anti-nuclear Abs were absent if T cells were deleted (TCRß(-/-) TCRδ(-/-) mice) or if T cells were unable to contribute to GC responses as the result of mutation of the adaptor molecule SAP. Thus, the autoimmunity of Lyn(-/-) mice was dependent on T cells and on TLR/MyD88 signaling in B cells and in DCs, supporting a model in which DC hyperactivity combines with defects in tolerance in B cells to lead to a T cell-dependent systemic autoimmunity in Lyn(-/-) mice.

Polysaccharide from Lentinus edodes inhibits the immunosuppressive function of myeloid-derived suppressor cells.

Reversing the function of immune suppressor cells may improve the efficacy of cancer therapy. Here, we have isolated a novel polysaccharide MPSSS (577.2 Kd) from Lentinus edodes and examined its effects on differentiation and function of myeloid-derived suppressor cells (MDSCs). MPSSS is composed of glucose (75.0%), galactose (11.7%), mannose (7.8%), and xylose (0.4%). In vivo, it inhibits the growth of McgR32 tumor cells, which is correlated with a reduced percentage of MDSCs in peripheral blood. In vitro, it induces both morphological and biophysical changes in MDSCs. Importantly, MPSSS up-regulates MHC II and F4/80 expression on MDSCs, and reverses their inhibition effect on CD4(+) T cells in a dose-dependent manner. The mechanism study shows that MPSSS may stimulate MDSCs through a MyD88 dependent NF-κB signaling pathway. Together, we demonstrated for the first time that MPSSS stimulates the differentiation of MDSCs and reverses its immunosuppressive functions, shedding new light on developing novel anti-cancer strategies by targeting MDSCs.

Ginsenoside-Rb1 and tetramethylpyrazine phosphate act synergistically to prevent dilated cardiomyopathy in cTnTR141W transgenic mice.

Ginsenoside-Rb1 (Rb1) is known to be partially associated with the inhibition of heparin-binding epidermal growth factor-like growth factor (HB-EGF). Tetramethylpyrazine phosphate (TMPP) inhibits the activation of the calcium/calmodulin/calmodulin-dependent protein kinase (Ca²âº/CaM/CaMKII) pathway. The α-myosin heavy chain cTnT(R141W) transgenic mouse was previously reported as a model for dilated cardiomyopathy (DCM), and it was used to test the effects of combinations of Rb1 and TMPP in reversing the progression of DCM and the potential mechanism. Survival, echocardiography, histologic features assessed the effectiveness of Rb1 and TMPP treatments. Western blot and reverse transcription polymerase chain reactions were used to determine expression levels of certain genes. This study clearly demonstrated that treatment with a combination of Rb1 and TMPP could inhibit the expression of HB-EGF, calmodulin1 (Calm1), and calcium/calmodulin-dependent protein kinase II beta (Camk2b). Rb1 alone mainly reduced the expression of HB-EGF, and TMPP alone mainly reduced the expression of Calm1 and Camk2b. Treatment with Rb1 and TMPP had synergistic effects on the amelioration of chamber dilation, contractile dysfunction, interstitial fibrosis, and ultrastructural degeneration in cTnT(R141W) mice when compared with the results of treatment with Rb1 or TMPP alone, and those were probably due to the inhibition of both HB-EGF and the Ca²âº/CaM/CaMKII pathway.

LMNA E82K mutation activates FAS and mitochondrial pathways of apoptosis in heart tissue specific transgenic mice.

The lamin A/C (LMNA), nuclear intermediate filament proteins, is a basic component of the nuclear lamina. Mutations in LMNA are associated with a broad range of laminopathies, congenital diseases affecting tissue regeneration and homeostasis. Heart tissue specific transgenic mice of human LMNA E82K, a mutation causing dilated cardiomyopathy, were generated. Lmna(E82K) transgenic mouse lines exhibited thin-walled, dilated left and right ventricles, a progressive decrease of contractile function assessed by echocardiography. Abnormalities of the conduction system, myocytes disarray, collagen accumulation and increased levels of B-type natriuretic peptide (BNP), procollagen type III α1 (Col3α1) and skeletal muscle actin α1 (Actα1) were detected in the hearts of Lmna(E82K) transgenic mice. The LMNA E82K mutation caused mislocation of LMNA in the nucleus and swollen mitochondria with loss of critae, together with the loss of nuclear envelope integrity. Most interestingly, we found that the level of apoptosis was 8.5-fold higher in the Lmna(E82K) transgenic mice than that of non-transgenic (NTG) mice. In the presence of the LMNA E82K, both of FAS and mitochondrial pathways of apoptosis were activated consistent with the increase of FAS expression, the release of cytochrome c from mitochondria to cytosol and activation of caspase-8, -9 and -3. Our results suggested that the apoptosis, at least for the LMNA E82K or the mutations in the rod region of Lamin A/C, might be an important mechanism causing continuous loss of myocytes and lead to myocardial dysfunction. It could be a potential therapeutic means to suppress and/or prevent inappropriate cardiac cell death in patients carrying LMNA mutation.