Sphingosine kinase 2 activates autophagy and protects neurons against ischemic injury through interaction with Bcl-2 via its putative BH3 domain

Our previous findings suggest that sphingosine kinase 2 (SPK2) mediates ischemic tolerance and autophagy in cerebral preconditioning. The aim of this study was to determine by which mechanism SPK2 activates autophagy in neural cells. In both primary murine cortical neurons and HT22 hippocampal neuronal cells, overexpression of SPK2 increased LC3II and enhanced the autophagy flux. SPK2 overexpression protected cortical neurons against oxygen glucose deprivation (OGD) injury, as evidenced by improvement of neuronal morphology, increased cell viability and reduced lactate dehydrogenase release. The inhibition of autophagy effectively suppressed the neuroprotective effect of SPK2. SPK2 overexpression reduced the co-immunoprecipitation of Beclin-1 and Bcl-2, while Beclin-1 knockdown inhibited SPK2-induced autophagy. Both co-immunoprecipitation and GST pull-down analysis suggest that SPK2 directly interacts with Bcl-2. SPK2 might interact to Bcl-2 in the cytoplasm. Notably, an SPK2 mutant with L219A substitution in its putative BH3 domain was not able to activate autophagy. A Tat peptide fused to an 18-amino acid peptide encompassing the native, but not the L219A mutated BH3 domain of SPK2 activated autophagy in neural cells. The Tat-SPK2 peptide also protected neurons against OGD injury through autophagy activation. These results suggest that SPK2 interacts with Bcl-2 via its BH3 domain, thereby dissociating it from Beclin-1 and activating autophagy. The observation that Tat-SPK2 peptide designed from the BH3 domain of SPK2 activates autophagy and protects neural cells against OGD injury suggest that this structure may provide the basis for a novel class of therapeutic agents against ischemic stroke

Prognostic Effect of Bisphosphonate Exposure for Patients With Diagnosed Solid Cancer: A Systematic Review With Meta-Analysis of Observational Studies

Background: Bisphosphonates are widely prescribed for the prevention and treatment of osteoporosis. Recent epidemiological studies indicate that people with bisphosphonate use may have lower cancer risk and have improved survival. The aim of this study is to determine the association between bisphosphonate use and survival outcomes in solid cancer patients using systematic review and meta-analysis.Methods: A systematic literature search was performed using the PubMed, Embase, and Cochrane databases. Original articles published until April, 2018 were selected. The survival outcome measures assessed included overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS). Pooled hazard ratio (HR) and their 95% confidence interval (95% CI) were derived using a random-effects model.Results: Out of 9,742 retrieved citations, six cohort studies and two nested case-control studies satisfying the inclusion criteria were included for analyses. Bisphosphonate use was significantly associated with improved OS (HR 0.84, 95% CI 0.76–0.93), CSS (HR 0.73, 95% CI 0.58–0.90) and RFS (HR 0.72, 95% CI 0.53–0.96). The results of subgroup analyses stratified by major study characteristics were generally consistent with the main findings. For individual cancer type, we found that bisphosphonate use was significantly associated with longer OS for patients with gastroesophageal cancer (HR 0.62, 95% CI 0.40–0.98), as well as longer CSS for patients with breast cancer (HR 0.73, 95% CI 0.55–0.95).Conclusions: Current evidence indicates that bisphosphonate use is significantly associated with improved survival for patients with solid cancer. However, the prognostic effects in specific solid tumors remains to be confirmed by further large prospective cohort studies

Molecular detection of Bartonella species in wild small mammals in western Yunnan Province, China

BackgroundSmall mammals serve as the main reservoir for Bartonella and as a proxy indicator of the potential risk of Bartonella transmission from nature to humans. They offer a valuable early warning for human infection. Nevertheless, geographical variations in the impact of the host on the occurrence of Bartonella infection are underestimated. This study was designed to investigate the infection characteristics of Bartonella and explore its species diversity in wild small mammals in western Yunnan Province, China.MethodsWild small mammals were captured from Yulong, Jianchuan, and Lianghe counties in western Yunnan Province between 2015 and 2016. Real-time quantitative PCR (qPCR) was used to detect Bartonella infection, and the Bartonella species were identified by phylogenetic analysis. The factors associated with Bartonella infection in small mammals were analyzed by the Chi-square Test.ResultsThe prevalence of Bartonella in small mammals was 47.85% (768/1605). Lianghe County had the highest Bartonella infection rate, with 56.27% of the samples tested positive, followed by a rate of 50.91% was tested in Yulong County, and 39.97% in Jianchuan County (p < 0.001). Bartonella was detected positive in a total 25 small mammal species, with infection rates ranging from 2.17% to 100%. Niviventer fulvescens had the highest Bartonella infection rate. In comparison with the dominant small mammal species, Eothenomys mileyus had the lowest Bartonella infection rate than that in Apodemus chevrieri, Rattus tanezumi, and Apodemus draco (p < 0.001). Male small mammals had a higher infection rate than females (p < 0.05). The prevalence of Bartonella in small mammals during the summer season was higher compared to the other three seasons (p < 0.001). Woodland landscape had the highest Bartonella infection rate (p < 0.001). Bartonella rochalimae, B. japonica, B. tribocorum, B. washoensis, B. sylvatica, and B. rattimassiliensis were obtained from infected small mammals.ConclusionThis study showed a high prevalence of Bartonella was detected with various Bartonella species in small mammals in Yulong, Jianchuan, and Lianghe counties of western Yunnan Province. These findings hold significant scientific clues, providing valuable reference points for further research of Bartonella natural foci in Yunnan or other analogues environments

Phosphoantigen/IL2 Expansion and Differentiation of Vγ2Vδ2 T Cells Increase Resistance to Tuberculosis in Nonhuman Primates

Dominant Vγ2Vδ2 T-cell subset exist only in primates, and recognize phosphoantigen from selected pathogens including M. tuberculosis(Mtb). In vivo function of Vγ2Vδ2 T cells in tuberculosis remains unknown. We conducted mechanistic studies to determine whether earlier expansion/differentiation of Vγ2Vδ2 T cells during Mtb infection could increase immune resistance to tuberculosis in macaques. Phosphoantigen/IL-2 administration specifically induced major expansion and pulmonary trafficking/accumulation of phosphoantigen-specific Vγ2Vδ2 T cells, significantly reduced Mtb burdens and attenuated tuberculosis lesions in lung tissues compared to saline/BSA or IL-2 controls. Expanded Vγ2Vδ2 T cells differentiated into multifunctional effector subpopulations capable of producing anti-TB cytokines IFNγ, perforin and granulysin, and co-producing perforin/granulysin in lung tissue. Mechanistically, perforin/granulysin-producing Vγ2Vδ2 T cells limited intracellular Mtb growth, and macaque granulysin had Mtb-bactericidal effect, and inhibited intracellular Mtb in presence of perforin. Furthermore, phosphoantigen/IL2-expanded Vγ2Vδ2 T effector cells produced IL-12, and their expansion/differentiation led to enhanced pulmonary responses of peptide-specific CD4+/CD8+ Th1-like cells. These results provide first in vivo evidence implicating that early expansion/differentiation of Vγ2Vδ2 T effector cells during Mtb infection increases resistance to tuberculosis. Thus, data support a rationale for conducting further studies of the γδ T-cell-targeted treatment of established TB, which might ultimately help explore single or adjunctive phosphoantigen expansion of Vγ2Vδ2 T-cell subset as intervention of MDR-tuberculosis or HIV-related tuberculosis

Antibacterial Bisabolane-Type Sesquiterpenoids from the Sponge-Derived Fungus Aspergillus sp.

Four new bisabolane-type sesquiterpenoids, aspergiterpenoid A (1), (−)-sydonol (2), (−)-sydonic acid (3), and (−)-5-(hydroxymethyl)-2-(2′,6′,6′-trimethyltetrahydro-2H- pyran-2-yl)phenol (4) together with one known fungal metabolite (5) were isolated from the fermentation broth of a marine-derived fungus Aspergillus sp., which was isolated from the sponge Xestospongia testudinaria collected from the South China Sea. Four of them (1–4) are optically active compounds. Their structures and absolute configurations were elucidated by using NMR spectroscopic techniques and mass spectrometric analysis, and by comparing their optical rotations with those related known analogues. Compounds 1–5 showed selective antibacterial activity against eight bacterial strains with the MIC (minimum inhibiting concentrations) values between 1.25 and 20.0 µM. The cytotoxic, antifouling, and acetylcholinesterase inhibitory activities of these compounds were also examined

The surge-like eruption of a miniature filament

We report on the rare eruption of a miniature H_alpha filament that took a surge form. The filament first underwent a full development within 46 minutes and then began to erupt 9 minutes later, followed by a compact, impulsive X-ray class M2.2 flare with a two ribbon nature only at the early eruption phase. During the eruption, its top rose, whereas the two legs remained rooted in the chromosphere and swelled little perpendicular to the rising direction. This led to a surge-like eruption with a narrow angular extent. Similar to the recent observations for standard and blowout X-ray jets by Moore et al., we thus define it as a "blowout H_alpha surge". Furthermore, our observations showed that the eruption was associated with (1) a coronal mass ejection guided by a preexisting streamer, (2) abrupt, significant, and persistent changes in the photospheric magnetic field around the filament, and (3) sudden disappearance of a small pore. These observations thus provide evidence that blowout surge is a small-scale version of large-scale filament eruption in many aspects. Our observations further suggest that at least part of H_alpha surges belong to blowout-type ones, and exact distinction between standard and blowout H_alpha surges is important in understanding their different origins and associated eruptive phenomena