Direct imaging of single-molecule electrochemical reactions in solution.

Chemical reactions tend to be conceptualized in terms of individual molecules transforming into products, but are usually observed in experiments that probe the average behaviour of the ensemble. Single-molecule methods move beyond ensemble averages and reveal the statistical distribution of reaction positions, pathways and dynamics1-3. This has been shown with optical traps and scanning probe microscopy manipulating and observing individual reactions at defined locations with high spatial resolution4,5, and with modern optical methods using ultrasensitive photodetectors3,6,7 that enable high-throughput single-molecule measurements. However, effective probing of single-molecule solution chemistry remains challenging. Here we demonstrate optical imaging of single-molecule electrochemical reactions7 in aqueous solution and its use for super-resolution microscopy. The method utilizes a chemiluminescent reaction involving a ruthenium complex electrochemically generated at an electrode8, which ensures minimal background signal. This allows us to directly capture single photons of the electrochemiluminescence of individual reactions, and to develop super-resolved electrochemiluminescence microscopy for imaging the adhesion dynamics of live cells with high spatiotemporal resolution. We anticipate that our method will advance the fundamental understanding of electrochemical reactions and prove useful for bioassays and cell-imaging applications.

Shared and malignancy-specific functional plasticity of dynamic brain properties for patients with left frontal glioma.

The time-varying brain activity may parallel the disease progression of cerebral glioma. Assessment of brain dynamics would better characterize the pathological profile of glioma and the relevant functional remodeling. This study aims to investigate the dynamic properties of functional networks based on sliding-window approach for patients with left frontal glioma. The generalized functional plasticity due to glioma was characterized by reduced dynamic amplitude of low-frequency fluctuation of somatosensory networks, reduced dynamic functional connectivity between homotopic regions mainly involving dorsal attention network and subcortical nuclei, and enhanced subcortical dynamic functional connectivity. Malignancy-specific functional remodeling featured a chaotic modification of dynamic amplitude of low-frequency fluctuation and dynamic functional connectivity for low-grade gliomas, and attenuated dynamic functional connectivity of the intrahemispheric cortico-subcortical connections and reduced dynamic amplitude of low-frequency fluctuation of the bilateral caudate for high-grade gliomas. Network dynamic activity was clustered into four distinct configuration states. The occurrence and dwell time of the weakly connected state were reduced in patients' brains. Support vector machine model combined with predictive dynamic features achieved an averaged accuracy of 87.9% in distinguishing low- and high-grade gliomas. In conclusion, dynamic network properties are highly predictive of the malignant grade of gliomas, thus could serve as new biomarkers for disease characterization.

Light-Driven Ion Transport through Single-Heterojunction Nanopores.

Inspired by natural photosynthesis, light has become an emerging ionic behavior regulator and ion-pumping source. Nanoprocessing technology has allowed the bridge between the light-regulated nanofluids and the optoelectronic properties of two-dimensional (2D) materials, which inspires applications like energy harvesting and enhances fundamental understandings in nanofluidics. However, unlike light-induced ion pumping based on densely layered membranes with multiple nanochannels, experimental implementation on atomically thin materials featuring only a single nanochannel remains challenging. Here, we report light-induced ion pumping based on a single artificial heterojunction nanopore. Under light illumination, the induced current through a single nanopore reaches tens of picoamperes. The hole-electron separation originating from the optoelectrical property of a van der Waals PN junction is proposed to capture the light-driven ion transport. Further, different methods are adopted to modify the ion behavior and response time, presenting potential applications in fluidic photoenergy harvesting, photoelectric ion transport control, and bionic artificial neurons.

Inducing Electric Current in Graphene Using Ionic Flow.

Classical nanofluidic frameworks account for the confined fluid and ion transport under an electrostatic field at the solid-liquid interface, but the electronic property of the solid is often overlooked. Harvesting the interaction of the nanofluidic transport with the electron transport in solid requires a route effectively coupling ion and electron dynamics. Here we report a nanofluidic analogy of Coulomb drag for exploring the dynamic ion-electron interactions at the liquid-graphene interface. An induced electric current in graphene by ionic flow with no bias directly applied to the graphene channel is observed experimentally, featuring an opposite electron current direction to the ion current. Our experiments and ab initio calculations show that the current generation stems from the confined ion-electron interactions via a nanofluidic Coulomb drag mechanism. Our findings may open up a new dimension for nanofluidics and transport control by ion-electron coupling.

Association between preoperative serum sodium and postoperative 30-day mortality in adult patients with tumor craniotomy.

BACKGROUND: Limited data exist regarding preoperative serum sodium (Na) and 30-day mortality in adult patients with tumor craniotomy. Therefore, this study investigates their relationship. METHODS: A secondary retrospective analysis was performed using data from the ACS NSQIP database (2012-2015). The principal exposure was preoperative Na. The outcome measure was 30-day postoperative mortality. Binary logistic regression modeling was conducted to explore the link between them, and a generalized additive model and smooth curve fitting were applied to evaluate the potential association and its explicit curve shape. We also conducted sensitivity analyses and subgroup analyses. RESULTS: A total of 17,844 patients (47.59% male) were included in our analysis. The mean preoperative Na was 138.63 ± 3.23 mmol/L. The 30-day mortality was 2.54% (455/17,844). After adjusting for covariates, we found that preoperative Na was negative associated with 30-day mortality. (OR = 0.967, 95% CI:0.941, 0.994). For patients with Na ≤ 140, each increase Na was related to a 7.1% decreased 30-day mortality (OR = 0.929, 95% CI:0.898, 0.961); for cases with Na > 140, each increased Na unit was related to a 8.8% increase 30-day mortality (OR = 1.088, 95% CI:1.019, 1.162). The sensitivity analysis and subgroup analysis indicated that the results were robust. CONCLUSIONS: This study shows a positive and nonlinear association between preoperative Na and postoperative 30-day mortality in adult patients with tumor craniotomy. Appropriate preoperative Na management and maintenance of serum Na near the inflection point (140) may reduce 30-day mortality.

Association between preoperative platelet and 30-day postoperative mortality of adult patients undergoing craniotomy for brain tumors: data from the American College of Surgeons National Surgical Quality Improvement Program database.

BACKGROUND: Evidence regarding the relationship between preoperative platelet and 30-day postoperative mortality of intracranial tumor patients undergoing craniotomy is still limited. Therefore, the present research was conducted to explore the link of the platelet and 30-day postoperative mortality. METHODS: Electronic medical records of 18,642 adult patients undergoing craniotomy for brain tumors from 2012 to 2015 in the American College of Surgeons National Surgical Quality Improvement Program, were subject to secondary retrospective analysis. A binary logistic regression model evaluated the independent association between preoperative platelet and 30-day postoperative mortality. A generalized additive model and smooth curve fitting was conducted to explore the exact shape of the curve between them. Additionally, We also conducted sensitivity analyses to test the robustness of the results, and performed subgroup analyses. RESULTS: Eighteen thousand sixty-three patients were included in this study analysis. Of these, 47.49% were male. The mean preoperative platelet value was (244.12 ± 76.77) × 109/L. The 30-day postoperative mortality of included participants was 2.5% (452/18,063). After adjusting covariates, the results showed that preoperative platelet was positively associated with 30-day postoperative mortality (OR = 0.999, 95%CI: 0.997, 1.000). There was also a nonlinear relationship between preoperative platelet and 30-day postoperative mortality, and the inflection point of the platelet was 236. The effect sizes (OR) on the right and left sides of the inflection point were 1.002 (1.000, 1.004) and 0.993 (0.990, 0.995), respectively. And sensitive analysis demonstrated the robustness of the results. Subgroup analysis showed a stronger association between preoperative platelet and 30-day postoperative mortality in non-emergency surgery patients when preoperative platelet value is less than 235 × 109/L. CONCLUSIONS: This research demonstrates a positive and non-linear relationship between preoperative platelet and 30-day postoperative mortality in U.S. adult brain tumor patients undergoing craniotomy. Preoperative platelet is strongly related to 30-day postoperative mortality when the platelet is less than 235 × 109/L. Proper preoperative management of platelet and maintenance of platelet near inflection point (235) could reduce risk of 30-day postoperative mortality in these cases.

Cucurbitane triterpenoid entities derived from Hemsleya penxianensis triggered glioma cell apoptosis via ER stress and MAPK signalling cross-talk.

In the present study, six new cucurbitane type compounds, including three triterpenoids hemsleyacins P-R (6-7, 13) and three cucurbitane-type triterpenoid glycosides hemsleyaosides L-N (15-17), along with seventeen known cucurbitacin analogues were separated from the root tuber of Hemsleya penxianensis and elucidated based on NMR and HRESIMS. Then, 23 analogues of three types, namely, polyhydroxy-type (I) (1-7), monohydroxy-type (II) (8-13), and glycosides-type (III) (14-23), were assessed for their antitumor activity and structure-activity relationship analysis (SAR). We determined temozolomide (TMZ)-resistant GBM cell was the most sensitive to the tested compounds, and found hemsleyaoside N (HDN) displayed the best antineoplastic potency. Furthermore, we confirmed the anti-glioma activity of HDN in patient-derived recurrent GBM strains, GBM organoid (GBO) and orthotopic nude mouse models. Investigations exploring the mechanism made clear that HDN induced synchronous activation of UPR and MAPK signaling, which triggered deadly ER stress and apoptosis. Taken together, the potent antitumor activity of HDN warrants further comprehensive evaluation as a novel anti-glioma agent.

Prognostic data analysis of surgical treatments for intracerebral hemorrhage.

Spontaneous intracerebral hemorrhage (ICH) is a commonly occurring disease in neurosurgery, yet its surgical treatment is controversial. This paper pertains to the study of the effects of different treatment regimens on the outcome of ICH population. Based on a globally shared third-party MIMIC-III database, the researchers firstly described the dissimilarities in survival probability, mortality, and neurological recovery among mainstream treatments for ICH; secondly, patient classification was determined by important clinical features; and outcome variations among treatment groups were compared. The 28-day, 90-day, and in-hospital mortality in the craniotomy group were significantly lower than minimally invasive surgery (MIS) and non-surgical group patients; and, the medium/long-term mortality in MIS group was significantly lower than the non-surgical group. The craniotomy group positively correlated with short-term GCS recovery compared with the MIS group; no difference existed between the non-surgical and MIS groups. The craniotomy group 90-day survival probability and short-term GCS recovery were superior to the other two treatments in the subgroups of first GCS 3-12; this tendency also presented in the MIS group over non-surgical group. For milder patients (first GCS > 12), the three treatment regimens had a minimal effect on patient survival, but the non-surgical group showed an advantage in short-term GCS recovery. Craniotomy patients have a lower mortality and a better short-term neurological recovery in an ICH population, especially in short-to-medium term mortality and short-term neurological recovery over MIS patients. In addition, surgical treatment is recommendable for patients with a GCS ≤ 12.

Dynamic Optical Visualization of Proton Transport Pathways at Water-Solid Interfaces.

Probing proton transport is of vital importance for understanding cellular transport, surface catalysis and fuel cells. Conventional proton transport measurements rely on the use of electrochemical conductivity and do not allow for the direct visualization of proton transport pathways. The development of novel experimental techniques to spatiotemporally resolve proton transport is in high demand. Here, building upon the general conversion of aqueous proton flux into spatially resolved fluorescence signals, we optically visualize proton transport through nanopores and along hydrophilic interfaces. We observed that the fluorescence intensity increased at negative voltage due to lateral transport. Thanks to the temporal resolution of optical imaging, our technique further empowers the analysis of proton transport dynamics.

Identification of prognostic values defined by copy number variation, mRNA and protein expression of LANCL2 and EGFR in glioblastoma patients.

BACKGROUND: Epidermal growth factor receptor (EGFR) and lanthionine synthetase C-like 2 (LanCL2) genes locate in the same amplicon, and co-amplification of EGFR and LANCL2 is frequent in glioblastoma. However, the prognostic value of LANCL2 and EGFR co-amplification, and their mRNA and protein expression in glioblastoma remain unclear yet. METHODS: This study analyzed the prognostic values of the copy number variations (CNVs), mRNA and protein expression of LANCL2 and EGFR in 575 glioblastoma patients in TCGA database and 100 glioblastoma patients in tumor banks of the Shenzhen Second People's Hospital and the Sun Yat-sen University Cancer Center. RESULTS: The amplification of LANCL2 or EGFR, and their co-amplification were frequent in glioblastoma of TCGA database and our tumor banks. A significant correlation was found between the CNVs of LANCL2 and EGFR (p < 0.001). CNVs of LANCL2 or EGFR were significantly correlated with IDH1/2 mutation but not MGMT promoter methylation. Multivariate analysis showed that LANCL2 amplification was significantly correlated with reduced overall survival (OS) in younger (< 60 years) glioblastoma patients of TCGA database (p = 0.043, HR = 1.657) and our tumor banks (p = 0.018, HR = 2.199). However, LANCL2 or EGFR amplification, and their co-amplification had no significant impact on OS in older (≥ 60 years) or IDH1/2-wild-type glioblastoma patients. mRNA and protein overexpression of LANCL2 and EGFR was also frequently found in glioblastoma. The mRNA expression rather than the protein expression of LANCL2 and EGFR was positively correlated (p < 0.001). However, mRNA or protein expression of EGFR and LANCL2 was not significantly correlated with OS of glioblastoma patients. The protein expression level of LANCL2, rather than EGFR, was elevated in relapsing glioblastoma, compared with newly diagnosed glioblastoma. In addition, the intracellular localization of LanCL2, not EGFR, was associated with the grade of gliomas. CONCLUSIONS: Taken together, amplification and mRNA overexpression of LANCL2 and EGFR, and their co-amplification and co-expression were frequent in glioblastoma patients. Our findings suggest that amplification of LANCL2 and EGFR were the independent diagnostic biomarkers for glioblastoma patients, and LANCL2 amplification was a significant prognostic factor for OS in younger glioblastoma patients.

Identify glioma recurrence and treatment effects with triple-tracer PET/CT.

BACKGROUND: Differential diagnosis of tumour recurrence (TuR) from treatment effects (TrE), mostly induced by radiotherapy and chemotherapy, is still difficult by using conventional computed tomography (CT) or magnetic resonance (MR) imaging. We have investigated the diagnostic performance of PET/CT with 3 tracers, 13N-NH3, 18F-FDOPA, and 18F-FDG, to identify TuR and TrE in glioma patients following treatment. METHODS: Forty-three patients with MR-suspected recurrent glioma were included. The maximum and mean standardized uptake values (SUVmax and SUVmean) of the lesion and the lesion-to-normal grey-matter cortex uptake (L/G) ratio were obtained from each tracer PET/CT. TuR or TrE was determined by histopathology or clinical MR follow-up for at least 6 months. RESULTS: In this cohort, 34 patients were confirmed to have TuR, and 9 patients met the diagnostic standard of TrE. The SUVmax and SUVmean of 13N-NH3 and 18F-FDOPA PET/CT at TuR lesions were significantly higher compared with normal brain tissue (13N-NH3 0.696 ± 0.558, 0.625 ± 0.507 vs 0.486 ± 0.413; 18F-FDOPA 0.455 ± 0.518, 0.415 ± 0.477 vs 0.194 ± 0.203; both P < 0.01), but there was no significant difference in 18F-FDG (6.918 ± 3.190, 6.016 ± 2.807 vs 6.356 ± 3.104, P = 0.290 and 0.493). L/G ratios of 13N-NH3 and 18F-FDOPA were significantly higher in TuR than in TrE group (13N-NH3, 1.573 ± 0.099 vs 1.025 ± 0.128, P = 0.008; 18F-FDOPA, 2.729 ± 0.131 vs 1.514 ± 0.141, P < 0.001). The sensitivity, specificity and AUC (area under the curve) by ROC (receiver operating characteristic) analysis were 57.7%, 100% and 0.803, for 13N-NH3; 84.6%, 100% and 0.938, for 18F-FDOPA; and 80.8%, 100%, and 0.952, for the combination, respectively. CONCLUSION: Our results suggest that although multiple tracer PET/CT may improve differential diagnosis efficacy, for glioma TuR from TrE, 18F-FDOPA PET-CT is the most reliable. The combination of 18F-FDOPA and 13N-NH3 does not increase the diagnostic efficiency, while 18F-FDG is not worthy for differential diagnosis of glioma TuR and TrE.

Moschamindole induces glioma cell apoptosis by blocking Mia40-dependent mitochondrial intermembrane space assembly and oxidative respiration.

Glioblastoma multiforme (GBM) is the most frequent, lethal, and aggressive tumor of the central nervous system in adults. In this study, we found for the first time that moschamindole (MCD), a rare phenolic amide with 8/6/6/5/5 rings, is a major bioactive constituent derived from Phragmites communis Trin (Poaceae) that exhibits a potential cytotoxic effect on both TMZ-resistant GBM cell lines and xenograft models. MCD-induced intrinsic apoptosis signals and mitochondrial dysfunction were confirmed by cell cycle arrest, caspase-3/7 activation, and membrane potential depolarization. Furthermore, investigations exploring the mechanism showed that MCD specifically inhibits Mia40-mediated oxidative folding of mitochondrial intermembrane space (IMS) proteins via PCR assay and immunoblot analysis. MCD relies on its positive charge to associate with mitochondrial oxidative respiration, thus blocking energy metabolism and inducing apoptosis. Overexpression and upregulation of Mia40 were proven to reverse MCD-induced apoptosis and were correlated with the chemoresistance of GBM in vitro and in vivo, respectively. Taken together, our study demonstrates that Mia40 is a potential target of the chemoresistance of glioblastoma and suggests that MCD might be a potential agent for the individualized treatment of chemoresistant GBM based on mitochondrial metabolic characteristics and Mia40 expression.

A pacemaker-assisted microvascular decompression for a patient with left primary facial spasm and arrhythmia: a case report.

BACKGROUND: Primary facial spasm accompanied by arrhythmia is a rare clinical phenomenon and has not been reported before. We describe this phenomenon and discuss its mechanism and treatment. CASE PRESENTATION: We herein present a rare case of a patient with left primary facial spasm and a third-degree atrioventricular block (III degree AVB), who was implanted with a temporary cardiac pacemaker to receive microvascular decompression (MVD) because of refusal of a permanent cardiac pacemaker. The symptoms of facial spasm disappeared after MVD. The temporary cardiac pacemaker was removed on the second day after surgery. Her ECG still showed the third-degree atrioventricular block after a follow-up period of 5 months. CONCLUSIONS: We are the first to report a patient with facial spasm and arrhythmia who was implanted with a temporary cardiac pacemaker to receive MVD. This case report demonstrated that the concomitant presence of a III degree AVB maybe not a contraindication for MVD, and the etiology of this facial spasm was the actual vascular compression of the facial nerve entry zone that was not related to the atrioventricular block.

Rh-relaxin-2 attenuates degranulation of mast cells by inhibiting NF-κB through PI3K-AKT/TNFAIP3 pathway in an experimental germinal matrix hemorrhage rat model.

BACKGROUND: Mast cells play an important role in early immune reactions in the brain by degranulation and the consequent inflammatory response. Our aim of the study is to investigate the effects of rh-relaxin-2 on mast cells and the underlying mechanisms in a germinal matrix hemorrhage (GMH) rat model. METHODS: One hundred seventy-three P7 rat pups were subjected to GMH by an intraparenchymal injection of bacterial collagenase. Clodronate liposome was administered through intracerebroventricular (i.c.v.) injections 24 h prior to GMH to inhibit microglia. Rh-relaxin-2 was administered intraperitoneally at 1 h and 13 h after GMH. Small interfering RNA of RXFP1 and PI3K inhibitor LY294002 were given by i.c.v. injection. Post-GMH evaluation included neurobehavioral function, Western blot analysis, immunofluorescence, Nissl staining, and toluidine blue staining. RESULTS: Our results demonstrated that endogenous relaxin-2 was downregulated and that RXFP1 level peaked on the first day after GMH. Administration of rh-relaxin-2 improved neurological functions, attenuated degranulation of mast cells and neuroinflammation, and ameliorated post-hemorrhagic hydrocephalus (PHH) after GMH. These effects were associated with RXFP1 activation, increased expression of PI3K, phosphorylated AKT and TNFAIP3, and decreased levels of phosphorylated NF-κB, tryptase, chymase, IL-6, and TNF-α. However, knockdown of RXFP1 and PI3K inhibition abolished the protective effects of rh-relaxin-2. CONCLUSIONS: Our findings showed that rh-relaxin-2 attenuated degranulation of mast cells and neuroinflammation, improved neurological outcomes, and ameliorated hydrocephalus after GMH through RXFP1/PI3K-AKT/TNFAIP3/NF-κB signaling pathway.

Intracisternal tuberculoma: a refractory type of tuberculoma indicating surgical intervention.

BACKGROUND: Central nervous system (CNS) tuberculoma is a rare disease with severe neurological deficits. This retrospective research is to review the data of patients diagnosed as CNS tuberculoma. Surgeries were performed in all patients. The clinical features especially the neurological image and the anatomical characters of the tuberculomas were concerned. METHODS: Totally 11 patients diagnosed as CNS tuberculoma were admitted in Guangzhou First People's Hospital (7cases) and Changzheng Hospital (4 cases) during 2006-2015. The data including preoperative condition, neurological imaging, and surgical findings was collected and analyzed. RESULTS: The lesions of nine patients (9/11) were totally or subtotally excised and two (2/11) were partially excised. Neurological functions of all patients were improved after surgery without secondary infection. Lesions of nine (9/11) patients preoperatively progressed as a result of paradoxical reaction. Of the 9 patients demonstrated paradoxical progression, all lesions were partially or totally located at the cisterns or the subarachnoid space. Preoperative ATTs lasted 2 to 12 months and tuberculomas were not eliminated. The arachnoid was found thickened and tightly adhered to the lesions during surgeries. Of the 2 cases that paradoxical reaction were excluded, both patients (case 6, intramedullary tuberculoma; case 11, intradural extramedullary tuberculoma) were admitted at onset of the disease. ATTs were preoperatively given for 1 week as neurological deficits aggravated. The tuberculous lesions of CNS or other system showed no obvious change and paradoxical reaction could not be established in both cases. CONCLUSIONS: Exudates of tuberculosis is usually accumulated in the cisterns and frequently results in the paradoxical formation of tuberculoma. Intracisternal tuberculoma is closely related to paradoxical reaction and refractory to anti-tuberculosis therapy. Micro-surgical excision is safe and effective. Early surgical intervention may be considered in the diagnosis of intracisternal tuberculoma especially when paradoxical reaction participates in the development of tuberculoma.

Pre-operative declining proportion of fractional anisotropy of trigeminal nerve is correlated with the outcome of micro-vascular decompression surgery.

BACKGROUND: Type 2 trigeminal neuralgia (TN) is an intractable neuropathic pain syndrome compared with type 1 TN because of the difficulty of diagnosis as well as the unsatisfactory prognosis. Neurovascular compression (NVC) is considered the major pathology of TN. Routine magnetic resonance imaging (MRI) sequences are inadequate for revealing the effect of NVC which is related to the surgical decision and outcome. The decreasing of fractional anisotropy (FA), one of the MRI diffusion tensor imaging (DTI) metrics, is correlated with the demyelination of trigeminal nerve (TGN) that reveal the severity of NVC. METHODS: A retrospective review of patients treated with micro-vascular decompression (MVD) surgery was undertaken. All the patients were diagnosed as type 2 TN. FA of TGN of both sides were measured. The FA declining proportion = ((the mean FA value of healthy lateral)-(the mean FA value of the symptomatic lateral))/(the mean FA value of healthy lateral). Declining proportion of FA value, discovery of surgery and outcome of MVD were recorded and analyzed. Logistic regression analysis and linear regression analysis were employed to analyze the risk factors of declining proportion of FA value and MVD outcome. RESULTS: Nineteen patients were assessed in our study. The average declining proportion of FA value for all patients was 0.25 ± 0.12. The average declining proportion of FA value of "success" and "failure" group was 0.32 ± 0.09 to 0.14 ± 0.10 (P = 0.002 < 0.05). The declining proportion of FA value of artery (including the artery plus vein situation) was 0.34 ± 0.06 in contrast to 0.15 ± 0.08 of vein (P = 0.000 < 0.05). MVD outcome was correlated with declining proportion of FA value (AUC = 0.900). Furthermore, declining proportion of FA value was higher in arterial compression situation. CONCLUSION: FA value quantitatively showed the alteration of TGN caused by NVC. It provided direct evidence about the effect of NVC which facilitated the diagnosis and surgical decision of type 2 TN. Besides, significant reduction of FA value may predict an optimistic outcome of MVD.

Paracrine Factors Secreted by MSCs Promote Astrocyte Survival Associated With GFAP Downregulation After Ischemic Stroke via p38 MAPK and JNK.

Astrocytes are critical for ischemic stroke, and understanding their role in mesenchymal stem cell (MSC)-mediated protection against ischemic injury is important. The paracrine capacity of MSCs has been proposed as the principal mechanism contributing to the protection and repair of brain tissue. In the present study, an in vitro oxygen-glucose deprivation (OGD) model was used to mimic ischemic injury. OGD-induced astrocytes were reperfused with MSC-conditioned medium (MSC-CM) or co-cultured with MSCs for 24 h to create an environment abundant in paracrine factors. The results indicated that both situations could protect astrocytes from apoptosis, increase cell metabolic activity, and reduce glial fibrillary acidic protein (GFAP) overexpression; however, the effects of co-culturing with MSCs were more positive. Paracrine factors suppressed the activation of p38 MAPK, JNK, and their downstream targets p53 and STAT1. Inhibition of p38 MAPK, JNK, p53, and STAT1 attenuated astrocyte injury and/or GFAP upregulation. Activation of p38 MAPK and JNK suppressed the beneficial effects of paracrine factors, resulting in decreased survival and GFAP overexpression. These results suggest that paracrine factors inhibit p38 MAPK and JNK, and most likely by regulating their downstream targets, p53 and STAT1, to promote astrocyte survival associated with GFAP downregulation after ischemic stroke in vitro.

MSCs inhibit bone marrow-derived DC maturation and function through the release of TSG-6.

Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that are characterized by the ability to take up and process antigens and prime T cell responses. Mesenchymal stem cells (MSCs) are multipotent cells that have been shown to have immunomodulatory abilities, including inhibition of DC maturation and function in vivo and in vitro; however, the underlying mechanism is far from clear. In this study we found that MSCs can inhibit the maturation and function of bone marrow-derived DCs by releasing TSG-6. In the presence of MSCs, lower expression of mature DC surface phenotype (CD80, CD86, MHC-II, and CD11c) was observed. In addition, typical DC functions, such as the production of IL-12 and the ability to prime T cells, were decreased when co-cultured with MSCs. In contrast, knockdown of TSG-6 reduced the inhibitory effect of MSCs on DC. Moreover, we found that TSG-6 can suppress the activation of MAPKs, and NF-κB signaling pathways within DCs during Lipopolysaccharides (LPS) stimulation. In conclusion, we suggest that TSG-6 plays an important role in MSCs-mediated immunosuppressive effect on DC.

Mesenchymal stem cells inhibit lipopolysaccharide-induced inflammatory responses of BV2 microglial cells through TSG-6.

Microglia are the primary immunocompetent cells in brain tissue and microglia-mediated inflammation is associated with the pathogenesis of various neuronal disorders. Recently, many studies have shown that mesenchymal stem cells (MSCs) display a remarkable ability to modulate inflammatory and immune responses through the release of a variety of bioactive molecules, thereby protecting the central nervous system. Previously, we reported that MSCs have the ability to modulate inflammatory responses in a traumatic brain injury model and that the potential mechanisms may be partially attributed to upregulated TNF-α stimulated gene/protein 6 (TSG-6) expression. However, whether TSG-6 exerts an anti-inflammatory effect by affecting microglia is not fully understood. In this study, we investigated the anti-inflammatory effects of MSCs and TSG-6 in an in vitro lipopolysaccharide (LPS)-induced BV2 microglial activation model. We found that MSCs and TSG-6 significantly inhibited the expression of pro-inflammatory mediators in activated microglia. However, MSC effects on microglia were attenuated when TSG-6 expression was silenced. In addition, we found that the activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways in LPS-stimulated BV2 microglial cells was significantly inhibited by TSG-6. Furthermore, we found that the presence of CD44 in BV2 microglial cells was essential for MSC- and TSG-6-mediated inhibition of pro-inflammatory gene expression and of NF-κB and MAPK activation in BV2 microglial cells. The results of this study suggest that MSCs can modulate microglia activation through TSG-6 and that TSG-6 attenuates the inflammatory cascade in activated microglia. Our study indicates that novel mechanisms are responsible for the immunomodulatory effect of MSCs on microglia and that MSCs, as well as TSG-6, might be promising therapeutic agents for the treatment of neurotraumatic injuries or neuroinflammatory diseases associated with microglial activation.

The role of γδT lymphocytes in atherosclerosis.

Atherosclerosis poses a significant threat to human health, impacting overall well-being and imposing substantial financial burdens. Current treatment strategies mainly focus on managing low-density lipids (LDL) and optimizing liver functions. However, it's crucial to recognize that Atherosclerosis involves more than just lipid accumulation; it entails a complex interplay of immune responses. Research highlights the pivotal role of lipid-laden macrophages in the formation of atherosclerotic plaques. These macrophages attract lymphocytes like CD4 and CD8 to the inflamed site, potentially intensifying the inflammatory response. γδ T lymphocytes, with their diverse functions in innate and adaptive immune responses, pathogen defense, antigen presentation, and inflammation regulation, have been implicated in the early stages of Atherosclerosis. However, our understanding of the roles of γδ T cells in Atherosclerosis remains limited. This mini-review aims to shed light on the characteristics and functions of γδ T cells in Atherosclerosis. By gaining insights into the roles of γδ T cells, we may uncover a promising strategy to mitigate plaque buildup and dampen the inflammatory response, thereby opening new avenues for effectively managing this condition.