Hepatoprotective effects of Niudali (Callerya speciosa) root aqueous extracts against tetrachloromethane-induced acute liver injury and inflammation.

Niudali (Callerya speciosa) is commonly grown in southeastern regions of China and consumed as a food ingredient. Although Niudali root extracts showed various biological activities, the hepatoprotective effects of Niudali root phytochemicals are not fully studied. Herein, we prepared two Niudali root aqueous extracts, namely, c and Niudali polysaccharides-enriched extract (NPE), and identified an alkaloid, (hypaphorine) in NEW. The hepatoprotective effects of NWE, NPE, and hypaphorine were evaluated in an acute liver injury model induced by carbon tetrachloride (CCl4) in mice. Pathohistological examination and blood chemistry assays showed that treatment of NWE, NPE, and hypaphorine alleviated CCl4-induced liver damage by lowering the liver injury score (by 75.51%, 80.01%, and 41.22%) and serum aspartate and alanine transaminases level (by 63.24%, 85.22%, and 49.74% and by 78.73%, 80.08%, and 81.70%), respectively. NWE, NPE, and hypaphorine also reduced CCl4-induced hepatic oxidative stresses in the liver tissue by decreasing the levels of malondialdehyde (by 40.00%, 51.25%, and 28.75%) and reactive oxygen species (by 30.22%, 36.14%, and 33.54%) while increasing the levels of antioxidant enzymes including superoxide dismutase (by 21.36%, 21.64%, and 8.90%), catalase (by 22.13%, 33.33%, and 5.39%), and glutathione (by 84.87%, 90.65%, and 80.53%), respectively. Mechanistic assays showed that NWE, NPE, and hypaphorine alleviated liver damage by mediating inflammatory biomarkers (e.g., pro-inflammatory cytokines) via the signaling pathways of mitogen-activated protein kinases and nuclear factor-κB. Findings from our study extend the understanding of Niudali's hepatoprotective effects, which is useful for its development as a dietary intervention for liver inflammation.

Bypassing spike sorting: Density-based decoding using spike localization from dense multielectrode probes.

Neural decoding and its applications to brain computer interfaces (BCI) are essential for understanding the association between neural activity and behavior. A prerequisite for many decoding approaches is spike sorting, the assignment of action potentials (spikes) to individual neurons. Current spike sorting algorithms, however, can be inaccurate and do not properly model uncertainty of spike assignments, therefore discarding information that could potentially improve decoding performance. Recent advances in high-density probes (e.g., Neuropixels) and computational methods now allow for extracting a rich set of spike features from unsorted data; these features can in turn be used to directly decode behavioral correlates. To this end, we propose a spike sorting-free decoding method that directly models the distribution of extracted spike features using a mixture of Gaussians (MoG) encoding the uncertainty of spike assignments, without aiming to solve the spike clustering problem explicitly. We allow the mixing proportion of the MoG to change over time in response to the behavior and develop variational inference methods to fit the resulting model and to perform decoding. We benchmark our method with an extensive suite of recordings from different animals and probe geometries, demonstrating that our proposed decoder can consistently outperform current methods based on thresholding (i.e. multi-unit activity) and spike sorting. Open source code is available at https://github.com/yzhang511/density_decoding.

Predicting rare outcomes in abdominal wall reconstruction using image-based deep learning models.

BACKGROUND: Deep learning models with imbalanced data sets are a challenge in the fields of artificial intelligence and surgery. The aim of this study was to develop and compare deep learning models that predict rare but devastating postoperative complications after abdominal wall reconstruction. METHODS: A prospectively maintained institutional database was used to identify abdominal wall reconstruction patients with preoperative computed tomography scans. Conventional deep learning models were developed using an 8-layer convolutional neural network and a 2-class training system (ie, learns negative and positive outcomes). Conventional deep learning models were compared to deep learning models that were developed using a generative adversarial network anomaly framework, which uses image augmentation and anomaly detection. The primary outcomes were receiver operating characteristic values for predicting mesh infection and pulmonary failure. RESULTS: Computed tomography scans from 510 patients were used with a total of 10,004 images. Mesh infection and pulmonary failure occurred in 3.7% and 5.6% of patients, respectively. The conventional deep learning models were less effective than generative adversarial network anomaly for predicting mesh infection (receiver operating characteristic 0.61 vs 0.73, P < .01) and pulmonary failure (receiver operating characteristic 0.59 vs 0.70, P < .01). Although the conventional deep learning models had higher accuracies/specificities for predicting mesh infection (0.93 vs 0.78, P < .01/.96 vs .78, P < .01) and pulmonary failure (0.88 vs 0.68, P < .01/.92 vs .67, P < .01), they were substantially compromised by decreased model sensitivity (0.25 vs 0.68, P < .01/.27 vs .73, P < .01). CONCLUSION: Compared to conventional deep learning models, generative adversarial network anomaly deep learning models showed improved performance on imbalanced data sets, predominantly by increasing model sensitivity. Understanding patients who are at risk for rare but devastating postoperative complications can improve risk stratification, resource utilization, and the consent process.

Chemical Constituents With Antiproliferative Activity From Pogostemon cablin (Blanco) Benth.

Two new patchoulene sesquiterpenoid glycosides (1-2), a natural patchoulane-type sesquiterpenoid (3) and a natural cadinene-type sesquiterpenoid (4), were isolated from the aerial parts of Pogostemon cablin (Blanco) Benth., together with eleven known sesquiterpenoids (5-15) and eleven known flavonoids (16-26). Their chemical structures were elucidated on the basis of spectroscopic methods, including NMR, HRESIMS, IR, and CD spectroscopic data analysis, as well as chemical hydrolysis. The isolated compounds 1-13 and 15-26 were tested for inhibitory effects on the proliferation of HepG2 cancer cells. Among them, compounds 17 and 19 displayed anti-proliferative effects against HepG2 cells with IC50 values of 25.59 and 2.30 µM, respectively. Furthermore, the flow cytometry analysis and Western blotting assays revealed that compound 19 significantly induced apoptosis of HepG2 cells by downregulating the ratio of Bcl-2/Bax and upregulating the expression of cleaved caspase-3 and cleaved caspase-9. Therefore, the potential pharmaceutical applications of P. cablin would be applied according to our study findings.

Extract of Jasminum grandiflorum L. alleviates CCl4-induced liver injury by decreasing inflammation, oxidative stress and hepatic CYP2E1 expression in mice.

Jasminum grandiflorum L. (JG) is a medicinal plant containing many bioactive ingredients. Herein, we analyzed the effects of four different extracts and two compounds of JG on acute liver injury caused by carbon tetrachloride (CCl4) and underlying molecular mechanisms. 7 weeks old C57BL/6 male mice were used to establish a liver injury model by injecting with 1% CCl4, 10 mL/kg ip. Four different extracts and two compounds of JG were given to mice by gavage for 3 days. Clinical and histological chemistry assays were performed to assess liver injury. Moreover, hepatic oxidative stress and inflammation related markers were determined by immunohistochemistry and western blotting. As a result, JG extracts and two functional components showed different degree of protect effects against CCl4-induced liver injury by the decrease of elevated serum transaminases and liver index, and the attenuation of histopathological changes in mice, among which JG extracted with petroleum ether (PET) had the most significant effect. In addition, PET remarkably alleviated hepatic oxidative stress and inflammation. Further studies revealed that PET significantly inhibited the TNF-α expression, signal pathway expression, NF-κB p65 and inflammatory factors IL-1ß and IL-6 expression in CCl4-induced liver injury mice. Nevertheless, hydroxytyrosol (HT) alleviated liver injury by reducing oxidative stress. Apart from PET extract, other extracts of JG can inhibit cytochrome CYP2E1 expression to protect liver tissue. These findings suggest that the extracts and its components of JG possesses the potential protective effects against CCl4-induced liver injury in mice by exerting antioxidative stress and anti-inflammation.

Gastroprotective effects of extract of Jasminum grandiflorum L. flower in HCl/EtOH-induced gastric mucosal ulceration mice.

Jasminum grandiflorum L. is a medicinal plant used to treat hepatitis and gastritis, but the mechanisms underlying its protective effects against gastrointestinal mucosal damage remain to be elucidated. In this study, we analyzed the effects of four different extracts and two compounds from the flower of J. grandiflorum in a mouse model of HCl/EtOH-induced gastric ulcer. The flower extracts alleviated gastric mucosal ulceration by increasing PGE2 production and the activity of antioxidant enzymes, along with the suppression of reactive oxygen species (ROS) generation, lipid peroxidation, apoptosis-related proteins, pro-inflammatory cytokines and nitric oxide (NO) production.

A Novel Blockade CD47 Antibody With Therapeutic Potential for Cancer.

Macrophages as components of the innate immune system play a critical role in antitumor responses. Strategies for targeting CD47 are becoming a hot spot for cancer therapy. The expression of CD47 is exercised by macrophages to make a distinction between "self" or "nonself." Anti-CD47 antibodies block the interaction between macrophage signal regulatory protein-α (SIRPα) and tumor surface CD47. In this study, we report and assess a novel anti-CD47 blocking antibody named 2C8, which exhibits high affinity and tremendous anticancer effects. More concretely, 2C8 significantly induces macrophages, including protumorigenic subtype M2 macrophages killing tumor cells in vitro, and is revealed to be more effective than commercially available anti-CD47 mAb B6H12.2. In vivo, 2C8 controls tumor growth and extends survival of xenograft mice. The antitumor ability of 2C8 might be applicable to many other cancers. The generation of a novel CD47 antibody contributes to consolidating clinical interest in targeting macrophages for the treatment of malignancy and, moreover, as a supplement therapy when patients are resistant or refractory to other checkpoint therapies or relapse after such treatments.

Bispecific CD3-HAC carried by E1A-engineered mesenchymal stromal cells against metastatic breast cancer by blocking PD-L1 and activating T cells.

BACKGROUND: PD-1/PD-L1 blockade can confer durable benefits in the treatment of metastatic cancers, but the response rate remains modest and potential adverse effects occur sometimes. Concentrating immunotherapeutic agents at the site of disease was believed to break local immune tolerance and reduce systemic toxicity. E1A-engineered mesenchymal stromal cell (MSC.E1A) was an attractive transfer system that preferentially homing and treating cancer metastasis, through which the tumor cells were modified by locally replicated adenoviruses to release CD3-HAC, a bifunctional fusion protein that anti-CD3 scfv linked with high-affinity consensus (HAC) PD-1. Subsequently, CD3-HAC, wbich was bound on PD-L1-positive breast cancer cells, recruited T cells to exhibit a potent antitumor immunity incombination with immune checkpoint blockade. METHODS: We constructed the CD3-HAC gene driven by human telomerase reverse transcriptase (hTERT) promoter into an adenoviral vector and the E1A gene into the lentiviral vector. The homing property of MSCs in vivo was analyzed with firefly luciferase-labeled MSCs (MSC.Luc) by bioluminescent imaging (BLI). The cytotoxicity of T cells induced by CD3-HAC towards PD-L1-positive cells was detected in vitro and in vivo in combination with 5-FU. RESULTS: Our data suggest that CD3-HAC could specifically bind to PD-L1-positive tumor cells and induce lymphocyte-mediated lysis effectively both in vitro and in vivo. The intervention with HAC diminished the effects of PD-1/PD-L1 axis on T cells exposed to MDA-MB-231 cells and increased lymphocytes activation. MSCs infected by AdCD3-HAC followed by LentiR.E1A could specially migrate to metastasis of breast cancer and produce adenoviruses in the tumor sites. Furthermore, treatment with MSC.CD3-HAC.E1A in combination with 5-FU significantly inhibited the tumor growth in mice. CONCLUSIONS: This adenovirus-loaded MSC.E1A system provides a promising strategy for the identification and elimination of metastasis with locally released immuno-modulator.

[Anti-angiogenesis effect of metronomic chemotherapy in multiple myeloma patients].

OBJECTIVE: To investigate effects of low-dose cyclophosphamide and prednisone (CP) metronomic chemotherapy on microvessel density of bone marrow, serum vascular endothelial growth factor (VEGF) and platelet derived growth factor BB (PDGF-BB)in multiple myeloma (MM) patients. METHODS: 54 refractory or relapsed MM patients were treated with CP metronomic chemotherapy consisted of oral cyclophosphamide (CTX, 50 mg/d) and prednisone (Pred, 15 mg/d). Bone marrow and peripheral blood of each patient were collected before and 2, 4, 6 months after treatment. Among the 37 assessable patients, 30 cases were responsive with the response rate of 81.08%. Another 17 cases were follow-uped less than 6 months or failure to obtain serum samples or lost to follow-up. Microvessel density of bone marrow was measured by immunohistochemistry and serum VEGF/PDGF-BB expression was analyzed by ELISA in the 37 assessable patients. RESULTS: 2, 4, 6 months following CP metronomic chemotherapy, microvessel densities of bone marrow in the responders were 33.1 ± 4.8/HP, 24.8 ± 3.7/HP, 19.7 ± 2.1/HP respectively; the expressions of VEGF were (394 ± 57) ng/L, (268 ± 32) ng/L and (217 ± 20) ng/L respectively; the expressions of PDGF-BB were (304 ± 31) ng/L, (274 ± 31) ng/L and (196 ± 22) ng/L respectively. After CP metronomic chemotherapy, there were significantly lower of microvessel density, VEGF and PDGF-BB levels than pretreatment \[MVD 48.5 ± 5.9/HP, VEGF (517 ± 60) ng/L, PDGF-BB (484 ± 60) ng/L\]in the responders (P < 0.01). While in the non-responders, after treated by CP metronomic chemotherapy for 2 months, microvessel density, the expression of VEGF and the expression of PDGF-BB were 32.5 ± 4.7/HP, 512 ± 39 ng/L and (452 ± 39) ng/L respectively. There were no significant changes of MVD, VEGF and PDGF-BB levels compared with pretreatment \[MVD 33.2 ± 5.6/HP,VEGF (498 ± 55) ng/L, PDGF-BB (488 ± 44) ng/L\] (P > 0.05). CONCLUSIONS: Our findings suggested that continuous low-dose CP metronomic chemotherapy could decrease microvessel density of bone marrow in MM patients. Furthermore, it down-regulated expression of serum VEGF and PDGF-BB to exert its anti-angiogenesis in MM.

A combination of thalidomide and arsenic trioxide is effective and well tolerated in patients with myelodysplastic syndromes.

Twenty-two patients with myelodysplastic syndromes (MDS) were treated with thalidomide plus arsenic trioxide (ATO). Twenty-two MDS patients receiving supportive care were used as controls. The remission was achieved in 4 patients (18.2%) receiving thalidomide/ATO, and none in the control group (p<0.05). Fifteen of 22 patients in the treatment group achieved hematologic improvement (68.2% vs. 27.3% in the control, p<0.05). The progression-free survival was longer in the treatment group than that in the control (26 vs. 10 months, p<0.05). The overall survival was also longer in the treatment group than that in the control (36 vs. 16 months, p<0.05). No severe adverse reactions were observed. These preliminary findings suggest that thalidomide/ATO combination treatment is effective and safe for MDS.