Ginkgo biloba extract protects against depression-like behavior in mice through regulating gut microbial bile acid metabolism.

Depression is a mental disorder with high morbidity, disability and relapse rates. Ginkgo biloba extract (GBE), a traditional Chinese medicine, has a long history of clinical application in the treatment of cerebral and mental disorders, but the key mechanism remains incompletely understood. Here we showed that GEB exerted anti-depressant effect in mice through regulating gut microbial metabolism. GBE protected against unpredictable mild stress (UMS)-induced despair, anxiety-like and social avoidance behavior in mice without sufficient brain distribution. Fecal microbiome transplantation transmitted, while antibiotic cocktail abrogated the protective effect of GBE. Spatiotemporal bacterial profiling and metabolomics assay revealed a potential involvement of Parasutterella excrementihominis and the bile acid metabolite ursodeoxycholic acid (UDCA) in the effect of GBE. UDCA administration induced depression-like behavior in mice. Together, these findings suggest that GBE acts on gut microbiome-modulated bile acid metabolism to alleviate stress-induced depression.

Matching Charge Extraction Contact for Infrared PbS Colloidal Quantum Dot Solar Cells.

Infrared solar cells (IRSCs) can supplement silicon or perovskite SCs to broaden the utilization of the solar spectrum. As an ideal infrared photovoltaic material, PbS colloidal quantum dots (CQDs) with tunable bandgaps can make good use of solar energy, especially the infrared region. However, as the QD size increases, the energy level shrinking and surface facet evolution makes us reconsider the matching charge extraction contacts and the QD passivation strategy. Herein, different to the traditional sol-gel ZnO layer, energy-level aligned ZnO thin film from a magnetron sputtering method is adopted for electron extraction. In addition, a modified hybrid ligand recipe is developed for the facet passivation of large size QDs. As a result, the champion IRSC delivers an open circuit voltage of 0.49 V and a power conversion efficiency (PCE) of 10.47% under AM1.5 full-spectrum illumination, and the certified PCE is over 10%. Especially the 1100 nm filtered efficiency achieves 1.23%. The obtained devices also show high storage stability. The present matched electron extraction and QD passivation strategies are expected to highly booster the IR conversion yield and promote the fast development of new conception QD optoelectronics.

Application of WALANT technique for repairing finger skin defect with a random skin flap.

BACKGROUND: Wide-awake local anesthesia no tourniquet (WALANT) technique has emerged among hand surgeons with other indications. Surgeries involving pedicled flap and revascularization are no longer used as contraindications. The present study aimed to evaluate the feasibility and merits of the WALANT technique in random skin flap surgery. METHODS: From May 2018 to March 2019, 12 patients with finger skin defects repaired with random skin flaps were reviewed. Abdominal skin flaps or thoracic skin flaps were used to cover the wound. Both the fingers and the donor sites were anesthetized by the WALANT technique. A 40-mL conventional volume consisted of a mixture of epinephrine and lidocaine. A volume of 5 mL was injected at the distal palmar for nerve block, the other 5 mL was injected around the wound for hemostasis, and the remaining was injected at the donor site of flaps for both analgesia and hemostasis. Baseline data with respect to sex, age, side, type of finger, donor sites, flap size, dosage of anesthetics, usage of finger tourniquet, intraoperative and postoperative pain, hemostasis effect, operation time, Disabilities of the Arm, Shoulder, and Hand Questionnaire (QuickDASH) score, and hospitalization expense, were collected. RESULTS: All patients tolerated the procedure, and none of them needed sedation. Single finger skin defect in 8 patients and double finger skin defect occurred in 4 patients; 5 patients were repaired by abdominal skin flaps, and 7 patients were repaired by thoracic skin flaps. The good surgical field visibility was 91.7%. All flaps survived adequately, without necrosis, pulling fingers out, and other complications. The average visual analog scale (VAS) score of the maximal pain was 1.1 in fingers vs. 2.1 in donor sites during the operation. On postoperative day one, the average VAS score of the maximal pain in fingers and donor sites was 1.3 and 1.1, respectively. The average hospitalization expense before reimbursement of the whole treatment was 11% less expensive compared to the traditional method. The average QuickDASH score was 9.1. CONCLUSIONS: Under wide-awake anesthesia, patients have the ability to control their injured upper extremities consciously, avoiding the complications due to pulling flap pedicles. With the merits of safety, painlessness, less bleeding, and effectivity, the WALANT technique in random skin flaps is feasible and a reliable alternative to deal with finger skin defect.

Enhanced Passivation and Carrier Collection in Ink-Processed PbS Quantum Dot Solar Cells via a Supplementary Ligand Strategy.

Solution-processed semiconductors have opened promising avenues for next-generation semiconductor and optoelectronic industries. Colloidal quantum dots (QDs) as one of the most typical materials are widely utilized for the design and development of light-emitting diodes, photodetectors, and solar cells. Recently, an emerging process of PbS QD ink has been employed to attain world record power conversion efficiency by surface passivation using a PbI2 ligand to form PbI2-PbS and the process optimization in the field of photovoltaics. However, the bonding and debonding of the ligands on the surface of PbS QDs are dynamic reversible processes in an ink environment. The uncoordinated Pb2+ defects induced by unbonded PbS QDs serve as the recombination sites. Thus, the present ink process leaves much room for the enhancement by surface passivation of PbS QDs. Herein, we devise an efficient strategy with a supplementary phenethylammonium iodide (PEAI) ligand for the formation of the PEAI-PbS interface in PbS QD ink-processed solar cells. This newly developed method can not only improve the passivation on the QD surface by iodine ions but also simultaneously enhance the carrier collection efficiency by a graded energy alignment between PbI2-PbS and PEAI-PbS layers. The corresponding power conversion efficiency of the optimized device has significantly increased by approximately 20% more than the control device. As a result, such a robust and efficient method regarded as a strategic candidate can overcome the bottleneck of imperfect passivation caused by a large specific surface area and loose bonding ligands, eventually promoting the industrial application of QDs.

Potential hepatic and renal toxicity induced by the biflavonoids from Ginkgo biloba.

Evidence continues to grow on potential health risks associated with Ginkgo biloba and its constituents. While biflavonoid is a subclass of the flavonoid family in Ginkgo biloba with a plenty of pharmacological properties, the potential toxicological effects of biflavonoids remains largely unknown. Thus, the aim of this study was to investigate the in vitro and in vivo toxicological effects of the biflavonoids from Ginkgo biloba (i.e., amentoflavone, sciadopitysin, ginkgetin, isoginkgetin, and bilobetin). In the in vitro cytotoxicity test, the five biflavonoids all reduced cell viability in a dose-dependent manner in human renal tubular epithelial cells (HK-2) and human normal hepatocytes (L-02), indicating they might have potential liver and kidney toxicity. In the in vivo experiments, after intragastrical administration of these biflavonoids at 20 mg·kg-1·d-1 for 7 days, serum biochemical analysis and histopathological examinations were performed. The activity of alkaline phosphatase was significantly increased after all the biflavonoid administrations and widespread hydropic degeneration of hepatocytes was observed in ginkgetin or bilobetin-treated mice. Moreover, the five biflavonoids all induced acute kidney injury in treated mice and the main pathological lesions were confirmed to the tubule, glomeruli, and interstitium injuries. As the in vitro and in vivo results suggested that these biflavonoids may be more toxic to the kidney than the liver, we further detected the mechanism of biflavonoids-induced nephrotoxicity. The increased TUNEL-positive cells were detected in kidney tissues of biflavonoids-treated mice, accompanied by elevated expression of proapoptotic protein BAX and unchanged levels of antiapoptotic protein BCL-2, indicating apoptosis was involved in biflavonoids-induced nephrotoxicity. Taken together, our results suggested that the five biflavonoids from Ginkgo biloba may have potential hepatic and renal toxicity and more attentions should be paid to ensure Ginkgo biloba preparations safety.

Chemical analysis, pharmacological activity and process optimization of the proportion of bilobalide and ginkgolides in Ginkgo biloba extract.

Variations on the efficacy of commercial Ginkgo biloba preparations have been reported, although all the products follow the same standards. Terpene trilactones (TTLs), including bilobalide (BB) and ginkgolides, are one of the main active components in G. biloba extract and have been received the most attention due to their chemical uniqueness and their importance for quality control. A plenty of studies demonstrated that BB and ginkgolides display differential activities on various biological processes. However, the influence of different ratios of BB and ginkgolides on the efficacy of TTLs has not been detected yet. The aims of this study were: (1) to test whether different ratios of BB and ginkgolides existed in commercial G. biloba preparations; (2) to detect the influence of different ratios of BB and ginkgolides on the in vivo efficacy of TTLs; and (3) to optimize the extraction process of G. biloba to approach the better BB and ginkgolides ratio with the maximum in vivo effects. First, the content and proportion of BB and ginkgolides in various G. biloba preparations were quantified by HPLC-MS analysis. As the results, an obvious fluctuation in the proportion of BB and ginkgolides was observed in the preparations from different commercial suppliers. The ratio was ranged from 0.3 to 0.8. Second, a zebrafish thrombosis model was used to evaluate the antithrombotic effects of different ratios of BB and ginkgolides. The result showed that the proportion of BB and ginkgolides at 1:2 produced the maximum antithrombotic effects. Third, the extraction process of G. biloba was optimized using a design space technique aiming to approach the best BB and ginkgolides ratio obtained from zebrafish experiment. The extraction process was modeled based on the results of Box-Behnken designed experiments. Design space was then calculated using a probability-based method. Within this design space, G. biloba extraction process can be guaranteed to achieve the better BB and ginkgolides ratio with high assurance. Normal operation space for G. biloba extraction process was recommended as ethanol concentration of 50% to 70%, liquid-to-solid ratio of 5.6 mL/g to 7.3 mL/g, and extraction time of 2.2 h to 3.0 h. This work not only suggest that the proportion of BB and ginkgolides should be used as a quality control index in ginkgo preparations besides the content of TTLs, but also provide a way to approach it with the extraction process parameters controlled in the normal operation ranges.

Metabolomics Reveals that Momordica charantia Attenuates Metabolic Changes in Experimental Obesity.

Momordica charantia L., also known as bitter melon, has been shown to ameliorate obesity and insulin resistance. However, metabolic changes regulated by M. charantia in obesity are not clearly understood. In this study, serums obtained from obese and M. charantia-treated mice were analyzed by using gas and liquid chromatography-mass spectrometry, and multivariate statistical analysis was performed by Orthogonal partial least squares discriminant analysis. The results from this study indicated that body weight fat and insulin levels of obese mice are dramatically suppressed by 8 weeks of dietary supplementation of M. charantia. Metabolomic data revealed that overproductions of energy and nutrient metabolism in obese mice were restored by M. charantia treatment. The antiinflammatory and inhibition of insulin resistance effect of M. charantia in obesity was illustrated with the restoration of free fatty acids and eicosanoids. The findings achieved in this study further strengthen the therapeutic value of using M. charantia to treat obesity. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of selenium-chitosan on blood selenium concentration, antioxidation status, and cellular and humoral immunity in mice.

One hundred and eighty Kunming mice were allotted to three groups in a randomized complete block design, including two treatments and one control. Mice in group 1 were fed a basal diet as control, while mice in groups 2 and 3 were fed the basal diet supplemented with 0.2 mg/kg selenium as sodium selenite (SS) or selenium-chitosan (SC), respectively. On day 28 of the experiment, blood selenium concentration, glutathione peroxidase (GPx) activity, plasma superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and Con A-induced splenocyte proliferation were determined, and plasma interleukin-2 (IL-2) and interferon-γ (IFN-γ) concentrations, splenic plaque-forming cell (PFC) responses, serum hemolysis level (HC50), and delayed-type hypersensitivity (DTH) responses were determined on day 15 of the experiment. The results showed that blood selenium concentration, GPx activity, splenic PFC response, and plasma IL-2 and IFN-γ concentrations in SC group were higher than those in the control and SS groups (P < 0.01 or P < 0.05), respectively. Plasma SOD activity, Serum hemolysis level, DTH responses, and Con A-induced splenocyte proliferation in SC group were higher than those in control (P < 0.01 or P < 0.05). Plasma SOD activity, serum hemolysis level, DTH responses, and Con A-induced splenocyte proliferation in SC group were also higher than those in SS group, while there was no significant difference between SC and SS groups (P > 0.05). Plasma MDA content in SC group was lower than those in the control and SS groups (P < 0.01 or P < 0.05). It is concluded that SC supplement can increase blood selenium concentration, antioxidation status, and cellular and humoral immunity, and SC has better biological activity than SS in mice.

Single domain antibody against carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) inhibits proliferation, migration, invasion and angiogenesis of pancreatic cancer cells.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is over-expressed in pancreatic cancer cells, and it is associated with the progression of pancreatic cancer. We tested a single domain antibody (sdAb) targeting CEACAM6, 2A3, which was isolated previously from a llama immune library, and an Fc conjugated version of this sdAb, to determine how they affect the pancreatic cancer cell line BxPC3. We also compared the effects of the antibodies to gemcitabine. Gemcitabine and 2A3 slowed down cancer cell proliferation. However, only 2A3 retarded cancer cell invasion, angiogenesis within the cancer mass and BxPC3 cell MMP-9 activity, three features important for tumour growth and metastasis. The IC50s for 2A3, 2A3-Fc and gemcitabine were determined as 6.5µM, 8µM and 12nM, respectively. While the 2A3 antibody inhibited MMP-9 activity by 33% compared to non-treated control cells, gemcitabine failed to inhibit MMP-9 activity. Moreover, 2A3 and 2A3-Fc inhibited invasion of BxPC3 by 73% compared to non-treated cells. When conditioned media that were produced using 2A3- or 2A3-Fc-treated BxPC3 cells were used in a capillary formation assay, the capillary length was reduced by 21% and 49%, respectively. Therefore 2A3 is an ideal candidate for treating tumours that over-express CEACAM6.

MDM2 is a useful prognostic biomarker for resectable gastric cancer.

Expression of MDM2 protein appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone, and in combination with JWA, on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry in three large cohorts (total n = 1131) of patient with gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non-cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with shorter overall survival (OS; P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) in improving OS compared with surgery alone was evident only in the high MDM2 group (hazard ratio = 0.57; 95% confidence interval, 0.37-0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA had a synergistic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant fluorouracil-leucovorin-oxaliplatin chemotherapy in resectable gastric cancer. The combination of MDM2 expression and JWA could serve as a more effective candidate prognostic biomarker for gastric cancer.

High FAK combined with low JWA expression: clinical prognostic and predictive role for adjuvant fluorouracil-leucovorin-oxaliplatin treatment in resectable gastric cancer patients.

BACKGROUND: The multifunctional protein JWA was previously identified as a novel regulator of focal adhesion kinase (FAK/PTK2) in suppressing cancer cell adhesion, invasion and metastasis. JWA is downregulated in gastric cancer (GC) and a prognostic and predictive biomarker for resectable GC. However, the value of FAK combined with JWA for GC patients as a biomarker has not been studied. Here we evaluated the roles of FAK alone and combined with JWA in GC patients treated with surgery alone or combined with adjuvant platinum-based chemotherapy. METHODS: Two tissue microarrays were constructed of specimens from resected GC (n = 709 in total) for detection of FAK and JWA expression by immunohistochemistry. Correlations between both proteins and clinicopathological features as well as prognostic and predictive values were evaluated. RESULTS: Compared with adjacent non-cancerous tissues, FAK protein levels were remarkably up-regulated in GC lesions (P < 0.001). High FAK alone or combined with low JWA expression significantly correlated with worse overall survival (OS) (both P < 0.001 in two cohorts). Simultaneously, JWA plus FAK expression was a more valuable prognostic biomarker than JWA or FAK alone. Moreover, the patients with high FAK only or combined with low JWA had significant benefit from adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) therapy compared with those with surgery alone (P = 0.003); however, the cases with adjuvant fluorouracil-leucovorin-cisplatin (FLP) therapy did not show these effects. CONCLUSION: FAK plus JWA may serve as a more prognostic and predictive biomarker for GC than each separately with a potential clinical application.

Prognostic and predictive role of JWA and XRCC1 expressions in gastric cancer.

PURPOSE: To investigate the expression pattern and significance of DNA repair genes JWA and X-ray repair cross complement group 1 (XRCC1) in gastric cancer. EXPERIMENTAL DESIGN: Expressions of JWA and XRCC1 were assessed by immunohistochemistry in a training cohort and they went into a second testing cohort and finally to a validating cohort. Prognostic and predictive role of JWA and XRCC1 expression status in cases treated with surgery alone or combined with adjuvant chemotherapy was evaluated, respectively. RESULTS: JWA and XRCC1 protein levels were significantly downregulated in gastric cancer lesions compared with adjacent noncancerous tissues. Low tumoral JWA or XRCC1 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients without adjuvant treatment. Multivariate regression analysis showed that low JWA and XRCC1 expressions, separately and together, were independent negative markers of OS. Adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) significantly improved OS compared with surgery alone (log-rank test, P = 0.01). However, this effect was evident only in the JWA or XRCC1 low expression group (HR = 0.44; 95% CI: 0.26-0.73; P = 0.002, and HR = 0.44, 95% CI: 0.26-0.75; P = 0.002, respectively); Adjuvant fluorouracil-leucovorin-platinol (FLP) did not improve OS, except in the patients with low JWA and XRCC1 expressions (P = 0.010 for JWA and 0.024 for XRCC1, respectively). CONCLUSIONS: JWA and XRCC1 protein expressions in tumor are novel candidate prognostic markers and predictive factors for benefit from adjuvant platinum-based chemotherapy (FLO or FLP) in resectable human gastric carcinoma.

Isolation of functional single domain antibody by whole cell immunization: implications for cancer treatment.

Carcinoembryonic antigen related cell adhesion molecule (CEACAM) 6 is over-expressed in different types of cancer cells. In addition, it has also been implicated in some infectious diseases. Targeting this molecule by an antibody might have applications in diverse tumor models. Single domain antibody (sdAb) is becoming very useful format in antibody engineering as potential tools for treating acute and chronic disease conditions such as cancer for both diagnostic as well as therapeutic application. Generally, sdAbs with good affinity are isolated from an immune library. Discovery of a new target antigen would require a new immunization with purified antigen which is not always easy. In this study, we have isolated, by phage display, an sdAb against CEACAM6 with an affinity of 5 nM from a llama immunized with cancer cells. The antibody has good biophysical properties, and it binds to the cells expressing the target antigen. Furthermore, it reduces cancer cells proliferation in vitro and shows an excellent tumor targeting in vivo. This sdAb could be useful in diagnosis as well as therapy of CEACAM6 expressing tumors. Finally, we envisage it would be feasible to isolate good sdAbs against other interesting tumor associated antigens from this library. Therefore, this immunization method could be a general strategy for isolating sdAbs against any surface antigen without immunizing the animal with the antigen of interest each time.

[Chemical constituents from Rehmannia glutinosa].

OBJECTIVE: To study the chemical constituents from the roots of Rehmannia glutinosa. METHOD: The compounds were isolated by various chromatographic methods and identified by spectroscopic analysis. RESULT: Twelve compounds were isolated and their structures were identified as 5-hydroxymethyl-pyrrole-2-carbaldehyde (1), 5-hydroxymethyl furfural (2), tyrosol (3), 5,6-dihydroxy-beta-ionone (4), 6-O-E-feruloyl ajugol (5), acteoside (6), leucosceptoside A (7), martynoside (8), isomartynoside (9), purpureaside C (10), jionoside A1 (11), and jionoside B1 (12). CONCLUSION: Compounds 1, 3 and 9 were isolated from the genus Rehmannia for the first time.