Adverse reactions associated with nivolumab and small molecule antiangiogenic drugs: A pharmacovigilance analysis.

AIMS: Immune checkpoint inhibitors, such as nivolumab, combined with small molecule antiangiogenic receptor tyrosine kinase inhibitors (TKIs), present a promising strategy for future immunotherapy. However, combination therapy can lead to specific adverse drug reactions (ADRs) in various clinical settings. Current research on the ADRs associated with combination therapy is limited. Our study aims to assess the safety of combination therapy. METHODS: We extracted ADR reports on combination therapy from the Food and Drug Administration (FDA) Adverse Event Reporting System database, covering the period from the first quarter of 2012 to the third quarter of 2023, and conducted a large-scale retrospective study. We evaluated ADR risk signals using the reporting odds ratio (ROR) and calculated the Ro/e ratio to compare the differences in the risk of fatal ADRs among various tumour types. RESULTS: We comprehensively reported the occurrence of ADRs in pan-cancer patients undergoing combination therapy. The combination therapy significantly increased the risk of sensitive skin (ROR: 231.43, 95% CI: 55.01-973.72, P < .05), metastatic renal cell carcinoma (ROR: 220.71, 95% CI: 28.99-1695.41, P < .05) and renal cell carcinoma (ROR: 188.22, 95% CI: 44.24-800.85, P < .05). We also compared the differences in ADRs resulting from different small molecule drug combinations, as well as the differences in ADRs among patients with different types of tumours under combination therapy. Furthermore, we analysed the characteristics of patients prone to experiencing fatal ADRs. CONCLUSION: These results can help enhance understanding of the ADRs commonly associated with combination therapy and assist oncologists in formulating screening protocols.

Individualized management of immunosuppressants in liver transplant recipients by using a novel immune score system.

BACKGROUND: There is no reliable means to evaluate the immune status of liver transplant recipients. We proposed a novel score model, namely Mingdao immune cell analysis and Mingdao immune score system, to quantify the immunity. METHODS: Data from those who underwent a single liver transplant between January 2017 and June 2020 at Beijing Chaoyang Hospital, were collected. In addition, healthy volunteers were also enrolled. The score model was based on the immune cell populations determined by flow cytometry. RESULTS: There were a total of 376 healthy controls with 376 tests and 148 liver transplant recipients with 284 tests in this study. Evaluated by Mingdao immune cell analysis and Mingdao immune score system, the mean scores of healthy controls were near zero suggesting a balanced immune system. In contrast, the mean scores of liver transplant recipients were negative both before and after surgery indicating a compromised immune system. When liver transplant recipients were given a reduced or routine first dose according to their preoperative score, they had similar recovery of liver function. Moreover, liver transplant recipients with increased scores ≥ 5 were associated with elevated aspartate transaminase and alanine amiotransferase. Finally, on multivariate analysis the score model was the only significant independent risk factor for clinical acute rejection (P = 0.021; Odds ratio, 0.913; 95% confidence interval, 0.845-0.987). CONCLUSION: The novel score model could be used as an indicator to reflect immunity and to regulate immunosuppressants in liver transplant recipients after surgery.

Impact of metabolic dysfunction-associated fatty liver disease on liver transplant recipients with hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease was proposed by international consensus to redefine the metabolic abnormal condition. However, its impact on liver transplant recipients with hepatitis B virus-related hepatocellular carcinoma has not been explored. METHODS: A two-center retrospective cohort study on liver transplant recipients with hepatitis B virus-related hepatocellular carcinoma was performed to analyze the impact of metabolic dysfunction-associated fatty liver disease on the clinicopathologic parameters and prognosis. RESULTS: There were 201 liver transplant recipients enrolled from two hospitals in our study. The pre- and post-transplant prevalences of metabolic dysfunction-associated fatty liver disease were 9.95% and 28.86%, respectively. The clinicopathological parameters revealed a similarity between patients with and without pre-transplant metabolic dysfunction-associated fatty liver disease. In contrast, the group with post-transplant metabolic dysfunction-associated fatty liver disease was linked with older age, a higher hepatitis recurrence rate and incidence of cardiovascular disease, usage of calcineurin inhibitors, a greater body mass index and waist circumference, lower albumin and high-density lipoprotein cholesterol levels, and poorer tumor-free survival and overall survival. The multivariate analysis showed the largest tumor size >4 cm (95% confidence intervals: 0.06~0.63, p = 0.006), microvascular invasion (95% confidence intervals: 1.61~14.92, p = 0.005), post-transplant metabolic dysfunction-associated fatty liver disease (95% confidence intervals: 1.40~10.60, p = 0.009), and calcineurin inhibitors-based regimen (95% confidence intervals: 0.33~0.96, p = 0.036) were the independent risk factors for recurrent hepatocellular carcinoma. CONCLUSIONS: Our study suggests that post-transplant metabolic dysfunction-associated fatty liver disease is more closely to metabolic abnormalities and that it can help identify liver transplant recipients at high risk of recurrent hepatocellular carcinoma.

Risk factors and clinical outcomes of basilar artery occlusion presenting with paroxysmal sympathetic hyperactivity as the initial manifestation: a prospective study.

BACKGROUND: Paroxysmal sympathetic hyperactivity (PSH) has been linked to a worse clinical prognosis in patients with traumatic brain injury. We aimed to identify the risk factors and clinical features associated with basilar artery occlusion (BAO) presenting with PSH as the first clinical presentation. METHODS: This study recruited patients with acute BAO who received endovascular therapy (EVT) at two stroke centers in China. PSH Assessment Measure ≥8 was included in the PSH+ group, while those with a score below 8 were classified as the PSH- group. Clinical data and radiological findings were compared between the two groups. A binary logistic regression model was employed to identify independent risk factors for PSH. RESULTS: 101 participants were enrolled, of whom 19 (18.8%) presented with PSH as the initial manifestation of BAO. Worse prognosis (modified Rankin Scale score of 4-6) at day 90 occurred in 14 (73.7%) of the PSH+ patients and 42 (51.2%) of the PSH- patients (P=0.076). The 90-day mortality rate was higher in the PSH+ group with 12 (63.2%) participants, compared with 31 (37.8%) participants in the PSH- group (P=0.044). A significantly increased risk of PSH was found in patients with midbrain involvement (OR 6.53, 95% CI 1.56 to 27.30, P=0.01) and a high baseline National Institutes of Health Stroke Scale (NIHSS) score (OR 1.15, 95% CI 1.01 to 1.31, P=0.037). CONCLUSIONS: Patients with BAO presenting with PSH as the initial clinical manifestation experience a higher risk of 90-day mortality, despite undergoing EVT. Midbrain infarction and baseline NIHSS score may be significant risk factors for PSH following BAO.

Gut microbiome-mediated glucose and lipid metabolism mechanism of star apple leaf polyphenol-enriched fraction on metabolic syndrome in diabetic mice.

BACKGROUND: Diabetes is a kind of metabolic syndrome (MetS) that seriously threatens human health globally. The leaf of star apple (Chrysophyllum cainito L.) is an incompletely explored folk medicine on diabetes. And, the effects and mechanisms on diabetes complicated glycolipid metabolism disorders are unknown till now. PURPOSE: This study aimed to investigate the constituents of star apple leaf polyphenol enriched-fraction (SAP), and elucidate their treatment effects and mechanism on diabetes and accompanied other MetS. METHODS: The components of SAP were tentatively identified by HPLC-Q-TOF-MS/MS. The antioxidant activity was determined by the scavenging of free radicals and hypoglycemic activities by inhibition of α-glucosidase in vitro. HepG2 cells were used for evaluating the alleviation effects of SAP on lipid accumulation. Streptozotocin and high-fat diet induced diabetic mice were grouped to evaluate the effects of different dosages of SAP. 16S rRNA was conducted to analysis gut microbiome-mediated glucose and lipid metabolism mechanism. RESULTS: It showed that myricitrin was one of the main active constituents of SAP. SAP not only showed low IC50 on -glucosidase (24.427± 0.626 µg/mL), OH·(3.680± 0.054 µg/mL) and ABTS· (9.155±0.234 µg/mL), but significantly induced the lipid accumulation in HepG2 cells (p < 0.05). SAP at 200 mg/kg·day significantly decreased the blood glucose, insulin and oral glucose tolerance test value (p < 0.05). The insulin resistance indexes and oxidative stress were alleviated after administration. SAP not only attenuated hepatic lipid deposition, but also reversed the hepatic glycogen storage. 16S rRNA sequencing results revealed that the interaction between SAP and gut microbiota led to the positive regulation of beneficial bacteria including Akkermansia, Unspecified S24_7, Alistipes and Unspecified_Ruminococcaceae, which might be one of the mechanisms of SAP on MetS. CONCLUSION: For the first time, this study explored the regulation effect of star apple leaf polyphenols on the hepatic glycolipid metabolism and studied the underlying mechanism from the view of gut microbiota. These findings indicated that SAP possesses great potential to serve as a complementary medicine for diabetes and associated MetS. It provided scientific evidence for folk complementary medicine on the treatment of diabetes-complicated multiple metabolic disorders.

Studies on the key constituents and the related mechanisms of Clerodendranthus spicatus in the treatment of diabetes based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Clerodendranthus spicatus is a traditional Chinese medicine and has been used to treat diabetes and some kidney diseases for a long history. AIM OF THE STUDY: The research aimed to study the active constituents, the potential targets and the related mechanisms of C. spicatus in the treatment of diabetes through network pharmacology method and verify the antidiabetic activity by molecular biology experiments. MATERIALS AND METHODS: A comprehensive network pharmacology strategy was used to predict the key active constituents, the key targets and the related mechanisms and pathways of C. spicatus in the treatment of diabetes. The strategy mainly included screening and predicting potential active constituents and targets by network construction, GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. Based on the predicted results, C. spicatus was extracted by ultrasonic method with 50% ethanol and enriched by using macroporous resin. The compounds with potential antidiabetic effects were separated through silica-gel column chromatography and HPLC (high performance liquid chromatography), and then identified by MS (mass spectrum) and NMR (nuclear magnetic resonance). The C. spicatus extract and isolated compounds were tested by in-vitro and cell experiments to verify their antidiabetic activities, including antioxidant activities, inhibition activities on α-glucosidase and α-amylase, the influence on glucose uptake in cell experiments and the Western blot of PI3K and Akt expression levels. RESULTS: A total of 18 active constituents and 16 key targets of C. spicatus in the treatment of diabetes were screened out through network pharmacology method. Phenolic acids might be the main target compounds for the next research. After extraction, enrichment and separation, the phenolic acids-enriched fraction of C. spicatus and four phenolic acid compounds (helisterculin C, salvianolic acid B, orthosiphoic acid E and ethyl caffeate) were obtained. Among them, salvianolic acid B was isolated from C. spicatus for the first time and orthosiphoic acid E was isolated from natural products for the first time. In experiment verification, the crude extract of C. spicatus, the phenolic acids-enriched fraction and the four compounds all showed antidiabetic potentials. The phenolic acids in C. spicatus had antioxidant activities, inhibitory activities on α-amylase and α-glucosidase and promoted glucose uptake in L6 cells through PI3K/Akt signaling pathway. CONCLUSIONS: This study showed that C. spicatus had antidiabetic activities with the mechanism of the mode of multi-compounds acting on multi-targets and multi-pathways. The main active phenolic acid compounds were also identified. It provided theoretical basis for further development and utilization of C. spicatus.

Influence of endotracheal tube and laryngeal mask airway for general anesthesia on perioperative adverse events in patients undergoing laparoscopic hysterectomy: A propensity score-matched analysis.

Background: To compare perioperative adverse events between general anesthesia with endotracheal tube (ETT) and general anesthesia with laryngeal mask airway (LMA) in patients undergoing laparoscopic hysterectomy. Materials and Methods: This was a large sample retrospective, propensity score-matched (PSM) study. We collected the data of 6739 female patients who underwent laparoscopic hysterectomy between January 2016 and June 2021 in our hospital, China. Patients were divided into two groups (ETT group and LMA group) according to different airway management modes. Data on all perioperative adverse events were collected. PSM analysis was performed to control confounding factors and differences in baseline values between the two groups. Finally, 4150 female patients were recruited after PSM. Results: The total number of patients taking intraoperative vasoactive drugs during surgery was higher in the ETT group than in the LMA group (P = 0.04). The LMA group had a higher incidence of vomiting (51 [2.46%]) and somnolence (165 [7.95]) in the postanesthesia care unit (PACU) than the ETT group (71 [3.42%] and 102 [4.92%], respectively) (P = 0.02 and P < 0.001). Hypothermia was significantly higher in the LMA group (183 [10.36%]) than in the ETT group (173 [8.34%]) in the PACU (P = 0.03). The number of patients with sore throat was significantly higher in the ETT group (434 [20.02%]) than in the LMA group (299 [14.41%]) in the ward (P < 0.001). Other variables such as hypoxemia, moderate to severe pain, abdominal distension, diarrhea, sleep disorders, wound bleeding, and skin itch were not significantly different between the two groups (P > 0.05). Conclusion: The ETT group had more incidences of vomiting, sore throat, and cough complications and needed more drug treatment than the LMA group. LMA is a better airway management mode and LMA general anesthesia can be safely used in patients undergoing laparoscopic nonemergency hysterectomy.

Establishment of rat allogenic vein replacement model and pathological characteristics of the replaced vessels.

Background: With the advancement of vascular anastomosis techniques in recent years, radical surgery for tumors combined with venous vascular resection and reconstruction has been widely used. This study intends to establish two different rat vein replacement models, and further analyze the pathological changes of blood vessels after replacement. Methods: Brown-Norway (BN) rats were selected as donors and recipients, randomly divided into control group, cuff group (1-week group, 2-week group, and 4-week group), and suture group (1-week group, 2-week group, and 4-week group), with 6 rats in each group. The perioperative conditions, inner diameter, flow velocity and histopathological changes of the replaced vessels at different time points were analyzed. Results: Both cuff group and suture group can safely establish the rat vein replacement model. From the surgical operation, the operation time and venous cross-clamp time in the cuff group were shorter than those in the suture group (P < 0.05). At 2 and 4 weeks after operation, the diameter of suture group was wider than that of cuff group, and the flow rate was faster (P < 0.05). With prolonged postoperative survival, the wall of the replaced vessels underwent infiltration of CD4+ and CD8+ lymphocytes and high TGF-ß1 gene expression. This leads to the proliferation of blood vessels and intimal layer. The results of vascular pathological staining showed that the infiltration degree of CD4+ lymphocytes at 2 weeks after operation and CD8+ lymphocytes at 4 weeks after operation in the suture group was lighter than that in the cuff group (P < 0.05). Meanwhile, TGF-ß1 gene content at 4 weeks after operation in suture group was significantly lower than that in cuff group (P < 0.05). Conclusion: Compared with cuff method, suture method is more suitable for the study of long-term pathological changes after vein replacement in rats. The main pathological changes in the long term after venous replacement in syngeneic background may be vascular fibrosis caused by inflammatory cell infiltration.

Inhibition of endoplasmic reticulum stress and the downstream pathways protects CD4+ T cells against apoptosis and immune dysregulation in sepsis.

Immunosuppression mediated by CD4+ T cell apoptosis and dysfunction is a key factor in promoting the progression of sepsis. Endoplasmic reticulum (ER) stress participates in the apoptosis and dysfunction of immune cells. We aimed to investigate the role of ER stress inhibition in CD4+ T cells in both in vitro and in vivo models of sepsis. In vitro model of sepsis was established with lipopolysaccharide (LPS) and the rat model of sepsis was established using cecal ligation and puncture (CLP). After the LPS treatment or CLP, ER stress inhibitors including 4-PBA, SNJ-1945, and SP600125 were used to treat cells or rats, and the CD4+ T cells were obtained by magnetic bead sorting. The effects of ER stress inhibitors on apoptosis and the function of CD4+ T cells were evaluated. After the LPS stimulation or CLP, the levels of ER stress and downstream markers (PERK, eIF2α, IRE-1α, ATF6, ATF4, XBP-1 s, GRP78, CHOP, and p-JNK) were increased in CD4+ T cells at the beginning of sepsis. Meanwhile, the number of apoptotic CD4+ T cells markedly increased. In addition, sepsis impaired the function of CD4+ T cells, manifested by the increased population of Th1, Th2, Th17, and Treg, as well as the production of TNF-α, interleukin (IL)-6, IL-4, and IL-10. However, inhibitors of ER stress, JNK, and calpain all decreased the induction of Th1 and Th17, enhanced the increase of Th2 and Treg, decreased the production of TNF-α and IL-6, and enhanced the production of IL-4 and IL-10. Our findings indicate that ER stress inhibitors may play a protective role by reducing CD4+ T cell apoptosis and maintaining CD4+ T cell function, which may be useful for enhancing the immune function and poor prognosis of patients with sepsis.

Anlotinib Downregulates RGC32 Which Provoked by Bevacizumab.

Background: Bevacizumab is the representative drug in antiangiogenic therapy for lung cancer. However, it induced resistance in some neoplasm. Anlotinib, a novel multi-target tyrosine kinase inhibitor which has an inhibitory action on both angiogenesis and malignancy, is possible to reverse the resistance. Methods: Transwell migration and invasion experiments of bevacizumab with or without anlotinib were conducted to verify the activated/inhibited ability of lung adenocarcinoma cells. We sequenced A549 cells with enhanced migration and invasion abilities after bevacizumab treatment, screened out the differentially expressed gene and further confirmed by western blot and q-PCR assays. We also investigated immunohistochemical staining of tumor tissue in mice and human lung adenocarcinoma. Results: Bevacizumab facilitated migration and invasion of lung adenocarcinoma cells. Differentially expressed gene RGC32 was screened out. Bevacizumab upregulated the expression of RGC32, N-cadherin, and MMP2 through ERK-MAPK and PI3K-AKT pathways. Anlotinib downregulated their expression and reversed the effect of bevacizumab on A549 cells. In vivo experiments confirmed that higher-dose bevacizumab facilitated metastasis in tumor-bearing nude mice and upregulated the expression of RGC32, N-cadherin, and MMP2, whereas anlotinib abrogated its effect. Expression of both RGC32 and N-cadherin positively correlated with lymph node metastasis and stage in lung adenocarcinoma was found. Survival analysis revealed that higher expressions of RGC32 and N-cadherin were associated with poor progression-free survival and overall survival. Conclusions: Bevacizumab may promote invasion and metastasis of lung adenocarcinoma cells by upregulating RGC32 through ERK-MAPK and PI3K-AKT pathways to promote epithelial-mesenchymal transition, whereas anlotinib reverses the effect. RGC32 and N-cadherin are independent prognostic factors in lung adenocarcinoma.

Spheroidization of ultrasonic degraded corn silk polysaccharide to enhance bioactivity by the anti-solvent precipitation method.

BACKGROUND: Corn silk is a very important by-product of corn production with medicinal value. Corn silk polysaccharide (CSP) is the main active ingredient. In the present study, ultrasound and spheroidization by anti-solvent were applied to improve the biological activity of CSP. RESULTS: The results showed that ultrasonic degradation improved the α-glucosidase inhibitory activity of CSP by changing its physicochemical characteristics. As the anti-solvent ratio increased, the particle size of the nanoparticles (NPs) from the spheroidization of ultrasonic-degraded corn silk polysaccharide (UCSP) gradually increased, and NP-1 exhibited the highest inhibitory effect of α-glucosidase. Isothermal titration calorimetry (ITC) results indicated that the enhanced activity might be due to more α-glucosidase binding sites with NP-1 compared with no spheroidization. Western blotting results showed that NP-1 could improve the 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) uptake in the L6 cells by regulating the phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway and the translocation of glucose transporter 4 (GLUT4). NP-1 also exhibited excellent stability in different environments. CONCLUSION: The study revealed that ultrasonic treatment and spheroidization processing showed potential applications for improving the biological activity of polysaccharides. © 2021 Society of Chemical Industry.

Recent Progress in Natural Anticancer Agents Discovery from Tea (Camellia sinensis): A Review.

BACKGROUND: Tea, as the bud from the plant Camellia sinensis, is the most consumed popular beverage just next to water; especially green tea has gained much attention because of its health effects. The anticancer effects of tea components including tea polyphenols, in particular epigallocatechin gallate and tea polysaccharides, are widely investigated in recent years. OBJECTIVES: Based on the articles and patents published in the last 10 years, this review focuses on the structural activities and molecular mechanisms of the anticancer effects of tea components (mainly tea polyphenols and tea polysaccharides) to provide references for future anticancer studies of tea. METHODS: In the database, a literature search was conducted with "tea polyphenols", "tea polysaccharides", "theanine" and "anticancer" as the keywords, and the limited time range was "2010-2021". After sorting out and analyzing the retrieval results, the structure, activity and molecular mechanism, as well as the research progress on the structural modification, drug delivery system and toxicology of natural agents in tea in recent years, were summarized. RESULTS: We found that the natural anticancer agents in tea mainly include tea polyphenols, tea polysaccharides, theanine, caffeine and other components by summarizing the literature. The anticancer mechanisms can be divided into the induction of cell apoptosis, inhibition of cell proliferation, metastasis and invasion, and inhibition of angiogenesis. In the past 10 years, there was little literature on the structural modification, drug delivery system and toxicological evaluation of natural anticancer agents in tea, and there were reports of novel research on nano preparations. The studies showed that nano preparation technology could effectively improve the bioavailability and targeting treatment of anticancer tea components. In addition, in the past decade, patents on tea and natural anticancer agents in tea were relatively rich, among which pharmaceutic preparation patents were the majority, and tea polyphenols were the main ones. CONCLUSION: This paper concluded that there are many kinds of natural anticancer agents in tea, and the anticancer mechanism is complex. Further research on the structural modification, drug delivery system and toxicological evaluation of relevant anticancer active components can be carried out. In general, tea components as new anticancer substances have a certain potential for development. In addition, future research can be focused on the comprehensive study of the structure-activity relationship, the in-depth study of the molecular mechanism, the in-depth understanding of the anticancer effects in vivo, and the verification of large-scale production.

Decreased granzyme B+CD19+B cells are associated with tumor progression following liver transplantation.

Lymphocytes play an important role in antitumor immunity following organ transplantation. However, the function of granzyme B+CD19+B cells on the hepatocellular carcinoma cells from liver transplant recipients remains largely unknown; we aimed to analyze the function and elucidate the mechanisms behind it. Blood samples and clinical data from liver transplant recipients and healthy controls at Beijing Chaoyang Hospital as well as from a validation cohort were collected and analyzed. In this study, we found decreased granzyme B+CD19+B cells were correlated with early hepatocellular carcinoma recurrence and could further identify liver transplant recipients with poor tumor differentiation, microvascular invasion, increased total tumor diameter, and tumor beyond Milan criteria. Notably, granzyme B+CD19+B cells directly inhibited the proliferation, migration, and invasion of hepatocellular carcinoma cells. Upon activation regulatory B cells from liver transplant recipients with hepatocellular carcinoma recurrence displayed a CD5+CD38+CD27+CD138+CD19+ granzyme B+ phenotype, but the increased expression of CD5, CD38, and CD138, and the decreased protein level and transcriptional level requiring JAK/STAT signaling. In an independent validation cohort, liver transplant recipients with decreased granzyme B+CD19+B cells had not only early hepatocellular carcinoma cell recurrence but also shorter survival. Our study provides comprehensive data from liver transplant recipients with hepatocellular carcinoma, indicating a critical role of granzyme B+CD19+B cells in preventing cancer progression. Our findings warrant further investigations for the design of future immunotherapies leading to immune responses and improved patient survival.

Remifentanil pretreatment ameliorates H/R-induced cardiac microvascular endothelial cell dysfunction by regulating the PI3K/Akt/HIF-1α signaling pathway.

Restoration of blood supply through medical or surgical intervention is a commonly adopted method for acute myocardial ischemia, but is also a trigger for cardiac ischemia/reperfusion injury. Studies have shown that remifentanil (REM) displays cardioprotective effects. In this study, the effects of REM on HCMEC viability were examined before and after the induction of H/R using Cell Counting Kit-8 assays. Wound healing and Matrigel angiogenesis assays were performed to assess HCMEC migration and angiogenesis, respectively. Commercial kits and western blotting were used to determine the endothelial barrier function of H/R-stimulated HCMECs with or without REM treatment. The expression of PI3K/Akt/hypoxia-inducible factor-1α (HIF-1α) pathway-related proteins was detected by western blotting. After pre-treatment with PI3K/Akt, the effects of REM on H/R-induced HCMEC injury were examined. We found that pre-treatment with REM displayed no impact on HCMEC viability under normal conditions but noticeably improved cell viability following H/R. The migratory abilities and tube-like structure formations of H/R-stimulated HCMECs were both enhanced by REM in a concentration-dependent manner. REM also decreased the permeability of H/R-stimulated HCMECs and upregulated the expression of tight junction proteins. Furthermore REM increased the expression of PI3K/Akt/HIF-1α signaling-related proteins in HCMECs. Inhibition of PI3K/Akt rescued REM-enhanced HCMEC function under H/R condition. Therefore, the present study demonstrated that REM pretreatment ameliorated H/R-induced HCMEC dysfunction by regulating the PI3K/Akt/HIF-1α signaling pathway.

Chrysophyllum cainito. L alleviates diabetic and complications by playing antioxidant, antiglycation, hypoglycemic roles and the chemical profile analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Chrysophyllum cainito L. (C. cainito) is a traditional folk medicine in tropical area which can be an alternative agent for diabetes mellitus. Although the antioxidant and antidiabetic activity of the extracts are reported, little is known on the antiglycation activity and effects on diabetic complications. AIM OF THE STUDY: This work was aimed to investigate the chemical profile, antidiabetic, antioxidant activities of C. cainito. Especially, the antiglycation potential as well as the relationships between components and activities were evaluated. MATERIALS AND METHODS: The content of the primary components (polyphenols, flavonoids, steroids, and triterpenes), antioxidant, and hypoglycemic effects of ethanolic extracts from C. cainito leaves (CCE-1, 2, 3, 4) and stems (CSE-1, 2, 3, 4) were analyzed and detected. The chemical profiles of CCE-2 were characterized by HPLC-Q-TOF-MS/MS. The antiglycation and protection against oxidative stress effects were determined by in vitro assays. Relationship between bioactivities and components was analyzed by principal component analysis (PCA), heatmap analysis, and Pearson correlation analysis. RESULTS: The composition was diverse between leaves and stem extracts with different activities. CCE-2 possessed the highest DPPH scavenging activity. CSE-2 displayed the highest ABTS scavenging activity and ferric reducing power. While CCE-3 showed the most effective inhibition on α-amylase and α-glucosidase activity (IC50 4.103 ± 0.332 µg/mL and 0.180 ± 0.006 mg/mL, respectively). PCA analysis showed that the most important variables in PC1 (60.7%) were total polyphenol and antioxidant activities. The hypoglycemic activity and contents of steroids showed important correlation. Advanced glycation end products formation was effectively inhibited by CCE-2 with myricetin 3-O-rhamnoside as the main constituent. CCE-3 displayed the highest protection effect against L02 cell line oxidation damage. CONCLUSIONS: C. cainito leaves might be a promising candidate for antioxidant, hypoglycemic and antiglycation dietary supplement or potential agent against diabetes associated chronic diseases.

Recent Developments in Inonotus obliquus (Chaga mushroom) Polysaccharides: Isolation, Structural Characteristics, Biological Activities and Application.

Inonotus obliquus (Chaga mushroom) is a kind of medicine and health food widely used by folk in China, Russia, Korea, and some occidental countries. Among the extracts from Inonotus obliquus, Inonotus obliquus polysaccharide (IOPS) is supposed to be one of the major bioactive components in Inonotus obliquus, which possesses antitumor, antioxidant, anti-virus, hypoglycemic, and hypolipidemic activities. In this review, the current advancements on extraction, purification, structural characteristics, and biological activities of IOPS were summarized. This review can provide significant insight into the IOPS bioactivities as their in vitro and in vivo data were summarized, and some possible mechanisms were listed. Furthermore, applications of IOPS were reviewed and discussed; IOPS might be a potential candidate for the treatment of cancers and type 2 diabetes. Besides, new perspectives for the future work of IOPS were also proposed.

The structural characteristic of acidic-hydrolyzed corn silk polysaccharides and its protection on the H2O2-injured intestinal epithelial cells.

This work aims to describe the purification and characterization of acidic-hydrolyzed corn silk polysaccharides (AH-CSP) and evaluate their protection on the H2O2-injured intestinalepithelial cells (IEC-6). Two fractions named AHP-1 and AHP-2 were obtained from AH-CSP, and physicochemical properties of them were investigated by gel permeation chromatography (GPC), gas chromatography (GC), nuclear magnetic resonance (NMR), fourier transform infrared (FT-IR) spectroscopy, scanning electronic microscopy (SEM), and Congo red test. Results showed that AHP-1 (2.80 × 104 Da) and AHP-2 (1.25 × 104 Da) were consisted of xylose, mannose, galactose, rhamnose, arabinose, and glucose. AHP-1 and AHP-2 had strong scavenging activities on 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-Azobis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), and OH· free radicals. Furthermore, pretreatment with AHP-2 could protect the H2O2-injured IEC-6 cells by effectively scavenging the overproduced reactive oxygen species (ROS) and regulating of Kelch-like ECH-associated protein 1(Keap1)/ nuclear factor erythroid 2-related factor 2 (Nrf2) signal pathway.