An updated meta-analysis on the efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitor treatment of anemia in nondialysis-dependent chronic kidney disease.

BACKGROUND: Renal anemia, a common complication and threat factor of chronic kidney disease (CKD), has long been treated with injectable erythropoietin-stimulating agents (ESAs). As concerns regarding cardiovascular safety and erythropoietin resistance to ESAs have emerged, alternative therapies are urgently needed. Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), an oral agent, has been proven to be effective in improving renal anemia. However, the effects of HIF-PHIs on nondialysis-dependent CKD (NDD-CKD) have yet to be supported by updated meta-analyses. METHODS: A meta-analysis of clinical randomized controlled trials (RCTs) on HIF-PHI treatment of NDD-CKD patients based on PubMed, EMBASE, and Cochrane databases as of July 16th, 2023, was conducted. The primary outcomes were the level of hemoglobin (Hb) postintervention and the ratio of Hb responses. Most of the analysis was conducted via RevMan 5.3 software using a random-effects model. Stata (version 15.0) was used to analyze the publication bias. RESULTS: Twenty-two studies with a total of 7178 subjects in the HIF-PHI group, 3501 subjects in the ESA group and 2533 subjects in the placebo group were enrolled. HIF-PHIs increased the level of Hb and improved iron metabolism but were not inferior to ESAs in terms of safety. CONCLUSIONS: HIF-PHIs may be a convenient and safe alternative to ESAs in patients with NDD-CKD and anemia.

Bibliometric and visual analysis in the field of traditional Chinese medicine in cancer from 2002 to 2022.

Objective: Traditional Chinese medicine (TCM) has been used as a complementary treatment for cancer patients, but there has been no quantitative comprehensive analysis of TCM's efficacy. The purpose of this paper is to explore the current status and hotspots of TCM in cancer research from 2002 to 2022 and to provide a reference for future research. Methods: We retrieved articles published between 2002 and 2022 from the Web of Science database and analyzed them using R software, VOSviewer, and CiteSpace software. Results: A total of 7,129 articles were included in this study. The publication rate of TCM cancer research increased steadily from 2002 to 2022, with a rapid increase from 2010 to 2021. China was the country with the most published articles, followed by the United States, Republic of Korea, Germany, and Japan. China was also the country with the most international collaborations, and China Medical University and Shanghai University of Traditional Chinese Medicine were the most representative cooperation centers. The Journal of Ethnopharmacology was the most published and cited journal. Apoptosis, expression, in vitro, activation, and other related keywords were commonly used in these articles. Breast cancer, colorectal cancer, gastric cancer, liver cancer, and lung cancer were the most studied cancer types in TCM research. Pathway-related apoptosis, anti-inflammation, and oxidative stress were the hotspots and trends of TCM's anti-cancer mechanism. Metabolomics combined with network pharmacology was the main research method. Conclusion: Traditional Chinese medicine as an anti-cancer drug has received increasing attention from researchers worldwide, and it is expected to be a hotspot for developing new anti-cancer drugs in the future. Our study provides a comprehensive analysis of the current status and hotspots of TCM cancer research, which could serve as a valuable reference for future studies.

Glutamine protects mouse spermatogonial stem cells against NOX1-derived ROS for sustaining self-renewal division in vitro.

Reactive oxygen species (ROS) are generated from NADPH oxidases and mitochondria; they are generally harmful for stem cells. Spermatogonial stem cells (SSCs) are unique among tissue-stem cells because they undergo ROS-dependent self-renewal via NOX1 activation. However, the mechanism by which SSCs are protected from ROS remains unknown. Here, we demonstrate a crucial role for Gln in ROS protection using cultured SSCs derived from immature testes. Measurements of amino acids required for SSC cultures revealed the indispensable role of Gln in SSC survival. Gln induced Myc expression to drive SSC self-renewal in vitro, whereas Gln deprivation triggered Trp53-dependent apoptosis and impaired SSC activity. However, apoptosis was attenuated in cultured SSCs that lacked NOX1. In contrast, cultured SSCs lacking Top1mt mitochondria-specific topoisomerase exhibited poor mitochondrial ROS production and underwent apoptosis. Gln deprivation reduced glutathione production; supra-molar Asn supplementation allowed offspring production from SSCs cultured without Gln. Therefore, Gln ensures ROS-dependent SSC-self-renewal by providing protection against NOX1 and inducing Myc.

Traditional Chinese herbal medicine complex supplementation improves reproductive performance, serum biochemical parameters, and anti-oxidative capacity in periparturient dairy cows.

This study was conducted to investigate the effects of a traditional Chinese herbal medicine complex (TCHMC) on the productive performance of periparturient dairy cows. Eighteen non-lactating pregnant Holstein dairy cows with similar body conditions with 1 to 2 parity were randomly divided into three groups (n = 6), receiving a basal diet with 0 (CON group), 200 (T-200 group), and 300 (T-300 group) g TCHMC per day from 14 to 9 days prepartum. The results demonstrated that TCHMC treatments decreased the days of gestation, calving to first service, and calving to first visible estrus. Compared with CON at specific time points, TCHMC treatments increased the concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2), whereas progesterone (P4) and E2 concentrations decreased. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK) concentrations were downregulated, whereas that of globulin (GLB) and immunoglobulin G (IgG) were upregulated by TCHMC treatments around the time of calving. Compared with CON and T-200 treatments, the T-300 treatment increased the serum concentrations of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT) and total antioxidant capacity (T-AOC) and decreased the malondialdehyde (MDA) concentration from 7 d prepartum to 21 d postpartum when. In addition, although TCHMC treatment had no effect on average birth weight, heart rate, respiratory rate, and body temperature of calves, the T-300 treatment increased serum albumin (ALB) and IgG concentrations in calves from 3 to 14 days postpartum. The addition of TCHMC used in the present study could serve as a potential effective strategy to improve the health and productive performance of periparturient dairy cows, and the optimal dose should be set at 300 g per day.

Xuebijing Injection Ameliorates H2S-Induced Acute Respiratory Distress Syndrome by Promoting Claudin-5 Expression.

OBJECTIVE: To investigate the protective effects and underlying mechanisms of Xuebijing Injection (XBJ) on the lung endothelial barrier in hydrogen sulfide (H2S)-induced acute respiratory distress syndrome (ARDS). METHODS: Sprague-Dawley rats were exposed to H2S (300 ppm) to establish ARDS model, while human pulmonary microvascular endothelial cells (HPMECs) were incubated with NaHS (a H2S donor, 500 µmol/L) to establish cell model. H2S and XBJ were concurrently administered to the rat and cell models. Lung hematoxylin and eosin staining, immunohistochemistry, transmission electron microscopy and wet/dry ratio measurement were used to confirm ARDS induced by H2S in vivo. The expression levels of claudin-5, phosphorylated protein kinase B (p-AKT)/t-AKT and p-forkhead box transcription factor O1 (FoxO1)/t-FoxO1 in vivo and in vitro were also assessed. Paracellular permeability and transepithelial electrical resistance (TEER) were measured to evaluate endothelial barrier function in the cell model. RESULTS: The morphological investigation showed that XBJ attenuated H2S-induced ARDS in rats. XBJ significantly ameliorated both the reduction in TEER and the increased paracellular permeability observed in NaHS-treated HPMECs (P<0.05). The protective effects of XBJ were blocked by LY294002, a phosphatidylinositol 3-kinase (PI3K)/AKT/FoxO1 pathway antagonist (P<0.05). Furthermore, XBJ promoted the expression of claudin-5 and increased the levels of p-AKT and p-FoxO1 in vivo and in vitro (P<0.05). CONCLUSIONS: XBJ ameliorated H2S-induced ARDS by promoting claudin-5 expression via the PI3K/AKT/FoxO1 signaling pathway.

A multi-parameter study of the etiological diagnosis of hyponatremia after hypothalamic tumor surgery.

OBJECTIVES: This study aimed to analyze the difference between cerebral salt-wasting syndrome (CSWS) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in patients with hyponatremia after hypothalamic tumor surgery, and to explore a convenient and effective way to identify CSWS and SIADH. METHODS: Patients undergoing craniotomy of hypothalamic tumor admitted to the Department of The Affiliated Hospital of Qingdao University from December 2018 to May 2020 were enrolled in this study. Plasma brain natriuretic peptide (BNP), 24-h urine sodium, 24-h urine volume, and the diameter of the inferior vena cava (IVCD) were measured daily before operation and 1-7 days after operation, to analyze differences in plasma BNP, 24-h urinary sodium excretion, 24-h urine volume, and IVCD between the CSWS and SIADH. RESULTS: The medical data of 31 patients with hypothalamic tumors were collected. Fifteen of these patients (48%) had postoperative hyponatremia, nine patients (29%) had CSWS, and six patients (19%) had SIADH. Plasma BNP, 24-h urinary sodium excretion, and 24-h urine volume in the CSWS group were significantly higher than those in the SIADH group. IVCD decreased in the CSWS group and increased in the SIADH group. CONCLUSIONS: When hyponatremia occurs after hypothalamic tumor surgery, plasma BNP, 24-h urinary sodium excretion, 24-h urine volume, and IVCD are of great help in identifying CSWS and SIADH.

The role of tumor-associated macrophages in osteosarcoma progression - therapeutic implications.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor. Compared with previous treatment modalities, such as amputation, more recent comprehensive treatment modalities based on neoadjuvant chemotherapy combined with limb salvage surgery have improved the survival rates of patients. Osteosarcoma treatment has, however, not further improved in recent years. Therefore, attention has shifted to the tumor microenvironment (TME) in which osteosarcoma cells are embedded. Therapeutic targets in the TME may be key to improving osteosarcoma treatment. Tumor-associated macrophages (TAMs) are the most common immune cells within the TME. TAMs in osteosarcoma may account for over 50% of the immune cells, and may play important roles in tumorigenesis, angiogenesis, immunosuppression, drug resistance and metastasis. Knowledge on the role of TAMs in the development, progression and treatment of osteosarcoma is gradually improving, although different or even opposing opinions still remain. CONCLUSIONS: TAMs may participate in the malignant progression of osteosarcoma through self-polarization, the promotion of blood vessel and lymphatic vessel formation, immunosuppression, and drug resistance. Besides, various immune checkpoint proteins expressed on the surface of TAMs, such as PD-1 and CD47, provide the possibility of the application of immune checkpoint inhibitors. Several clinical trials have been carried out and/or are in progress. Mifamotide and the immune checkpoint inhibitor Camrelizumab were both found to be effective in prolonging progression-free survival. Thus, TAMs may serve as attractive therapeutic targets. Targeting TAMs as a complementary therapy is expected to improve the prognosis of osteosarcoma. Further efforts may be made to identify potential beneficiaries of TAM-targeted therapies.

Benefits of resistant starch type 2 for patients with end-stage renal disease under maintenance hemodialysis: a systematic review and meta-analysis.

Background: Resistant starch type 2 (RS2) has been documented to regulate gut microbiota and to improve the clinical outcomes of several diseases. However, whether RS2 may benefit patients with end-stage renal disease under maintenance hemodialysis (MHD) remains unknown. Methods: We conducted a systemic review and meta-analysis of randomized controlled trials (RCTs). Adult patients receiving MHD were treated with RS2 (CRD42020160332). The primary outcomes were changes of uremic toxins, and the secondary outcomes were changes of inflammatory indicators, albumin and phosphorus. Results: After screening 65 records, five RCTs (n = 179) were included. A significant decrease of blood urea nitrogen (weighted mean difference (WMD) = -6.91, 95% CI: -11.87 to -1.95, I2 = 0%, P = 0.006), serum creatinine (WMD = -1.11, 95% CI: -2.18 to -0.05, I2 = 44%, P = 0.04) and interleukin (IL)-6 in blood (standard mean difference (SMD) = -1.08, 95% CI: -1.64 to -0.53, I2 = 35%, P = 0.0001) was revealed in the RS2 group. Analyses of blood levels of uric acid, p-cresyl sulfate, indoxyl sulfate, high sensitive C-reaction protein, albumin and phosphorus yielded no significant difference. Conclusions: Our results suggest that RS2 may improve the residual renal function of patients under MHD and mitigate a proinflammatory response.

Effect of Danhong Injection () on Improving Coronary Microcirculation Injury after Percutaneous Coronary Intervention.

OBJECTIVE: To explore the effectiveness of Danhong Injection () on improving microcirculatory injury after percutaneous coronary intervention (PCI) in patients with coronary heart disease (CHD). METHODS: A randomized controlled trial was conducted and 90 patients were enrolled. A random sequence was generated using statistical analysis software. Patients with microcirculatory injuries after PCI were randomly divided into 3 groups for treatment (30 subjects in each group): Danhong Injection group: after PCI, Danghong Injections were given with intravenous administration with 40 mL twice a day for a week; statins intensive group: after PCI, atorvastatin calcium tablets were given oral medication with 80 mg once, and then atorvastatin 40 mg daily for 1 week; the control group: after PCI, atorvastatin calcium tablets were given oral medication with 10-20 mg daily for 1 week. The index of microcirculation resistance (IMR) was used to assess microcirculatory injury during PCI. The IMR of the target vessel was reexamined after 1 week of drug treatment. RESULTS: After one week's drug treatment, IMR was significantly decreased in both statins intensive group and Danhong Injection group compared with the control group (P<0.01), but no difference was found between statins intensive group and Danhong injection group (14.03 ± 2.54 vs. 16.03 ± 5.72 U, P=0.080). CONCLUSIONS: The efficacy of Danhong Injection is non-inferior to statin. Early use of Danhong Injection after PCI can effectively improve coronary microcirculation injury after PCI.

Protective effect of 2-dodecyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione, isolated from Averrhoa carambola L., against Aß1-42-induced apoptosis in SH-SY5Y cells by reversing Bcl-2/Bax ratio.

BACKGROUND AND PURPOSE: Aß1-42-induced neurotoxicity has been considered as a possible mechanism to aggravate the onset and progression of Alzheimer's disease (AD). In this study, we aim to determine the protective effect of DMDD on the apoptosis of SH-SY5Y cells induced by Aß1-42 and elucidate potential mechanism of DMDD's protective function in apoptosis. EXPERIMENTAL APPROACH: CCK-8, AnnexinV-FITC/PI flow cytometry, and transmission electron microscopy analysis were used to determine the protection of DMDD on Aß1-42-evoked apoptosis of SH-SY5Y cells. Cytochrome c release, JC-1 staining, and measuring the protein of Bcl-2 family by Western blot were applied to elucidate the mechanism of DMDD's protective function in apoptosis. KEY RESULTS: Three concentration of DMDD (5 µmol/L, 10 µmol/L, and 20 µmol/L) rescues the cell viability loss and apoptosis of SH-SY5Y cells cultivated in Aß1-42. The expressions of cleaved Caspase-3, -8, -9, the cytochrome c release, and mitochondrial membrane potential loss were inhibited by DMDD in Aß1-42-insulted SH-SY5Y cells. The Western blot analysis showed that DMDD pretreatment clearly downregulated the protein of Bax and upregulated Bcl-2. Moreover, the Bcl-2/Bax ratio was obviously decreased in cells only exposed to Aß1-42, but, which was suppressed by treated with DMDD. CONCLUSION AND IMPLICATIONS: DMDD attenuated the apoptosis of SH-SY5Y cells induced by Aß1-42 through reversing the Bcl-2/Bax ratio.

Convulsive status epilepticus as the initial presentation of superwarfarin poisoning: a case report.

Bromadiolone, a widely-used rodent control drug, could act as a long-acting anticoagulant. Patients of bromadiolone poisoning often present with multiorgan hemorrhage. However, neurological symptoms of bromadiolone poisoning are seldom reported. We report a rare case with convulsive status epilepticus as the initial presentation of bromadiolone poisoning. A previously healthy 18-year-old man presented with persistent unconsciousness and repeated convulsive seizures. Magnetic resonance imaging revealed lesions in the corpus callosum. Laboratory test revealed the microscopic hematuria, prolonged prothrombin time, prolonged activated partial thromboplastin time and the presence of bromadiolone. The patient was diagnosed as the bromadiolone poisoning and treated with hemofiltration, vitamin K and prothrombin complex. Consciousness of the patient was regained and all neurological symptoms diminished after 7 days. Coagulopathy was totally corrected after 3 weeks, and a 2-month regimen of vitamin K supplementation was prescribed after discharge. Our case suggests that bromadiolone poisoning may involve the central nervous system. The atypical and initial symptoms of neurological disorders might lead to misdiagnosis of bromadiolone poisoning. Poisoning should be considered when acute neurological symptoms are combined with bleeding tendency. The vitamin K treatment is effective for both coagulopathy and central nervous system disorders in bromadiolone poisoning.

Protective Effect of Benzoquinone Isolated from the Roots of Averrhoa carambola L. on Streptozotocin-Induced Diabetic Mice by Inhibiting the TLR4/NF-κB Signaling Pathway.

BACKGROUND: Studies have demonstrated that the roots of Averrhoa carambola L. (Oxalidaceae), a traditional Chinese medicine, can be used to treat diabetes and diabetes-related diseases. Nevertheless, the potential beneficial effects and mechanism of benzoquinone isolated from the roots of Averrhoa carambola L. (BACR) on diabetes remain unclear. METHODS: Diabetic Kunming mice were injected with STZ (120 mgkg-1) in the tail vein. Fasting blood glucose (FBG) and the change of body weight were measured after oral administration of BACR (120, 60, 30 mg/kg/d) every week. The levels of the total cholesterol (TC), triglyceride (TG), free fatty acids (FFA), glucosylated hemoglobin (GHb), fasting insulin (FINS), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured. The histological examination of pancreatic tissues and the TLR4/NF-κB pathway was analyzed by RT-PCR, immunohistochemistry and Western blot. RESULTS: The study found that clearly the BACR obviously reduced the blood glucose, serum lipids, GHb and FINS. In addition, BACR treatment markedly reduced the release of inflammatory factors, including IL-6 and TNF-α, and down-regulated the expression of the TLR4/NF-κB pathway. CONCLUSION: BACR has potential benefits for the treatment of diabetes by ameliorating metabolic functions and attenuating the inflammatory response via inhibition of the activation of theTLR4/NF-κB pathway.

[Xuebijing injection attenuates hydrogen sulfide-induced endothelial barrier dysfunction by upregulating claudin-5 expression].

OBJECTIVE: To study the new mechanism of Xuebijing injection improving the function of pulmonary vascular barrier from the perspective of claudin-5 protein. METHODS: Acute lung injury (ALI) model was induced by hydrogen sulfide (H2S) exposure. (1) In vivo study: Sprague-Dawley (SD) rats were divided into control group, H2S exposure group (exposure to 300×10-6 H2S for 3 hours), Xuebijing control group (Xuebijing injection 4 mL/kg , twice a day, for 3 days), and Xuebijing intervention group (H2S exposure after pretreatment of Xuebijing injection) according to random number method, with 6 rats in each group. At different time points (0, 6, 12 and 24 hours) after the model was made successfully, the total protein content in plasma and bronchoalveolar lavage fluid (BALF) of rats were detected respectively, and the pulmonary permeability index (PPI) was calculated (PPI = protein content in BALF/protein content in plasma), lung dry/wet weight ratio (W/D) was detected, and claudin-5 mRNA expression in lung tissue was measured by real time-polymerase chain reaction. (2) In vitro test: human pulmonary microvascular endothelial cells (HPMECs) were divided into blank control group, NaHS treatment group (co-incubated with 500 µmol/L NaHS for 12 hours), Xuebijing control group (2 g/L Xuebijing injection for 24 hours), and Xuebijing intervention group (2 g/L Xuebijing injection pre-treated for 24 hours, then co-incubated with 500 µmol/L NaHS for 12 hours). The HPMECs claudin-5 protein expression and monolayer permeability changes were measured at different co-incubation time (1, 3, 6, 12 and 24 hours) by Western Blot and fluoresceinsodium. RESULTS: (1) In vivo study: compared with the control group, the lung W/D ratio increased significantly at 6 hours and peaked at 12 hours after H2S exposure in rats (4.67±0.11 vs. 4.26±0.06, P < 0.01). The expression of claudin-5 mRNA in lung tissue was significantly decreased, which was 89% of control group 6 hours after exposure (P < 0.01). The total protein content in BALF and PPI at 12 hours after exposure were significantly higher than those in the control group [total protein content (mg/L): 262.31±14.24 vs. 33.30±3.09, PPI: (11.72±0.57)×10-3 vs. (1.21±0.08)×10-3, both P < 0.01], while the results in Xuebijing intervention group were significantly decreased [total protein content (mg/L): 153.25±7.32 vs. 262.31±14.24, PPI: (5.79±0.23)×10-3 vs. (11.72±0.57)×10-3, both P < 0.01]. (2) In vitro test: compared with the blank control group, after incubating HPMECs with NaHS, the permeability of monolayer endothelial cells gradually increased, reaching the highest level in 12 hours, about twice of that in the blank control group, while claudin-5 protein expression decreased to the lowest level at 12 hours (claudin-5/ß-actin: 0.42±0.03 vs. 1.03±0.05, P < 0.01). After intervention with Xuebijing, the permeability of endothelial cells was significantly improved (fluorescence intensity of fluorescein sodium: 1.46±0.10 vs. 1.89±0.11, P < 0.01), and the decrease of claudin-5 protein was reduced (claudin-5/ß-actin: 0.68±0.04 vs. 0.38±0.03, P < 0.01). CONCLUSIONS: Xuebijing injection may improve pulmonary vascular barrier function in ALI by upregulating claudin-5 expression.

Association between Chinese Medicine Therapy and Survival Outcomes in Postoperative Patients with NSCLC: A Multicenter, Prospective, Cohort Study.

OBJECTIVE: To evaluate the association between Chinese medicine (CM) therapy and disease-free survival (DFS) outcomes in postoperative patients with non-small cell lung cancer (NSCLC). METHODS: This multiple-center prospective cohort study was conducted in 13 medical centers in China. Patients with stage I, II, or IIIA NSCLC who had undergone radical resection and received conventional postoperative treatment according to the National Comprehensive Cancer Network (NCCN) guidelines were recruited. The recruited patients were divided into a CM treatment group and a control group according to their wishes. Patients in the CM treatment group received continuous CM therapy for more than 6 months or until disease progression. Patients in the control group received CM therapy for less than 1 month. Follow-up was conducted over 3 years. The primary outcome was DFS, with recurrence/metastasis rates as a secondary outcome. RESULTS: Between May 2013 and August 2016, 503 patients were enrolled into the cohort; 266 were classified in the CM treatment group and 237 in the control group. Adjusting for covariates, high exposure to CM was associated with better DFS [hazard ratio (HR) = 0.417, 95% confidential interval (CI): 0.307-0.567)]. A longer duration of CM therapy (6-12 months, 12-18 months, >24 months) was associated with lower recurrence and metastasis rates (HR = 0.225, 0.119 and 0.083, respectively). In a subgroup exploratory analysis, CM therapy was also a protective factor of cancer recurrence and metastasis in both stage I-IIIA (HR=0.50, 95% CI: 0.37-0.67) and stage IIIA NSCLC postoperative patients (HR = 0.48, 95% CI: 0.33-0.71), DFS was even longer among CM treatment group patients. CONCLUSIONS: Longer duration of CM therapy could be considered a protective factor of cancer recurrence and metastasis. CM treatment is associated with improving survival outcomes of postoperative NSCLC patients in China. (Registration No. ChiCTR-OOC-14005398).

2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione isolated from Averrhoa carambola L. root ameliorates diabetic nephropathy by inhibiting the TLR4/MyD88/NF-κB pathway.

BACKGROUND: Averrhoa carambola L. is a traditional medicinal herb that has long been used to treat diabetes. Our previous studies found that 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) isolated from A. carambola L. roots could ameliorate diabetic nephropathy (DN), but its exact mechanism remains unclear. METHODS: A DN model was established by streptozotocin (STZ, 100 mg/kg body weight) in TLR4 knockout (TLR4-/-, KO) mice and wild-type (WT) mice. Body weight and blood glucose were evaluated after oral administration of DMDD (12.5, 25, 50 mg/kg body weight/d) in diabetic mice. The levels of serum lipids, including TC, TG, HDL, and LDL and kidney function indexes Scr and BUN, were detected by biochemical equipment. The levels of inflammatory cytokines including IL-6 and TNF-α, were determined by ELISA kits. Furthermore, changes in renal ultrastructure were observed by electron microscopy. Western blot analysis and RT-PCR were used to assess the protein expression and mRNA levels of TLR4, MyD88 and NF-κB. RESULTS: DMDD treatment attenuated diabetic nephropathy, as a result of a decline in blood glucose, serum creatinine, and blood urine nitrogen levels and an increase in the quantity and density of podocytes, combined with improved dyslipidaemia. DMDD treatment inhibited the inflammatory response and downregulated the expression of the TLR4/MyD88/NF-κB pathway in diabetic mice, and these changes were significantly different in TLR4-/- mice. CONCLUSION: DMDD alleviates diabetic nephropathy by mitigating kidney damage and inflammation via the inhibition of the TLR4/MyD88/NF-κB signalling pathway.

[Mechanism of ß-carboline alkaloids inhibiting migration and invasion of SGC-7901 cells].

To explore the mechanism of ß-carboline alkaloids inhibiting the migration and invasion of SGC-7901 cells and its correlation with FAK gene expression,CCK-8 method was used to determine the inhibitory rate of ß-carboline alkaloids on the proliferation of gastric cancer SGC-7901 cells under different concentrations.The effect of ß-carboline alkaloids on the migration and invasion of SGC-7901 cells was used by Transwell compartment.Detection of mRNA and protein expression of FAK genes were used by qRT-PCR and Western blot.Then si-FAK-1051 recombinant plasmid was transfected into SGC-7901 cells.FAK gene silencing effect was identified by qRT-PCR and Western blot technique again.Finally,the effects of FAK gene silencing on proliferation and migration of gastric cancer SGC-7901 cells were detected by CCK-8 kit and Transwell chamber assay respectively.With the increase of the concentration ofß-carboline alkaloids,the inhibitory rate of SGC-7901 cells in human gastric cancer cells increased gradually,with IC5013.364 mg·L-1.The number of SGC-7901 cells of Transwell compartment in the positive experimental group(5-FU,5 mg·L-1) and the ß-carboline alkaloids group decreased significantly(P<0.01) and the number of SGC-7901 cells in the ß-carboline alkaloids group was significantly lower than that in the positive experimental group(P<0.01).Compared with the blank control group,the mRNA and protein expression level of FAK genes in the positive experimental group was significantly lower than that in the experimental group of ß-carboline alkaloids(P<0.05).After transfection of si-FAK-1051 into gastric cancer SGC-7901 cells,the expression of mRNA and protein of FAK gene was significantly down regulated(P<0.05).SGC-7901 cell proliferation and cell migration ability also decreased significantly(P<0.05).ß-carboline alkaloids are more effective than 5-FU in inhibiting migration and invasion of gastric cancer SGC-7901 cells,and the mechanism may be related to the inhibition of mRNA and protein expression of FAK gene by ß-carboline alkaloids.

Application of highly efficient and lowly toxic bufadienolides screened from toad skin in lymphatic chemotherapy for colorectal cancer through a lymphatic metastatic model.

BACKGROUND: Lymph node metastasis (LNM) remains a major obstacle to treat colorectal cancer (CRC). Increasing evidences have suggested that bufadienolides contain several fractions displaying antitumor activity and may be applied in lymphatic chemotherapy. However, effects of the highly efficient and lowly toxic (HELT) bufadienolides on CRC in lymphatic chemotherapy have not been reported. METHODS: Adenosine triphosphate tumor chemosensitivity assays (ATP-TCA) was performed to detect the inhibition rate (IR) of fractions of bufadienolides to cytokine-induced killer (CIK) cells and tumor cells. HELT fraction-loaded emulsions of different concentrations were prepared. Nude mouse bearing HCT116 tumors in footpad received high-dose emulsion (HD-E), middle-dose emulsion (MD-E), low-dose emulsion (LD-E), control emulsion (CE), Cinobufacini Injection (CI), or normal saline (NS), respectively. Hematoxylin and eosin (H&E) staining, Flow Cytometry (FCM), enzyme-linked immune sorbent assay (ELISA) and hematological examination were applied to evaluate therapeutic effects and potential toxicity. RESULTS: F18 and F19 were screened out as HELT fractions in vivo and F18-loaded emulsions of different concentrations for lymphatic administration were prepared. We confirmed that HD-E and MD-E produced obvious antitumor activities in footpad tumors and LNM compared with other groups in vitro. We also verified the effects of F18-loaded emulsions on activating hematopoietic function, stimulating proliferation of the spleen and natural killer (NK) cells, and promoting the secretion of IFN-γ and IgG1, although HD-E performed mild toxicity on liver. CONCLUSION: The present study demonstrated that lymphatic chemotherapy with HELT fraction of bufadienolides could be an effective approach to the treatment of CRC patients with LNM.

On-line measurement of fluorescent aerosols near an industrial zone in the Yangtze River Delta region using a wideband integrated bioaerosol spectrometer.

In this work, we present on-line fluorescent aerosol measurements by the wideband integrated bioaerosol spectrometer (WIBS-4A) near an industrial zone in Nanjing, a megacity in the Yangtze-River-Delta (YRD) region. The fieldwork was conducted from April 1 to May 8, 2014. A TSI. 3321 aerosol-particle-sizer (APS) was simultaneously deployed to measure the total number size distribution of aerosol with diameter from 0.8-20 µm. Both WIBS-4A and APS reported similar number concentration and temporal profiles (R2 = 0.72). However, the daily average number of potential bioaerosols was only 0.5 ±â€¯0.2% of the total particles detected by the WIBS-4A and displayed a completely different diurnal profile from that of APS. In addition, WIBS-4A can only provide integrated fluorescent signals, which strongly limited the potential to specifically identify the bioaerosols. Accordingly, hierarchical-agglomerative-cluster-analysis (HACA) was utilized to identify and speciate the potential bioaerosols from the WIBS-4A dataset. By maximizing the total distances among all potential cluster centers, a 12-cluster solution was accepted as the optimum result. These clusters were further identified according to their fluorescent signatures, size, and morphology, i.e., non-bioaerosols, bacteria, and fungal spores and/or pollen fragments. Bacteria were the dominant bioaerosol species detected in this work. The diurnal profiles of bioaerosols correlated very well with relatively humidity (RH), reaching daily maxima around 3 AM~6 AM, indicating the presence of humidity controlled bioaerosol emission mechanism, i.e., bacteria may flourish under moderate ambient temperature, RH, and the absence of UV radiation. The size- and AF-distributions of bioaerosols indicated that bioaerosols normally varied substantially in size and assumed a rather irregular shape. Although the number concentration of bioaerosols was relatively small, most bioaerosols can efficiently serve as ice nuclei by providing rough and irregular surfaces, verified by the observation results. Therefore, WIBS-4A measurements can still be informative for investigations of bioaerosols in the atmosphere, especially when HACA method was incorporated into the data processing.

Curcumin Reverses 5-Fluorouracil Resistance by Promoting Human Colon Cancer HCT-8/5-FU Cell Apoptosis and Down-regulating Heat Shock Protein 27 and P-Glycoprotein.

OBJECTIVE: To investigate the potential mechanisms that curcumin reverses 5-fluorouracil (5-FU) multidrug resistance (MDR). METHODS: Cell growth and the inhibitory rate of curcumin (2-25 µg/mL) and/or 5-FU (0.05-1000 µg/mL) on human colon cancer HCT-8 and HCT-8/5-FU (5-FU-resistant cell line) were determined using cell counting kit-8 (CCK-8) assay. Apoptosis and cell cycle after 5-FU and/or curcumin treatment were detected by flow cytometry (FCM) and transmission electron microscopy (TEM). The expression of the multidrug resistance related factors p-glycoprotein (P-gp) and heat shock protein 27 (HSP-27) genes and proteins were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting (WB), respectively. RESULTS: The inhibitory rate of curcumin or 5-FU on HCT-8 and HCT-8/5-FU cells proliferation at exponential phase were in a dosedependent manner, HCT-8 cell line was more sensitive to curcumin or 5-FU when compared the inhibitory rate of HCT-8/5-FU. The 50% inhibitory concentration (IC50) of combination 5-FU and curcumin (4.0 µg/mL) in HCT-8/5-FU was calculated as 179.26 µg/mL, with reversal fold of 1.85. Another IC50 of combination 5-FU and curcumin (5.5 µg/mL) in HCT-8/5-FU was calculated as 89.25 µg/mL, with reversal fold of 3.71. Synergistic effect of 5-FU and curcumin on HCT-8 and HCT-8/5-FU cells were found. The cell cycle analysis performed by FCM showed that HCT-8 and HCT-8/5-FU cells mostly accumulated at G0/G1 phase, which suggested a synergistic effect of curcumin and 5-FU to induce apoptosis. FCM analysis found that the percentage of apoptosis of cells treated with curcumin, 5-FU and their combination were significantly increased compared to the control group (P<0.05), and the percentage of apoptosis of the combination groups were slightly higher than other groups (P<0.05). The mRNA levels of P-gp (0.28±0.02) and HSP-27 (0.28±0.09) in HCT-8/5-FU cells treated with combination drugs were lower than cells treated with 5-FU alone (P-gp, 0.48±0.07, P=0.009; HSP-27, 0.57±0.10, P=0.007). The protein levels of P-gp (0.25±0.06) and HSP-27 (0.09±0.02) in HCT-8/5-FU cells treated with combination drugs were decreased when compared to 5-FU alone (P-gp, 0.46±0.02, P=0.005; HSP-27, 0.43±0.01, P=0.000). CONCLUSIONS: Curcumin can inhibit the proliferation of human colon cancer cells. Curcumin has the ability of reversal effects on the multidrug resistance of human colon cancer cells lines HCT-8/5-FU. Down-regulation of P-gp and HSP-27 may be the mechanism of curcumin reversing the drug resistance of HCT-8/5-FU to 5-FU.

Efficacy of Probiotics Supplementation On Chronic Kidney Disease: a Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Dysbiosis of the intestinal microbiota may accelerate the progression of chronic kidney disease (CKD) by increasing the levels of urea toxins. In recent years, probiotics have been recognized to maintain the physiological balance of the intestinal microbiota. In this study, we aim to assess the therapeutic effects of probiotics on CKD patients with and without dialysis via meta-analysis. METHODS: We conducted a meta-analysis of randomized controlled trials (RCTs) by searching the databases of Pubmed, EMBASE and Cochrane Library (No. CRD42018093080). Studies on probiotics for treatment of CKD adults lasting for at least 4 weeks were selected. The primary outcomes were the levels of urea toxins, and the second outcomes were the levels of interleukin (IL)-6, C-reactive protein (CRP) and hemoglobin (Hb). The risk of bias was assessed by Cochrane Collaboration' tool, and the quality of evidence was appraised with the Grading of Recommendation Assessment. Means and standard deviations were analyzed by random effects analysis. Stratified analysis was done and sensitivity analysis was performed when appropriate. RESULTS: Totally, eight studies with 261 patients at CKD stage 3 to 5 with and without dialysis were included. We found a decrease of p-cresyl sulfate (PCS) of 3 studies with 125 subjects (P = 0.01, SMD -0.57, 95% CI, -0.99 to -0.14, I2 = 25%) and an increase of IL-6 in 3 studies with 134 subjects (P = 0.03, 95% CI, SMD 0.37, 0.03 to 0.72, I2 = 0%) in the probiotics groups. Analysis of serum creatinine (P = 0.47), blood urine nitrogen (P = 0.73), CRP (P = 0.55) and Hb (P = 0.49) yielded insignificant difference. CONCLUSION: Limited number of studies and small sample size are limitations of our study. Probiotics supplementation may reduce the levels of PCS and elevate the levels of IL-6 whereby protecting the intestinal epithelial barrier of patients with CKD.