Canagliflozin regulates metabolic reprogramming in diabetic kidney disease by inducing fasting-like and aestivation-like metabolic patterns.

AIMS/HYPOTHESIS: Sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) are antihyperglycaemic drugs that protect the kidneys of individuals with type 2 diabetes mellitus. However, the underlying mechanisms mediating the renal benefits of SGLT2i are not fully understood. Considering the fuel switches that occur during therapeutic SGLT2 inhibition, we hypothesised that SGLT2i induce fasting-like and aestivation-like metabolic patterns, both of which contribute to the regulation of metabolic reprogramming in diabetic kidney disease (DKD). METHODS: Untargeted and targeted metabolomics assays were performed on plasma samples from participants with type 2 diabetes and kidney disease (n=35, 11 women) receiving canagliflozin (CANA) 100 mg/day at baseline and 12 week follow-up. Next, a systematic snapshot of the effect of CANA on key metabolites and pathways in the kidney was obtained using db/db mice. Moreover, the effects of glycine supplementation in db/db mice and human proximal tubular epithelial cells (human kidney-2 [HK-2]) cells were studied. RESULTS: Treatment of DKD patients with CANA for 12 weeks significantly reduced HbA1c from a median (interquartile range 25-75%) of 49.0 (44.0-57.0) mmol/mol (7.9%, [7.10-9.20%]) to 42.2 (39.7-47.7) mmol/mol (6.8%, [6.40-7.70%]), and reduced urinary albumin/creatinine ratio from 67.8 (45.9-159.0) mg/mmol to 47.0 (26.0-93.6) mg/mmol. The untargeted metabolomics assay showed downregulated glycolysis and upregulated fatty acid oxidation. The targeted metabolomics assay revealed significant upregulation of glycine. The kidneys of db/db mice undergo significant metabolic reprogramming, with changes in sugar, lipid and amino acid metabolism; CANA regulated the metabolic reprogramming in the kidneys of db/db mice. In particular, the pathways for glycine, serine and threonine metabolism, as well as the metabolite of glycine, were significantly upregulated in CANA-treated kidneys. Glycine supplementation ameliorated renal lesions in db/db mice by inhibiting food intake, improving insulin sensitivity and reducing blood glucose levels. Glycine supplementation improved apoptosis of human proximal tubule cells via the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. CONCLUSIONS/INTERPRETATION: In conclusion, our study shows that CANA ameliorates DKD by inducing fasting-like and aestivation-like metabolic patterns. Furthermore, DKD was ameliorated by glycine supplementation, and the beneficial effects of glycine were probably due to the activation of the AMPK/mTOR pathway.

Celastrus orbiculatus extract suppresses gastric cancer stem cells through the TGF-ß/Smad signaling pathway.

Cancer stem cells (CSCs) are the primary source of tumor recurrence and chemoresistance, which complicates tumor treatment and has a significant impact on poor patient prognosis. Therefore, the discovery of inhibitors that specifically target CSCs is warranted. Previous research has established that the TGF-ß/Smad signaling pathway is critical for the maintenance of CSCs phenotype, thus facilitating CSCs transformation. In this regard, Celastrus orbiculatus ethyl acetate extract (COE) was shown to exert anticancer properties; however, its therapeutic impact on gastric cancer stem cells (GCSCs) remains unknown. We here demonstrate that COE displayed a strong inhibitory effect on GCSCs growth and CSCs markers. Moreover, COE was shown to efficiently inhibit the development of tumor spheres and accelerate GCSCs apoptosis. Mechanistically, we established that COE could suppress the stemness phenotype of GCSCs by inhibiting the activity of the TGF-ß/Smad signaling pathway. To summarize, our data indicate that COE suppresses the malignant biological phenotype of GCSCs via the TGF-ß/Smad signaling pathway. These findings shed new light on the anticancer properties of COE and suggest new strategies for the development of efficient GCSCs therapeutics.

The anti-tumor effects of Celastrus orbiculatus Thunb. and its monomer composition: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Celastrus orbiculatus Thunb. has been included in "The Plant List" (http://www. theplantlist.org) and is the most widely researched species in its genus. It is called Nanshe Teng in China. Celastrus orbiculatus Thunb. is a plant of Euonymus and it's medicinal part is the vine and stem. It is also called Alias Dragon grass, Yellow Yine, etc. It has good anti-tumor, anti-inflammatory and other effects. More and more studies have shown that Celastrus orbiculatus Thunb. has a significant therapeutic effect on a variety of malignant tumors. The research on Celastrus orbiculatus Thunb. has a good application prospect for the development of anti-tumor drugs. However, no systematic reports on Celastrus orbiculatus Thunb. have been published before. AIM OF THE REVIEW: This paper summarizes the metabolic products for anti-tumor and the mechanism for anti-tumor of Celastrus orbiculatus Thunb. to provide reference for further development and research. MATERIALS AND METHODS: The relevant information on Celastrus orbiculatus Thunb. was collected from the scientific databases including PubMed, CNKI, ScienceDirect, Wiley, Springer, Web of Science, Google Scholar, Baidu Scholar, Pharmacopoeia of the People's Republic of China and Flora Republicae Popularis Sinicae, etc. RESULTS: At present, more than 200 compounds have been identified from Celastrus orbiculatus Thunb., including terpenoids, flavonoids, phenylpropanoids, polyketides and benzene derivatives, etc. Pharmacological studies have shown that Celastrus orbiculatus Thunb. has a variety effects of inhibiting tumor cell proliferation, inducing tumor cell apoptosis, inhibiting tumor cells invasion, metastasis and angiogenesis, reversing multi-drug resistance, and also collaborativing Micro RNA to inhibit tumor growth, etc. It has a significant effect on gastric cancer, liver cancer, lung cancer, etc. The extracts of Celastrus orbiculatus Thunb. have been widely used in experiments, and the toxic and side effects are small. CONCLUSIONS: Celastrus orbiculatus Thunb. is rich in chemical constituents, diverse in pharmacological activities and abundant in resources, which is widely used in clinics from traditional to modern. However, there is no systematic report on the chemical compounds and anti-tumor effects of Celastrus orbiculatus Thunb. We organize and summarize it to provide reference for further development and research.

Novel magnetic graphoxide/biochar composite derived from tea for multiple SAs and QNs antibiotics removal in water.

Antibiotics pollution is an urgent public health issue. Biochar is a kind of promising composite for removal antibiotic in aqueous environment. In this study, a novel magnetic graphoxide/biochar composite (mGO/TBC) was synthesized by simple impregnation method and used as an efficient and recyclable persulfate (PS) activator for degradation and removal of sulfonamides (SAs) and quinolones (QNs) antibiotics. Based on the synergism pre-adsorption and degradation between graphoxide and biochar, the removal rates of mGO/TBC on sarafloxacin hydrochloride, sulfadimethoxine, sulfapyridine, sulfadoxine, sulfamonomethoxine, sulfachloropyridazine, enrofloxacin, and ciprofloxacin were increased above 95%. Moreover, the mGO/TBC could be reused at least seven times after degradation-recovery cycles. Quenching experiment and ESR analysis proved that 1O2, •OH, and SO4•- from mGO/TBC/PS system were the primary oxidation active species to degrade SAs and QNs. It is a promising substrate for antibiotic bioremediation with good application prospects.

Celastrus orbiculatus Thunb. extract inhibits EMT and metastasis of gastric cancer by regulating actin cytoskeleton remodeling.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine herb Celastrus orbiculatus Thunb. is an important folk medicinal plant in China that has been used as an anti-inflammatory, antitumor, and analgesic in various diseases. Recent years, many studies have reported the significant effects of Celastrus orbiculatus Thunb. extract (COE) on gastric cancer. However, the specific mechanism by which COE regulates gastric cancer cytoskeleton remodeling and thus inhibits EMT has not yet been reported. AIM OF STUDY: To study the effect and mechanism of COE in inhibiting the epithelial-mesenchymal transition (EMT) and metastasis of gastric cancer cells, laying an experimental foundation for the clinical application and further development of COE. METHODS: The high-content cell dynamic tracking system was used to continuously track the trajectory of cell movement in real time. Through the high-content data, the average movement distance and movement speed of the cells are calculated. Additionally, the dynamic images of the cell movement in the high-content imaging system are derived to analyze the impact of COE on the movement of gastric cancer cells. Cytoskeleton staining experiment was performed to detect the effect of COE on the assembly of gastric cancer cell cytoskeleton proteins. Western blot was employed to detect the changes of EMT and metastasis-related proteins in the gastric cancer cells treated by COE. The effect of COE on the key regulatory protein Cofilin-1 (CFL1) of cell movement was examined by Western blot and protein degradation experiment. The effect of COE on EMT and metastasis of the gastric cancer cells lacking CFL1 was assessed by a transwell assay. The in vivo inhibitory effect of COE on EMT and metastasis of gastric cancer was determined by the animal living image system. IHC assays were used to detect the levels of EMT-related proteins in COE reversal in vivo. RESULT: The results showed that the movement distance and average movement speed of gastric cancer cells after COE treatment were significantly lower than those of the control group. Cytoskeleton staining experiments revealed that COE can significantly change the distribution of skeletal proteins in gastric cancer cells. Additionally, COE treatment significantly reduced the expression of Matrix metalloproteinases (MMP-2, MMP-9) and other proteins. Furthermore, COE can significantly accelerate the degradation of CFL1 protein, and both COE treatment and CFL1 deletion can significantly inhibit EMT and metastasis of gastric cancer cells. Lastly, the number of peritoneal metastases of gastric cancer cells was significantly reduced in animals after COE treatment. COE can reverse the levels of EMT-related proteins while reducing the expression levels of CFL1 protein in vivo. CONCLUSION: COE can significantly inhibit EMT and metastasis of gastric cancer cells in vivo and in vitro. This effect may be achieved by reducing the stability of CFL1 and inhibiting the assembly of actin in gastric cancer cells.

Triptonoterpene, a Natural Product from Celastrus orbiculatus Thunb, Has Biological Activity against the Metastasis of Gastric Cancer Cells.

Cancer is one of the greatest threats to human health. Gastric cancer (GC) is the fifth most common malignant tumor in the world. Invasion and metastasis are the major difficulties in the treatment of GC. Herbal medicines and their extracts have a lengthy history of being used to treat tumors in China. The anti-tumoral effects of the natural products derived from herbs have received a great deal of attention. Our previous studies have shown that the traditional Chinese herb Celastrus orbiculatus Thunb extract (COE) can inhibit the invasion and metastasis of GC cells, but the specific anti-cancer components of COE are still unclear. Dozens of natural products from COE have been isolated and identified by HPLC spectroscopy in our previous experiments. Triptonoterpene is one of the active ingredients in COE. In this study, we focused on revealing whether Triptonoterpene has an excellent anti-GC effect and can be used as an effective component of Celastrus orbiculatus Thunb in the treatment of tumors. We first observed that Triptonoterpene reduces GC cell proliferation through CCK-8 assays and colony formation experiments. The cell adhesion assays have shown that Triptonoterpene inhibits adhesion between cells and the cell matrix during tumor invasion. In addition, the cell migration assay has shown that Triptonoterpene inhibits the invasion and migration of GC cells. The high-connotation cell dynamic tracking experiment has also shown the same results. The effects of Triptonoterpene on epidermal mesenchymal transition (EMT)-related and matrix metalloproteinases (MMPs)-related proteins in gastric cancer cells were detected by Western blots. We found that Triptonoterpene could significantly inhibit the changes in EMT-related and invasion and metastasis-related proteins. Altogether, these results suggest that Triptonoterpene is capable of inhibiting the migration and invasion of GC cells. Triptonoterpene, as a natural product from Celastrus orbiculatus Thunb, has significant anti-gastric cancer effects, and is likely to be one of the major equivalent components of Celastrus orbiculatus Thunb.

Incidence and risk factors for suicidal ideation in a sample of Chinese patients with mixed cancer types.

PURPOSE: Suicidal ideation (SI) is often overlooked as a risk factor for people with cancer. Because it is often a precursor for suicidal behavior, it is critical to identify and address SI in a timely manner. This study investigated SI incidence and risk factors in a cohort of Chinese patients with mixed cancer types. METHODS: Data from this cross-sectional study were collected from 588 patients receiving medical therapy for tumors at Nanfang Hospital and the Integrated Hospital of Traditional Chinese Medicine at Southern Medical University. SI was measured using the Self-rating Idea of Suicide Scale (SIOSS). Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). The Chinese version of the Demoralization Scale II (DS-II-C) was used to assess demoralization. Univariate and correlation analyses were used to identify correlative factors of SI and multiple stepwise linear regression analysis was used to characterize potential risk factors. RESULTS: SI was reported in 24.7% of participants and the SIOSS score was 14.00 (13.00, 15.00) in the SI group. Multiple linear regression results showed that demoralization, medical financial burden, cancer type, living condition, caretaker, working state, residence, gender, and marital status explained 32.1% of the SI in this cohort (F = 28.705, P < 0.001). CONCLUSION: Approximately one-quarter of cancer patients in this study reported SI influenced by both external and internal factors. Characterizing these factors can be informative for prevention and treatment efforts.

Poria Acid, Triterpenoids Extracted from Poria cocos, Inhibits the Invasion and Metastasis of Gastric Cancer Cells.

BACKGROUND: Poria cocos (P. cocos) is an important medicinal fungus in traditional Chinese medicine. Poria acid (PA), a triterpenoid compound, is an effective component of traditional Chinese medicine P. cocos. This experiment investigated the anti-gastric cancer biological activity of PA in vitro. METHODS: The effect of PA on the viability of gastric cancer cells was detected by the thiazolyl blue (MTT) assay. Cell adhesion assays were used to detect changes in the adhesion of cells treated after PA (0, 20, 40, and 80 µmol/L). The ability of cell invasion and migration were detected by Transwell assays and wound healing assays. A high-content imaging system was used to dynamically record the motility of the gastric cancer cells after PA (0, 20, 40, and 80 µmol/L) treatment. Western blotting was used to detect the expression of epithelial-mesenchymal transformation (EMT), invasion and migration related proteins. RESULTS: The MTT assay showed that the proliferation of gastric cancer cells was significantly inhibited after PA treatment. Cell adhesion experiments showed that the adhesion of gastric cancer cells was significantly decreased after PA treatment. Compared with the control group, the wound healing area of the gastric cancer cells treated with different concentrations of PA decreased. The Transwell assay showed that the number of gastric cancer cells passing through the cell membrane were significantly reduced after PA treatment. In addition, after PA treatment, the cells' movement distance and average movement speed were significantly lower than those of the control group. Finally, PA can significantly alter the expression of EMT-related proteins E-cadherin, N-cadherin, and Vimentin and decreased the expressions of metastasis-related proteins matrix metalloproteinase (MMP) 2, MMP-9 and tissue inhibition of matrix metalloproteinase (TIMP)1 in the gastric cancer cells. CONCLUSIONS: Triterpenoids from P. cocos have significant biological activity against gastric cancer, and the mechanism may be involved in the process of epithelial-mesenchymal transformation.

Thioridazine Enhances Cisplatin-Induced DNA Damage in Cisplatin-Resistant Human Lung Cancer Cells.

Thioridazine was used to sensitize cisplatin against cisplatin-resistant human lung cancer cells. Cells received thioridazine, cisplatin, or both drugs (the combination). Thioridazine synergized cisplatin to increase percentages of dead and apoptotic cells. DNA damage was detected using the comet assays; the combination led to the highest alkaline- and neutral-comet percentages, demonstrating exacerbation of both single- and double-strand breaks. After thioridazine treatment, levels of glutathione, and BRCA2, RAD51, and ERCC1 proteins were decreased. These data manifested that thioridazine decreased the capacities of detoxification and DNA repair, thereby enhancing cisplatin-induced DNA damage in resistant cells.

Childhood ischaemic stroke in the basal ganglia can lead to fine motor and anxiety disorders: a retrospective analysis and follow-up of 109 cases.

BACKGROUND: Stroke in children easily causes long-term dysfunction. Whether the prognoses of motor and anxiety disorders are related to the affected stroke area has not been reported. METHODS: One hundred nine cases of children with ischaemic stroke were reviewed and divided into three groups: lenticular nucleus lesions only (lenticular nucleus group), lenticular nucleus and caudate head lesions (caudate head group), and lenticular nucleus and thalamus lesions (thalamus group). Overall prognosis was evaluated by the mRS score. The SCAS-P was used to evaluate anxiety in children aged ≥6 years. RESULTS: mRS scores were ≤ 2 points (mean: 0.62), no significant difference among groups. 3/21 (14.2%) patients in the caudate head group changed handedness, which is significantly higher than other groups. Patients with lesions in thalamus group had significantly higher SCAS-P scores. CONCLUSIONS: The overall prognosis of children with basal ganglia ischaemic stroke is good. However, hand preference changes and anxiety disorders may develop. Patients in the caudate head groups are more likely to suffer from fine motor disorders and changes in handedness. Patients within the thalamus group are more prone to anxiety than patients in the other groups. Anxiety disorders should be noted in children with basal ganglia stroke.

[Detection of Autoimmune Hemolytic Anemia Induced by Salvianolate and Evaluation of Blood Transfusion Efficacy].

OBJECTIVE: To evaluate the characteristics of autoimmune hemolytic anemia caused by salvianolate by antibody detection and clinical index monitoring. METHODS: Micro-column gel anti-human globulin method was used for irregular antibody screening and antibody identification. Salvianolate, sodium creatine phosphate and levocarnitine were used to sensitize red blood cells that were compatible with the patient's plasma, and the RBCs were used to test drug antibody in patient plasma respectively. The patient's clinical examination of hemolysis index and blood transfusion effect were analyed retrospectively. RESULTS: The patients were positive for irregular antibody screening, and there were antoanti-Ce antibodies in serum. The erythrocytes sensitized with salvianolate in the patient's serum were positive, while those sensitized with sodium creatine phosphate and levocarnitine were negative. CONCLUSION: Salvianolate causes drug-induced autoimmune hemolytic anemia in this patient.

[Clinical effect of electroacupuncture at Baihui and Shuigou points in treatment of brain injury in patients with sepsis-associated encephalopathy].

OBJECTIVE: To investigate the clinical effect of electroacupuncture at Baihui (GV20) and Shuigou (GV26) points in the treatment of brain injury in patients with sepsis-associated encephalopathy(SAE). METHODS: A total of 70 patients with SAE were randomly divided into control group and treatment group, with 35 patients in each group. The patients in the control group were given routine western medicine treatment, including anti-infective therapy, nerve nutrition, and mechanical ventilation, and those in the treatment group were given electroacupuncture at GV20 and GV26 in addition to the treatment in the control group. The course of treatment was 1 week for both groups. Serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and neuron-specific enolase (NSE) were measured for both groups, the Montreal Cognitive Assessment (MoCA) scale was used to assess the change in cognitive function, and Glasgow Coma Scale (GCS) score was determined before and after treatment and was used to evaluate treatment outcome after treatment. RESULTS: Both groups had significant reductions in the serum levels of CRP, IL-6, and NSE after 24 h and one week of treatment (P<0.05), and compared with the control group, the treatment group had significant reductions in the levels of CRP, IL-6 and NSE after treatment (P<0.05). The treatment group had significant increases in the total score of MoCA and the scores of all dimensions except attention after one week of treatment (P<0.05), and the treatment group had significantly higher scores than the control group after treatment (P<0.05). Both groups had a significant increase in GCS score after one week of treatment (P<0.05), and the treatment group had a significantly higher GCS score than the control group after treatment (P<0.05). The treatment group had a significantly higher total effective rate than the control group ï¼»88.6% (31/35) vs 57.1% (20/35), P<0.05ï¼½. CONCLUSION: Electroacupuncture at GV20 and GV26 can effectively improve brain injury and effective rate in SAE patients.

Inhibitory effect of oridonin on proliferation of RPMI8226 cells and the possible underlying mechanism.

OBJECTIVE: To observe the effects of oridonin on proliferation and apoptosis of myeloma RPMI8226 cells and to investigate the potential underlying mechanisms. METHODS: RPMI8226 cells were treated with various concentrations of oridonin. Cell proliferation was analyzed using the thiazolyl blue tetrazolium bromide method. Ultramicrostructure was observed by transmission electron microscopy. Annexin-V/PI staining and flow cytometry was performed to determine cell apoptosis. Expression of apoptosis-related proteins was evaluated by western blot analysis. RESULTS: Oridonin suppressed the proliferation of RPMI8226 cells and induced apoptosis in a time-and dose-dependent manner. Transmission electron microscopy confirmed apoptotic morphology upon treatment with 20 µmol/L oridonin and western blot revealed decreased expressions of the apoptosis suppressors survivin, Bcl-2 and pro-caspase-3 proteins, and the increased expression of the apoptosis inducer Bax. CONCLUSION: Our results show that oridonin exhibits an inhibitory effect on the proliferation of RPMI8226 cells and induces apoptosis. This is associated with altering the balance between Bcl-2 and Bax protein expressions and decreased survivin and pro-caspase-3 expressions.

Luteolin inhibited hydrogen peroxide-induced vascular smooth muscle cells proliferation and migration by suppressing the Src and Akt signalling pathways.

OBJECTIVES: Luteolin is a naturally occurring flavonoid found in many vegetables, fruits and medicinal plants. The migration and proliferation of vascular smooth muscle cells (VSMCs) are the critical pathological processes in various cardiovascular diseases, such as atherosclerosis. In this study, we investigated the effect of luteolin and its latent mechanism on the proliferation and migration of VSMCs stimulated by hydrogen peroxide (H(2) O(2) ). METHODS: VSMC proliferation and cell viability was assayed using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) method or by cell counting, and H(2) O(2) -elicited migration of VSMCs was measured using a transwell migration assay. The phosphorylation levels of Src, 3-phosphoinositide-dependent kinase 1 (PDK1) and Akt (protein kinase B) were analysed by immunoblotting. KEY FINDINGS: This study demonstrated that luteolin showed a particularly inhibitory effect on H(2) O(2) -elicited VSMC proliferation and migration. In previous research, we originally explored the function of luteolin in blocking H(2) O(2) -triggered Src and Akt signalling pathways. The activation of Src, PDK1, Akt (308), Akt (473) in the luteolin-treated group was significantly lower than that seen in the H(2) O(2) group. CONCLUSIONS: These findings strongly suggested that luteolin suppresses H(2) O(2) -directed migration and proliferation in VSMCs partially due to down-regulation of the Akt and Src signalling pathways, which are important participants in the processes of migration and proliferation of VSMCs.