Postoperative adjuvant tyrosine kinase inhibitors combined with anti-PD-1 antibodies improves surgical outcomes for hepatocellular carcinoma with high-risk recurrent factors.

Background: The clinical value of postoperative adjuvant therapy (PAT) for hepatocellular carcinoma (HCC) remains unclear. This study aimed to explore the effect of PAT with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies on the surgical outcomes of HCC patients with high-risk recurrent factors (HRRFs). Methods: HCC patients who underwent radical hepatectomy at Tongji Hospital between January 2019 and December 2021 were retrospectively enrolled, and those with HRRFs were divided into PAT group and non-PAT group. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups after propensity score matching (PSM). Prognostic factors associated with RFS and OS were determined by Cox regression analysis, and subgroup analysis was also conducted. Results: A total of 250 HCC patients were enrolled, and 47 pairs of patients with HRRFs in the PAT and non-PAT groups were matched through PSM. After PSM, the 1- and 2-year RFS rates in the two groups were 82.1% vs. 40.0% (P < 0.001) and 54.2% vs. 25.1% (P = 0.012), respectively. The corresponding 1- and 2-year OS rates were 95.4% vs. 69.8% (P = 0.001) and 84.3% vs. 55.5% (P = 0.014), respectively. Multivariable analyses indicated that PAT was an independent factor related to improving RFS and OS. Subgroup analysis demonstrated that HCC patients with tumor diameter > 5 cm, satellite nodules, or vascular invasion could significantly benefit from PAT in RFS and OS. Common grade 1-3 toxicities, such as pruritus (44.7%), hypertension (42.6%), dermatitis (34.0%), and proteinuria (31.9%) were observed, and no grade 4/5 toxicities or serious adverse events occurred in patients receiving PAT. Conclusions: PAT with TKIs and anti-PD-1 antibodies could improve surgical outcomes for HCC patients with HRRFs.

Erratum: Moxibustion improves ovarian function based on the regulation of the androgen balance.

[This corrects the article DOI: 10.3892/etm.2021.10664.].

Moxibustion improves ovarian function based on the regulation of the androgen balance.

The effect of androgens on follicular development and female reproduction has become an active research topic. Moxibustion is a Traditional Chinese Medicine therapy that has been reported to be able to prevent and treat numerous ovary-related problems. However, studies on the effect of moxibustion for diminished ovarian reserve (DOR) on androgen balance are still lacking. The present study aimed to assess the efficacy of moxibustion intervention prior to disease onset and at the early stage of disease in a rat model of DOR and explore the mechanisms of its effect on ovarian function. A total of 32 rats were randomly divided into four groups: Blank group, Model group (a drug-induced model of DOR), Moxibustion group 1 and Moxibustion group 2. Moxibustion was performed on the BL23 and RN4 acupoints of female rats daily for a total of 20 days (once a day, five times a week for a total of 4 weeks). The two moxibustion groups were established with different intervention times: One group was subjected to pre-disease intervention and the other group to early-disease intervention. The ovarian function was evaluated by detecting anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), estradiol (E2), testosterone (T), dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT) and androgen receptor (AR) levels in the serum or the ovary samples. To further investigate the downstream regulatory factors for AR after moxibustion treatment for pre-disease or early-disease intervention, FSH receptor (FSHR) and microRNA (miR)-125b expression in ovaries were also analyzed. The results indicated that AMH and DHT levels were reduced in the model group compared with those in the blank group, while FSH, T and DHEA levels were increased. AMH and DHT levels were increased in Moxibustion group 1 compared with those in the model group, while FSH, T and DHEA levels were reduced. There was no difference in E2 levels between Moxibustion group 1 and the model group. Compared with that in the model group, the AR content in the ovary was increased in Moxibustion group 1. There was no difference in FSHR mRNA in the ovaries between Moxibustion group 1 and the model group. miR-125b levels were significantly increased in Moxibustion group 1 as compared with those in the model group. Furthermore, AMH and DHT levels were increased in Moxibustion group 2 compared with those in the model group, while FSH, T and DHEA levels were reduced. E2 levels were significantly decreased in Moxibustion group 2 compared with those in the model group. The relative mRNA expression of AR, FSHR and miR-125b was decreased following establishment of the model. Compared with that in the model group, the AR content in the ovary was increased in Moxibustion group 2. In comparison with the blank and model groups, the FSHR content in the ovary of Moxibustion group 2 was significantly increased. miR-125b levels were not obviously altered in Moxibustion group 2 as compared with those in the model group. In addition, there was no significant difference in AMH, FSH, T and DHEA levels between the two moxibustion groups. E2 and DHT levels were higher in Moxibustion group 1 than in Moxibustion group 2. There was no difference in AR mRNA expression between the two moxibustion groups. FSHR mRNA levels were lower in Moxibustion group 1 than in Moxibustion group 2, while miR-125b mRNA levels were higher in Moxibustion group 1 than in Moxibustion group 2. In conclusion, the present study suggested that moxibustion intervention prior to disease onset and at the early disease stage was able to improve ovarian function via modulation of the AR-mediated stable equilibrium of androgens. However, the effects and mechanisms of moxibustion intervention for pre-disease and early-disease intervention of DOR appear to be different. The appropriate duration of treatment and the time-effect relationship require to be further studied.

Induction chemotherapy with lobaplatin and fluorouracil versus cisplatin and fluorouracil followed by chemoradiotherapy in patients with stage III-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma. METHODS: In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed. FINDINGS: From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported. INTERPRETATION: Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma. FUNDING: National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A Combined Phytochemistry and Network Pharmacology Approach to Reveal the Effective Substances and Mechanisms of Wei-Fu-Chun Tablet in the Treatment of Precancerous Lesions of Gastric Cancer.

Wei-Fu-Chun (WFC) tablet is a commercial medicinal product approved by China Food and Drug Administration, which is made of Panax ginseng C.A.Mey., Citrus aurantium L., and Isodon amethystoides (Benth.). WFC has been popularly used for the treatment of precancerous lesions of gastric cancer (PLGC) in clinical practice. In this study, a UHPLC-ESI-Q-TOF/MS method in both positive and negative ion mode was employed to rapidly survey the major constituents of WFC. 178 compounds including diterpenoids, triterpenes, sesquiterpenes, flavonoids, saponins, phenylpropanoids, lignans, coumarins, organic acids, fatty acids, quinones, and sterols, were identified by comparing their retention times, accurate mass within 5 ppm error, and MS fragmentation ions. In addition, 77 absorbed parent molecules and nine metabolites in rat serum were rapidly characterized by UHPLC-ESI-Q-TOF/MS. The network pharmacology method was used to predict the active components, corresponding therapeutic targets, and related pathways of WFC in the treatment of PLGC. Based on the main compounds in WFC and their metabolites in rat plasma and existing databases, 13 active components, 48 therapeutic targets, and 61 pathways were found to treat PLGC. The results of PLGC experiment in rats showed that WFC could improve the weight of PLGC rats and the histopathological changes of gastric mucosa partly by inhibiting Mitogen-activated protein kinase (MAPK) signaling pathway to increase pepsin secretion. This study offers an applicable approach to identify chemical components, absorbed compounds, and metabolic compounds in WFC, and provides a method to explore bioactive ingredients and action mechanisms of WFC.

Deep learning for risk prediction in patients with nasopharyngeal carcinoma using multi-parametric MRIs.

BACKGROUND: Magnetic resonance images (MRI) is the main diagnostic tool for risk stratification and treatment decision in nasopharyngeal carcinoma (NPC). However, the holistic feature information of multi-parametric MRIs has not been fully exploited by clinicians to accurately evaluate patients. OBJECTIVE: To help clinicians fully utilize the missed information to regroup patients, we built an end-to-end deep learning model to extract feature information from multi-parametric MRIs for predicting and stratifying the risk scores of NPC patients. METHODS: In this paper, we proposed an end-to-end multi-modality deep survival network (MDSN) to precisely predict the risk of disease progression of NPC patients. Extending from 3D dense net, this proposed MDSN extracted deep representation from multi-parametric MRIs (T1w, T2w, and T1c). Moreover, deep features and clinical stages were integrated through MDSN to more accurately predict the overall risk score (ORS) of individual NPC patient. RESULT: A total of 1,417 individuals treated between January 2012 and December 2014 were included for training and validating the end-to-end MDSN. Results were then tested in a retrospective cohort of 429 patients included in the same institution. The C-index of the proposed method with or without clinical stages was 0.672 and 0.651 on the test set, respectively, which was higher than the that of the stage grouping (0.610). CONCLUSIONS: The C-index of the model which integrated clinical stages with deep features is 0.062 higher than that of stage grouping alone (0.672 vs 0.610). We conclude that features extracted from multi-parametric MRIs based on MDSN can well assist the clinical stages in regrouping patients.

The Active Compounds of Yixin Ningshen Tablet and Their Potential Action Mechanism in Treating Coronary Heart Disease- A Network Pharmacology and Proteomics Approach.

Yixin Ningshen tablet is a CFDA-approved TCM formula for treating coronary heart disease (CHD) clinically. However, its active compounds and mechanism of action in treating CHD are unknown. In this study, a novel strategy with the combination of network pharmacology and proteomics was proposed to identify the active components of Yixin Ningshen tablet and the mechanism by which they treat CHD. With the application of network pharmacology, 62 active compounds in Yixin Ningshen tablet were screened out by text mining, and their 313 potential target proteins were identified by a tool in SwissTargetPrediction. These data were integrated with known CHD-related proteomics results to predict the most possible targets, which reduced the 313 potential target proteins to 218. The STRING database was retrieved to find the enriched pathways and related diseases of these target proteins, which indicated that the Calcium, MAPK, PI3K-Akt, cAMP, Rap1, AGE-RAGE, Relaxin, HIF-1, Prolactin, Sphingolipid, Estrogen, IL-17, Jak-STAT signaling pathway, necroptosis, arachidonic acid metabolism, insulin resistance, endocrine resistance, and steroid hormone biosynthesis might be the main pathways regulated by Yixin Ningshen tablet for the treatment of CHD. Through further enrichment analysis and literature study, EGFR, ERBB2, VGFR2, FGF1, ESR1, LOX15, PGH2, HMDH, ADRB1, and ADRB2 were selected and then validated to be the target proteins of Yixin Ningshen tablet by molecular docking, which indicated that Yixin Ningshen tablet might treat CHD mainly through promoting heart regeneration, new vessels' formation, and the blood supply of the myocardial region and reducing cardiac output, oxygen demand, and inflammation as well as arteriosclerosis (promoting vasodilation and intraplaque neoangiogenesis, lowering blood lipid). This study is expected to benefit the clinical application of Yixin Ningshen tablet for the treatment of CHD.

Rapid action of mechanism investigation of Yixin Ningshen tablet in treating depression by combinatorial use of systems biology and bioinformatics tools.

ETHNOPHARMACOLOGICAL RELEVANCE: Yixin Ningshen tablet is a CFDA-approved TCM formula for treating depression clinically. However, little is known about its active compounds and related potential target proteins, so far, no researches have been performed to investigate its mechanism of action for the treatment of depression. AIM OF THE STUDY: Here we develop an original bioinformatics pipeline composed of text mining tools, database querying and systems biology combinatorial analysis, which is applied to rapidly explore the mechanism of action of Yixin Ningshen tablet in treating depression. MATERIALS AND METHODS: Text mining and database query were applied to identify active compounds in Yixin Ningshen tablet for the treatment of depression. Then SwissTargetPrediction was used to predict their potential target proteins. PubMed was retrieved to summarize known depression related systems biology results. Ingenuity Pathway Analysis (IPA) tools and STRING were applied to construct a compound-target protein-gene protein-differential protein-differential metabolite network with the integration of compound-target interaction and systems biology results, as well as enrich the target proteins related pathways. ChEMBL and CDOCKER were used to validate the compound-target interactions. RESULTS: 62 active compounds and their 286 potential target proteins were identified in Yixin Ningshen tablet for the treatment of depression. The construction of compound-target protein-gene protein-differential protein-differential metabolite network shrinked the number of potential target proteins from 286 to 133. Pathway enrichment analysis of target proteins indicated that Neuroactive ligand-receptor interaction, Calcium signaling pathway, Serotonergic synapse, cAMP signaling pathway and Gap junction were the common primary pathways regulated by both Yixin Ningshen Tablet and anti-depressant drugs, and MAPK, Relaxin, AGE-RAGE, Estrogen, HIF-1, Jak-STAT signaling pathway, Endocrine resistance, Arachidonic acid metabolism and Regulation of actin cytoskeleton were the specifically main pathways regulated by Yixin Ningshen tablet for the treatment of depression. Further validations based on references and molecular docking results demonstrated that Yixin Ningshen tablet could primarily target MAPT, CHRM1 and DRD1, thus regulating serotonergic neurons, cholinergic transmission, norepinephrine and dopamine reuptake for the treatment of depression. CONCLUSIONS: This study displays the power of extensive mining of public data and bioinformatical repositories to provide answers for a specific pharmacological question. It furthermore demonstrates how the usage of such a combinatorial approach is advantageous for the biologist in terms of experimentation time and costs.

Effects of sEA on Slow Transit Constipation through the Microbiota-Gut-Brain Axis in Rats.

To investigate the effect of sacral electroacupuncture (sEA) on the microbiota-gut-brain axis in the treatment of slow transit constipation, this study established a drug-induced model of slow transit constipation in rats and carried out sEA at the Baliao acupoints (BL31-BL34). On the 14th day of the therapeutic period (24 h fecal pellets), the aquaporin 3 (AQP3), 5-hydroxytryptamine (5-HT), and substance P (SP) transcripts from the distal colon and hypothalamus were analyzed. 16S rDNA has been widely used to analyze the diversity of the microbial communities. Therefore, in the present study, changes in the intestinal microbiota were analyzed by 16S rDNA gene sequencing. The results showed that sEA significantly increased the number of fecal pellets and the water content in the feces and reduced the reabsorption of intestinal water in 24 h. sEA also upregulated the level of SP mRNA expression in the distal colon and the hypothalamus, but downregulated the level of 5-HT mRNA expression in the distal colon. Moreover, sEA improved the Bacteroidetes to Firmicutes (B/F) ratio, which is beneficial to the general structure of the intestinal microflora. Our findings suggested that the microbiota-gut-brain axis constitutes a crucial pathological basis in the development of slow transit constipation. sEA improved the slow transit constipation by regulating the balance of the microbiota-gut-brain axis.

Minimally invasive surgery alone compared with intensity-modulated radiotherapy for primary stage I nasopharyngeal carcinoma.

BACKGROUND: The National Comprehensive Cancer Network guidelines recommend intensity-modulated radiotherapy (IMRT) as the primary curative treatment for newly diagnosed nasopharyngeal carcinoma (NPC), but the radiation-related complications and relatively high medical costs remain a consequential burden for the patients. Endoscopic nasopharyngectomy (ENPG) was successfully applied in recurrent NPC with radiation free and relatively low medical costs. In this study, we examined whether ENPG could be an effective treatment for localized stage I NPC. METHODS: Ten newly diagnosed localized stage I NPC patients voluntarily received ENPG alone from June 2007 to September 2017 in Sun Yat-sen University Cancer Center. Simultaneously, the data of 329 stage I NPC patients treated with IMRT were collected and used as a reference cohort. The survival outcomes, quality of life (QOL), and medical costs between two groups were compared. RESULTS: After a median follow-up of 59.0 months (95% CI 53.4-64.6), no death, locoregional recurrence, or distant metastasis was observed in the 10 patients treated with ENPG. The 5-year overall survival, local relapse-free survival, regional relapse-free survival, and distant metastasis-free survival among the ENPG-treated patients was similar to that among the IMRT-treated patients (100% vs. 99.1%, 100% vs. 97.7%, 100% vs. 99.0%, 100% vs. 97.4%, respectively, P > 0.05). In addition, compared with IMRT, ENPG was associated with decreased total medical costs ($ 4090.42 ± 1502.65 vs. $ 12620.88 ± 4242.65, P < 0.001) and improved QOL scores including dry mouth (3.3 ± 10.5 vs. 34.4 ± 25.8, P < 0.001) and sticky saliva (3.3 ± 10.5 vs. 32.6 ± 23.3, P < 0.001). CONCLUSIONS: ENPG alone was associated with promising long-term survival outcomes, low medical costs, and satisfactory QOL and might therefore be an alternative strategy for treating newly diagnosed localized stage I NPC patients who refused radiotherapy. However, the application of ENPG should be prudent, and prospective clinical trials were needed to further verify the results.

UPLC-Q-TOF/MS characterization of efficacy substances on osteoblasts differentiation and function in rat serum after administration of Wang-Bi tablet.

Wang-Bi tablet (WB) is popularly used for the treatment of rheumatoid arthritis. However, few studies have been carried out on its active ingredients and mechanism. In this study, the effect of WB medicated serum on the changes in differentiation and function in osteoblast was investigated, the results showed that WB induced the production of ALP and mineralized nodules to promote the final maturation of osteoblasts and enhance the function of osteoblasts. The potential mechanism may that WB significantly inhibits gene expressions of RANKL and miR-141, up-regulates the gene expressions of RUNX2 and OPG, decreases expression of DKK-1 and increases levels of ß-catenin protein to promote the activation of Wnt/ß-catenin signaling pathways, which enhances osteogenesis and bone repair function. To investigate which compounds contributed to the activity and mechanisms, a total of 138 compounds were characterized from WB, and 13 parent molecules and eight metabolites in rat serum were rapidly characterized by UPLC-Q-TOF/MS. Total glycosides of paeony, loganin, α-linolenic acid, linoleic acid and naringin from WB may contribute to the actions on osteoblasts according to our study and literature review. Our research provides a method to explore the bioactive ingredients and action mechanisms of WB.

Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: A phase III multicentre randomised controlled trial.

BACKGROUND: The role of neoadjuvant chemotherapy (NACT) for locoregionally advanced nasopharyngeal carcinoma (NPC) is unclear. We aimed to evaluate the feasibility and efficacy of NACT followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone in locoregionally advanced NPC. METHODS: Patients with stage III-IVB (excluding T3N0-1) NPC were randomly assigned to receive NACT followed by CCRT (investigational arm) or CCRT alone (control arm). Both arms were treated with 80 mg/m2 cisplatin every 3 weeks concurrently with radiotherapy. The investigational arm received cisplatin (80 mg/m2 d1) and fluorouracil (800 mg/m2 civ d1-5) every 3 weeks for two cycles before CCRT. The primary end-point was disease-free survival (DFS) and distant metastasis-free survival (DMFS). Secondary end-point was overall survival (OS). Survival curves for the time-to-event endpoints were analyzed by the Kaplan-Meier method and compared using the log-rank test. The P value was calculated using the 5-year endpoints. RESULTS: Four hundred seventy six patients were randomly assigned to the investigational (n = 238) and control arms (n = 238). The investigational arm achieved higher 3-year DFS rate (82.0%, 95% CI = 0.77-0.87) than the control arm (74.1%, 95% CI = 0.68-0.80, P = 0.028). The 3-year DMFS rate was 86.0% for the investigational arm versus 82.0% for the control arm, with marginal statistical significance (P = 0.056). However, there were no statistically significant differences in OS or locoregional relapse-free survival (LRRFS) rates between two arms (OS: 88.2% versus 88.5%, P = 0.815; LRRFS: 94.3% versus 90.8%, P = 0.430). The most common grade 3-4 toxicity during NACT was neutropenia (16.0%). During CCRT, the investigational arm experienced statistically significantly more grade 3-4 toxicities (P < 0.001). CONCLUSION: NACT improved tumour control compared with CCRT alone in locoregionally advanced NPC, particularly at distant sites. However, there was no early gain in OS. Longer follow-up is needed to determine the eventual therapeutic efficacy.

Iridoid glycoside from Cornus officinalis ameliorated diabetes mellitus-induced testicular damage in male rats: Involvement of suppression of the AGEs/RAGE/p38 MAPK signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis (CO) has been widely used as a traditional Chinese medicine for treating diabetes mellitus (DM) and its complications. Iridoid glycoside from C. officinalis (IGCO) can resist apoptosis, hyperglycemia, oxidation and so on. The aim of this study was to investigate the therapeutic effects of IGCO on DM-induced testicular damage through inhibition of the AGEs/RAGE/p38 MAPK signaling pathway. MATERIALS AND METHODS: A DM model of male Wistar rats was induced with streptozotocin injection (30mg/kg, i.p.) and high-fat diet. The DM rats were administrated with IGCO at low and high doses (15 and 30mg/kg, p.o.) for 12 weeks. Testicular damage was evaluated by estimating relative testicular weights, testicular pathohistology, sperm count, live sperm rate, endogenous sex hormone level and activity of testicular marker enzymes. Besides, general diabetic symptoms, renal function, oxidative stress parameters and testicular apoptosis marker were also determined. Finally, the mechanism was explored based on the AGEs/RAGE/p38 MAPK pathway. RESULTS: IGCO effectively mitigated the general symptoms of DM rats including weight loss, polydipsia, polyphagia, polyuria, elevated blood glucose level and low serum insulin level. Nourishing the kidney evidently, IGCO reduced serum creatinine, urea nitrogen and urine protein excretion, and also markedly protected against DM-induced testicular damage by increasing testis/body weight ratio and live sperm rate, improving the histomorphology of testes, upregulating testosterone, LH, FSH and GnRH levels and preventing the decrease of testicular marker enzymes LDH, ACP and γ-GT. Moreover, IGCO showed considerable anti-oxidative and anti-apoptotic effects, which downregulated the increase of ROS and MDA levels, restored SOD and CAT activities, and decreased spermatogenic cell apoptosis and Bax/Bcl-2 ratio. In the end, the increased AGEs, RAGE and p-p38 MAPK protein levels in DM rats were also reversed by IGCO significantly. CONCLUSIONS: The kidney tonic IGCO well protected DM rats from testicular damage, which may be related to suppression of the AGEs-RAGE-p38 MAPK pathway.

Food-advanced glycation end products aggravate the diabetic vascular complications via modulating the AGEs/RAGE pathway.

The aim of this study was to investigate the effects of high-advanced glycation end products (AGEs) diet on diabetic vascular complications. The Streptozocin (STZ)-induced diabetic mice were fed with high-AGEs diet. Diabetic characteristics, indicators of renal and cardiovascular functions, and pathohistology of pancreas, heart and renal were evaluated. AGEs/RAGE/ROS pathway parameters were determined. During the experiments, the diabetic mice exhibited typical characteristics including weight loss, polydipsia, polyphagia, polyuria, high-blood glucose, and low-serum insulin levels. However, high-AGEs diet effectively aggravated these diabetic characteristics. It also increased the 24-h urine protein levels, serum levels of urea nitrogen, creatinine, c-reactive protein (CRP), low density lipoprotein (LDL), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in the diabetic mice. High-AGEs diet deteriorated the histology of pancreas, heart, and kidneys, and caused structural alterations of endothelial cells, mesangial cells and podocytes in renal cortex. Eventually, high-AGEs diet contributed to the high-AGE levels in serum and kidneys, high-levels of reactive oxygen species (ROS) and low-levels of superoxide dismutase (SOD) in serum, heart, and kidneys. It also upregulated RAGE mRNA and protein expression in heart and kidneys. Our results showed that high-AGEs diet deteriorated vascular complications in the diabetic mice. The activation of AGEs/RAGE/ROS pathway may be involved in the pathogenesis of vascular complications in diabetes.

Effect of morroniside on glomerular mesangial cells through AGE-RAGE pathway.

Diabetes mellitus is an endocrine and metabolic disease characterized by high blood glucose. Diabetic nephropathy (DN) is one of the most typical diabetic complications. Cornus officinalis is a type of traditional Chinese medicine that replenishes the liver and kidney. Morroniside is one of the main characteristic components of C. officinalis. In this study, an in vitro model for simulating DN damage was established by stimulating rat glomerular mesangial cells by the advanced glycation end products. The protective mechanism and effect of morroniside in regulating receptor for advanced glycation end products signaling pathway in DN was investigated to provide experimental evidence for the prevention and treatment of DN.

Synergistic interaction of effective parts in Rehmanniae Radix and Cornus officinalis ameliorates renal injury in C57BL/KsJ-db/db diabetic mice: Involvement of suppression of AGEs/RAGE/SphK1 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Rehmanniae Radix (RR) and Cornus officinalis (CO) are two traditional Chinese medicines widely used in China for treating diabetes mellitus and its complications, such as diabetic nephropathy. Iridoid glycoside of Cornus officinalis (IGCO), triterpenoid acid of Cornus officinalis (TACO) and iridoid glycoside of Rehmanniae Radix (IGRR) formed an innovative formula named combinatorial bioactive parts (CBP). The aims of the present study were to investigate the renoprotective effects of CBP on DN through the inhibition of AGEs/RAGE/SphK1 signaling pathway activation, and identify the advantage of CBP compared with IGCO, TACO, IGRR. MATERIALS AND METHODS: The db/db diabetic renal injury model was used to examine the renoprotective effects of CBP, IGCO, TACO and IGRR. For mechanistic studies, diabetic symptoms, renal functions, and pathohistology of pancreas and kidney were evaluated. AGEs/RAGE/SphK1 pathway were determined. RESULTS: CBP, IGCO, TACO and IGRR inhibited the decrease in serum insulin levels and the increases in urine volume, food consumption, water intake, TC, TG, glycated serum protein, fasting blood glucose levels, 24h urine protein levels, and serum levels of urea nitrogen and creatinine. It also prevented ECM accumulation and improved the histology of pancreas and kidney, and alleviated the structural alterations in mesangial cells and podocytes in renal cortex. Moreover, CBP, IGCO, TACO and IGRR down-regulated the elevated staining, protein levels of RAGE, SphK1, TGF-ß and NF-κB. Among the treatment groups, CBP produced the strongest effects. CONCLUSIONS: These findings suggest that the inhibitory effect of CBP, IGCO, TACO and IGRR on the activation of AGEs/RAGE/SphK1 signaling pathway in db/db diabetic mice kidney is a novel mechanism by which CBP, IGCO, TACO and IGRR exerts renoprotective effects on DN. Among all the groups, CBP produced the strongest effect while IGCO, TACO and IGRR produced weaker effects.

Effects of Evodiamine on the Pharmacokinetics of Dapoxetine and Its Metabolite Desmethyl Dapoxetine in Rats.

The objective of this work was to investigate the effect of orally administered evodiamine on the pharmacokinetics of dapoxetine and its active metabolite desmethyl dapoxetine in rats. Twelve healthy male Sprague-Dawley rats were randomly divided into 2 groups: the control group (received oral 10 mg/kg dapoxetine alone) and the combination group (10 mg/kg dapoxetine orally co-administered with 100 mg/kg evodiamine). The plasma concentration of dapoxetine and desmethyl dapoxetine were estimated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and different pharmacokinetic parameters were calculated using the Drug and Statistics 2.0 software. Compared to the control group, the pharmacokinetic parameter of t1/2, AUC(0-∞) and Tmax of dapoxetine in combination group was significantly increased by 63.3% (p < 0.01), 44.8% (p < 0.01) and 50.4% (p < 0.01), respectively. Moreover, evodiamine had significantly decreased the pharmacokinetic parameter of t1/2 and AUC(0-∞) of desmethyl dapoxetine. This study demonstrated that evodiamine inhibits the metabolism of dapoxetine. Henceforth, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing dapoxetine to the patients already taking evodiamine.

Positive effect of high RKIP expression on reduced distant metastasis by chemotherapy when combined with radiotherapy in locoregionally advanced nasopharyngeal carcinoma: a prospective study.

The purpose of this prospective study is to investigate the predictive and prognostic significance of the Raf kinase inhibitory protein (RKIP) in locoregionally advanced nasopharyngeal carcinoma (NPC). Immunohistochemical assays were performed to detect the RKIP protein expression of samples from 212 patients with locoregionally advanced NPC. All patients were assigned randomly into the inductive chemotherapy plus radiation therapy (IC + RT) group, the concurrent chemoradiotherapy (CCRT) group, the inductive chemotherapy plus concurrent chemoradiotherapy (IC + CCRT) group, and the radiation therapy alone (RT) group. The patients in the IC + RT group were treated with IC using 2-3 cycles of cisplatin (80 mg/m(2)) and fluorouracil (500 mg/m(2)), repeated every 3 weeks, followed by radiotherapy. Those in the CCRT group were treated with weekly cisplatin (40 mg/m(2)) for 6-7 cycles during radiotherapy. In the IC + CCRT group, the chemotherapy prior to radiation was similar to the cisplatin-fluorouracil regimen in the IC + RT group, whereas it cisplatin regimen was identical to that in the CCRT group. The results show that RKIP is an independent prognostic factor for 5-year distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS). Patients with high RKIP expression benefited more from reduced metastasis in the IC + RT and the IC + CCRT group, with improved OS and PFS in each treatment group compared with that among patients with low RKIP expression. In the high RKIP expression subgroup, chemotherapy combined with radiotherapy improved the DMFS when compared with the RT group, but this effect was not observed in the low RKIP expression subgroup. RKIP was predictive of distant metastasis with good sensitivity and specificity. Clinically, high RKIP expression inhibited distant metastasis in advanced NPC, and its detection might be used to predict distant metastasis with good sensitivity and specificity. The effect of chemotherapy on distant metastasis in combined chemoradiotherapy might be related to the RKIP expression level. Patients with high RKIP expression showed more improved OS and PFS than their low RKIP expression counterparts. Higher RKIP expression improves the DMFS of patients who receive inductive high-dose cisplatin-based chemoradiotherapy, with or without concurrent cisplatin. Low RKIP expression is also a predictive marker for cancer progression and metastasis, which could be used to stratify patients with high risk of metastasis and death.