Inhibitory interaction of flavonoids with organic anion transporter 3 and their structure-activity relationships for predicting nephroprotective effects.

The organic anion transporter 3 (OAT3), an important renal uptake transporter, is associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OAT3 inhibitors with little toxicity in natural products, especially flavonoids, in reducing OAT3-mediated AKI is of great value. The five strongest OAT3 inhibitors from the 97 flavonoids markedly decreased aristolochic acid I-induced cytotoxicity and alleviated methotrexate-induced nephrotoxicity. The pharmacophore model clarified hydrogen bond acceptors and hydrophobic groups are the critical pharmacophores. These findings would provide valuable information in predicting the potential risks of flavonoid-containing food/herb-drug interactions and optimizing flavonoid structure to alleviate OAT3-related AKI.

[Research progress in pharmacotherapy of insomnia].

Insomnia is extremely common and is a risk factor for a variety of physical and psychological disorders in addition to contributing to the reduced quality of life of patients and the burden of healthcare costs. Although cognitive behavioral therapy is the first-line treatment for insomnia, its difficulty of access and high cost have hindered its application. Therefore, pharmacotherapy remains the common treatment choice for patients and clinicians. Existing chemical drugs including benzodiazepine receptor agonists, dual orexin receptor antagonists, melatonin and its receptor agonists, histamine antagonists, antidepressants, and antipsychotics are able to induce and/or maintain sleep and have good therapeutic effects on acute insomnia, but their efficacy on chronic insomnia is indefinite. Furthermore, they have several side effects and affect sleep structure and physiological function. Under the guiding principle of holistic view and treatment based on syndrome differentiation, traditional Chinese medicine(TCM) has shown a good effect in clinical practice, but with little high-grade clinical evidence. The mechanism, dose, half-life period, adjustment of sleep structure, and side effects of hypnotic drugs are key factors to be considered for clinical use. This paper analyzed and summarized the drugs for insomnia from the above aspects, and is expected to provide references for the application and development of sedative and hypnotic drugs.

Inhibitory interaction of flavonoids with organic cation transporter 2 and their structure-activity relationships for predicting nephroprotective effects.

Organic cation transporter 2 (OCT2) is mainly responsible for the renal secretion of various cationic drugs, closely associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OCT2 inhibitors with little toxicity in natural products in reducing OCT2-mediated AKI is of great value. Flavonoids are enriched in various vegetables, fruits, and herbal products, and some were reported to produce transporter-mediated drug-drug interactions. This study aimed to screen potential inhibitors of OCT2 from 96 flavonoids, assess the nephroprotective effects on cisplatin-induced kidney injury, and clarify the structure-activity relationships of flavonoids with OCT2. Ten flavonoids exhibited significant inhibition (>50%) on OCT2 in OCT2-HEK293 cells. Among them, the six most potent flavonoid inhibitors, including pectolinarigenin, biochanin A, luteolin, chrysin, 6-hydroxyflavone, and 6-methylflavone markedly decreased cisplatin-induced cytotoxicity. Moreover, in cisplatin-induced renal injury models, they also reduced serum blood urea nitrogen (BUN) and creatinine levels to different degrees, the best of which was 6-methylflavone. The pharmacophore model clarified that the aromatic ring, hydrogen bond acceptors, and hydrogen bond donors might play a vital role in the inhibitory effect of flavonoids on OCT2. Thus, our findings would pave the way to predicting the potential risks of flavonoid-containing food/herb-drug interactions in humans and optimizing flavonoid structure to alleviate OCT2-related AKI.

Antidepressant-like effects of geniposide in chronic unpredictable mild stress-induced mice by regulating the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 networks.

Evidence exists suggesting the anti-depressive activities of geniposide (GP), a major compound in Gardenia jasminoides Ellis. Accordingly, the present study attempts to explore the anti-depressive mechanism of GP in chronic unpredictable mild stress (CUMS)-induced depression-like behaviors of mice. CUMS-induced mice were given GP daily and subjected to behavioral tests to observe the effect of GP on the depression-like behaviors. It was noted that GP administration reduced depression-like behaviors in CUMS mice. Transcriptome sequencing was conducted in three control and three CUMS mice. Differentially expressed circRNAs, lncRNAs and mRNAs were then screened by bioinformatics analyses. Intersection analysis of the transcriptome sequencing results with the bioinformatics analysis results was followed to identify the candidate targets. We found that Gata2 alleviated depression-like behaviors via the metabolism- and synapse-related pathways. Gata2 was a target of miR-25-3p, which had binding sites to circ_0008405 and Oip5os1. circ_0008405 and Oip5os1 competitively bound to miR-25-3p to release the expression of Gata2. GP administration ameliorated depression-like behaviors in CUMS mice through regulation of the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 crosstalk networks. Taken together, GP may exert a potential antidepressant-like effect on CUMS mice, which is ascribed to regulation of the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 crosstalk networks.

Association between coffee drinking and endometrial cancer risk: A meta-analysis.

AIM: Coffee drinking is considered as a risk factor of endometrial cancer (EC). Here, we conducted a meta-analysis of observational study to evaluate the relationship between coffee drinking and the risk of EC. METHODS: The MEDLINE and EMBASE databases were searched until July 2018. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: A total of 24 studies (12 case-control and 12 cohort studies) on coffee intake with 9833 incident cases of EC and 699 234 subjects were included in the meta-analysis. The pooled RR of endometrial cancer for the highest versus the lowest categories of coffee intake was 0.71 (95% CI: 0.65-0.77; I2  = 14%, p for heterogeneity = 0.26). By study design, the pooled RRs were 0.68 (95% CI: 0.56-0.83) for case-control studies and 0.70 (95% CI: 0.63-0.77) for cohort studies. For different regions, the pooled RRs were 0.74 (95% CI: 0.62-0.88) in Europe, 0.71 (95% CI: 0.64-0.79) in United States/Canada, and 0.40 (95% CI: 0.28-0.57) in Japan. By additional subgroup analysis, a stronger inverse association was shown in caffeinated coffee drinkers (RR 0.66, 95% CI: 0.52-0.83), individuals with the higher body mass index (BMI) (RR 0.65, 95% CI: 0.54-0.79), never smokers (RR 0.68, 95% CI: 0.56-0.84), ever smokers (RR 0.56, 95% CI: 0.45-0.70), and those who never used hormone replacement therapy (HRT) (RR 0.88, 95% CI: 0.79-0.98). The consumption of filtered or boiled coffee showed no significant association. CONCLUSIONS: Increased coffee intake is associated with a reduced risk of EC.

Impact of abdominal massage on enteral nutrition complications in adult critically ill patients: A systematic review and meta-analysis.

BACKGROUND: Adult critically ill patients are prone to complications when receiving enteral nutrition, including feeding intolerance. Although abdominal massage is an effective intervention, its effects on enteral nutrition complications in adult critically ill patients are controversial. OBJECTIVE: To summarize and evaluate the effect of abdominal massage on enteral nutrition complications in adult critically ill patients. METHODS: We searched databases (e.g., PubMed, the Cochrane Library, Embase, and Web of Science) from inception until November 2020 for relevant studies published in English. The methodological quality of selected studies was assessed with the Cochrane Risk of Bias 2.0 tool. And we used of PRISMA 2020 guidelines. The meta-analysis results were reported as mean difference (MD) and events, and the heterogeneity of the studies was evaluated using I2. RESULTS: Seven studies including 472 participants (aged≥18 years) met the inclusion criteria. The mean gastric residual volume (GRV) (MD=-42.41, 95% confidence interval [CI]: -71.43, -13.39; P = 0.004) and incidence of abdominal distension (odds ratio [OR]=0.08, 95%CI: 0.03, 0.19; P < 0.00001) were significantly lower in the massage therapy group compared with controls. The incidence of vomiting (OR=0.09, 95%CI: 0.01, 0.72; P = 0.02) and ventilator-associated pneumonia (VAP) (OR=0.20, 95%CI: 0.05, 0.77; P = 0.02) were statistically significantly lower in the abdominal massage group compared with controls. CONCLUSION: Abdominal massage reduces GRV, vomiting, abdominal distension, and VAP in adult critically ill patients. Given the limited number of reviewed studies, small number of patients examined, and short intervention periods, further randomized controlled trials are needed that use accurate methodology, longer interventions, and larger sample sizes to confirm the effect of abdominal massage on feeding intolerance in adult critically ill patients.

[Effect of neoadjuvant chemotherapy on nutritional status of locally advanced gastric cancer].

OBJECTIVE: To study the effect of neoadjuvant chemotherapy on nutritional status in patients with locally advanced gastric cancer. METHODS: Cases inclusion criteria: (1)18-65 years old; (2) Gastric cancer confirmed by gastroscopic biopsy; (3) Preoperative TNM stage III( according to the AJCC stage 2000 standard; (4) Kamosfsky functional status score> 60 points; (5)Receiving neoadjuvant chemotherapy voluntarily and signing the informed consent form. Case exclusion criteria: (1)Having contraindications of chemotherapy and surgery; (2) Suffering from heart, liver and kidney and other underlying diseases; (3) Concurrent with malignant diseases, wasting disease or other digestive diseases. According to the above criteria, clinical data of 73 patients of stage III( gastric cancer receiving neoadjuvant chemotherapy at Weifang People's Hospital from May 2015 to March 2017 were prospectively collected. The cohort study was adopted. After removing 3 patients who did not complete the chemotherapy, a total of 70 patients who completed the chemotherapy were included in the study. All the patients received SOX chemotherapy without nutritional support during chemotherapy. Changes of body composition and nutritional indicators were analyzed before and after chemotherapy, and according to the tumor regression after chemotherapy, patients were divided into response group (complete or sub-total tumor regression) and non-response group (tumor part, with or without a small amount of retreat) for stratified analysis. RESULTS: Of 70 gastric cancer patients, 40 were male and 30 were female with a age of (53.8±6.4) (28 to 64) years. There were 26 cases (37.1%) of stage III(a, 35 cases (50.0%) of stage III(b and 9 cases (12.9%) of stage III(c. There were 41 cases in response group and 29 cases in non-response group. Three patients (4.3%) were complete remission (CR) and 38 patients (54.3%) were partial remission (PR) in response group, while 23 cases (32.9%) were stable disease (SD) and 6 cases (8.6%) were progressive disease (PD). After neoadjuvant chemotherapy, the extracellular fluid of the whole patients increased from (13.3±1.7) L to (13.5±1.6) L (t=-2.044, P=0.045); the intracellular fluid decreased from (21.4±2.5) L to (21.1±2.4) L (t=2.369, P=0.021); the lymphocyte count decreased from (0.31±0.10)×109/L to (0.29±0.10)×109/L (t=1.706, P=0.009); the other indexes were not significantly different (all P>0.05). Stratified analysis showed that after neoadjuvant chemotherapy in response group, body mass increased from (60.1±8.8) kg to (61.0±8.3) kg (t=-2.773, P=0.008); body mass index increased from (21.9±2.4) kg/m2 to (22.3±1.9) kg/m2(t=-3.479, P=0.001), while above two parameters did not differ significantly in non-response group. No significant differences in body mass, body mass index, skeletal muscle, inorganic salt, extracellular fluid, body fat, protein, upper arm circumference and intracellular fluid were found between two groups before and after neoadjuvant chemotherapy(all P>0.05). Except slight decrease in hemoglobin and lymphocyte, the other nutritional indicators were slightly elevated in response group, while the differences were not statistically significant(all P>0.05). All nutritional indicators in non-response group were slightly decreased without significant differences as well (all P>0.05). CONCLUSION: Neoadjuvant chemotherapy does not aggravate malnutrition in patients with locally advanced gastric cancer.

Sodium tanshinone IIA silate inhibits high glucose-induced vascular smooth muscle cell proliferation and migration through activation of AMP-activated protein kinase.

The proliferation of vascular smooth muscle cells may perform a crucial role in the pathogenesis of diabetic vascular disease. AMPK additionally exerts several salutary effects on vascular function and improves vascular abnormalities. The current study sought to determine whether sodium tanshinone IIA silate (STS) has an inhibitory effect on vascular smooth muscle cell (VSMC) proliferation and migration under high glucose conditions mimicking diabetes without dyslipidemia, and establish the underlying mechanism. In this study, STS promoted the phosphorylation of AMP-activated protein kinase (AMPK) at T172 in VSMCs. VSMC proliferation was enhanced under high glucose (25 mM glucose, HG) versus normal glucose conditions (5.5 mM glucose, NG), and this increase was inhibited significantly by STS treatment. We utilized western blotting analysis to evaluate the effects of STS on cell-cycle regulatory proteins and found that STS increased the expression of p53 and the Cdk inhibitor, p21, subsequent decreased the expression of cell cycle-associated protein, cyclin D1. We further observed that STS arrested cell cycle progression at the G0/G1 phase. Additionally, expression and enzymatic activity of MMP-2, translocation of NF-κB, as well as VSMC migration were suppressed in the presence of STS. Notably, Compound C (CC), a specific inhibitor of AMPK, as well as AMPK siRNA blocked STS-mediated inhibition of VSMC proliferation and migration. We further evaluated its potential for activating AMPK in aortas in animal models of type 2 diabetes and found that Oral administration of STS for 10 days resulted in activation of AMPK in aortas from ob/ob or db/db mice. In conclusion, STS inhibits high glucose-induced VSMC proliferation and migration, possibly through AMPK activation. The growth suppression effect may be attributable to activation of AMPK-p53-p21 signaling, and the inhibitory effect on migration to the AMPK/NF-κB signaling axis.

Clinical characteristics of non-perianal fistulating Crohn's disease in China: a single-center experience of 184 cases.

BACKGROUND: There is little information of non-perianal fistulating Crohn's disease in the consensus published by the European Crohn's and Colitis Organization in 2006 and 2010. This study was designed to demonstrate the clinical characteristics of non-perianal fistulating Crohn's disease among homogenous Chinese population. METHODS: One-hundred-and-eighty-four patients were retrospectively collected. All of these patients were diagnosed of Crohn's disease between February 2001 and April 2011. RESULTS: The male-to-female ratio was 2.7:1. The most common symptoms at onset were abdominal pain (88.0%), diarrhea (34.7%), and fever (28.3%). The most common disease location and behavior at diagnosis were small bowel (56.0%) and penetrating (51.6%). Among 324 non-perianal fistulae, the most common types were ileocolonic anastomotic (30.9%), terminal ileocutaneous (19.7%), and enteroenteric anastomotic (11.4%). One-hundred-and-thirty- eight (75.0%) patients received antibiotics, and ß-lactam (85.5%) and metronidazole (67.4%) are most frequently used. One-hundred-and-seventy-eight (96.7%) patients suffered 514 surgical operations, and the cumulative surgical rates after 1, 3, and 5 years were 38.0%, 52.2%, and 58.7% respectively. Nine patients died during the follow-up period, and the cumulative survival rates after 1, 3, and 5 years were 97.8%, 96.7%, and 96.2% respectively. CONCLUSIONS: This study displayed the clinical characteristics of non-perianal fistulating Crohn's disease in our center. Large population-based studies are required for further investigation in China.

[Maintenance effect of polyglycosides of Tripterygium wilfordii on remission in postoperative Crohn disease].

OBJECTIVE: To observe the maintenance effect of polyglycosides of Tripterygium wilfordii (GTW) on remission in postoperative Crohn disease (CD). METHODS: From 2005 to 2007, 45 adult cases of postoperative Crohn disease were randomly divided into two groups, GTW group and mesalazine group, which received GTW and mesalazine treatment respectively. CD activity index (CDAI) and clinical markers were collected at 0, 3, 6, 12 months or at the onset of symptoms. Ileocolonoscopy was performed at the end of the trial (1 year after operation) or at the onset of symptoms, and recurrence score were recorded. RESULTS: No clinical recurrence was ascertained in both groups at 3 months. Four patients (18.2%) in GTW group relapsed and 5 (21.7%) in mesalazine group relapsed at 6 months (P=0.530). Seven patients (31.8%) in GTW group and 9 (39.1%) in mesalazine group relapsed at one year (P=0.421). Ten patients (45.5%) in GTW group had endoscopic recurrence compared with 14 (60.9%) in mesalazine group at one year(P=0.231). There were no significant differences between two groups. CONCLUSION: GTW is similar to mesalazine in maintenance of remission of postoperative Crohn disease.

Efficacy of T2 in active Crohn's disease: a prospective study report.

To date few therapies have been shown to reliably prevent the evolution of Crohn's disease (CD). The traditional Chinese medicine, Tripterygium wilfordii Hook F (TWHF), has both immunomodulatory and anti-inflammatory activities. Our aim was to investigate the potential efficacy of T2, the major constituent of extracts of TWHF, in inducing remission of active CD. Twenty adult patients with active CD were enrolled to be treated with T2 pills (60 mg daily) for 12 weeks. Plasma levels of C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta were measured at entry and every 2 weeks thereafter until week 12. At each visit the CD Activity Index (CDAI) was calculated. The CD Endoscopic Index of Severity was measured at entry and week 12. Sixteen patients completed the study. A significant decrease in serum levels of CRP, TNF-alpha, and IL-1beta occurred rapidly after commencement of treatment. CDAI scores showed a rapid decline during the first 8 weeks and reached their lowest at week 10. Endoscopic improvements were observed at week 12. In conclusion, T2 appears to be effective for the treatment of mildly or moderately active CD. Further controlled studies are warranted for this promising drug.

Refeeding syndrome in patients with gastrointestinal fistula.

OBJECTIVE: Although refeeding syndrome has been well documented in starved patients, obese patients, those with anorexia nervosa, malnourished elderly individuals, and certain postoperative patients, little is known about the presence and the importance of refeeding syndrome in patients with gastrointestinal fistula and insufficient nutrition support over the long term. The objective of this study was to estimate the morbidity of this syndrome in these patients, to assess the safety and efficacy of our graduated refeeding regimen, and to emphasize the importance of this syndrome. METHODS: One hundred fifty-eight patients with gastrointestinal fistula during the past 2 y were reviewed. RESULTS: Fifteen of these patients were diagnosed as having refeeding syndrome. They were started on the refeeding procedure according to our regimen, and changes in their serum levels of electrolytes were recorded. The symptoms and signs they presented were noted. All patients were successfully advanced to full nutrition support. During the refeeding procedure, patients presented with weakness, paralysis of limbs, slight dyspnea, paresthesia, tachycardia, edema, and diarrhea. Serum phosphorus concentration decreased in all patients within 24 h of refeeding, reaching a mean nadir after 3.3 +/- 1.5 d and another 6.1 +/- 2.1 d to return to above 0.70 mM/L upon phosphorus supplementation. Three patients treated with growth hormone presented more severe hypophosphatemia (<0.20 mM/L) than the others. CONCLUSIONS: 1) Refeeding syndrome occurs commonly in patients with malnutrition secondary to gastrointestinal fistula. 2) Alterations in phosphate metabolism are central to the refeeding syndrome. 3) Supplementation with electrolytes (including especially phosphate) and vitamins is the focal point of the treatment of this syndrome. 4) Growth hormone treatment may aggravate hypophosphatemia.