Risk Factors for Worsening of Bone Loss in Patients Newly Diagnosed with Inflammatory Bowel Disease.

Background: Bone loss is common in patients with inflammatory bowel disease (IBD). The aim of the present study was to determine the prevalence of metabolic bone disease in patients newly diagnosed with IBD and to identify the risk factors for bone loss over time. Methods: We performed a retrospective, both cross-sectional and longitudinal, study to extract the risk factors of bone loss (including osteopenia and osteoporosis) in patients newly diagnosed with IBD, using dual-energy X-ray absorptiometry (DXA). Results: A total of 639 patients newly diagnosed with IBD that had at least one DXA were included in the cross-sectional study. Osteopenia and osteoporosis were diagnosed in 24.6% and 5.4% of patients, respectively. Age at diagnosis, body mass index, and serum phosphorus were identified as independent factors associated with bone loss at baseline. A total of 380 of the 639 IBD patients (including 212 CD patients and 168 UC patients) with at least a second DXA scan were included in the longitudinal study. 42.6% of the patients presented a worsening of bone loss in the follow-up study. Menopause, albumin, and use of corticosteroids were identified as independent factors associated with worsening of bone loss. Conclusions: Metabolic bone disease is common in IBD patients, and there is a significant increase in prevalence of bone loss over time. Postmenopausal female, malnourished patients, and those requiring corticosteroid treatment are at risk for persistent bone loss. Therefore, BMD measurements and early intervention with supplementation of calcium and vitamin D are recommended in IBD patients with high-risk factors.

Current status of novel biologics and small molecule drugs in the individualized treatment of inflammatory bowel disease.

Treatment strategies for inflammatory bowel disease (IBD) are rapidly evolving with the development of biologics and small molecule drugs (SMDs). However, these drugs are not guaranteed to be effective in all patients, and a "ceiling effect" of biologic monotherapy may occur. This issue highlights an unmet need for optimizing the use of biologics and predicting therapeutic responses. Thus, the development of new drugs with novel mechanisms of action is urgently needed for patients with primary nonresponse and secondary loss of response to conventional biologics and SMDs. In addition, combining different biologics or SMDs has been proposed as a novel strategy to enhance treatment efficacy in IBD, which theoretically has multidimensional anti-inflammatory potential. Based on the current evidence available for IBD, dual targeted therapy may be a promising strategy for refractory IBD patients who have failed in multiple biologic trea-tments or who have extraintestinal manifestation. Additionally, identifying the subgroup of IBD patients who are responding to biological combination therapies is also equally important in stable disease remission. In this review, we sum-marize the newly developed biologics and SMDs and the current status of bio-logics/SMDs to highlight the development of individualized treatment in IBD.

12ß-Acetyloxyperforatin, a New Limonoid from Harrisonia Perforata.

A new A, D-seco limonoid, named 12-acetyloxyperforatin (1), along with three known ones, were isolated from the leaves of Harrisonia perforata. Their structures were elucidated on the basis of spectroscopic analysis, including extensive NMR techniques and computational modelling. These compounds showed no inhibitory activity against the 11ß-HSD1 enzyme.

Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway.

Bisindolylmaleimides, a series of derivatives of a PKC inhibitor staurosporine, exhibit potential as anti-cancer drugs and have received considerable attention in clinical trials. This study aims to investigate the effects of a bisindolylmaleimide alkaloid 155Cl (BMA-155Cl) with a novel structure on autophagy and apoptosis in human hepatocarcinoma HepG-2 cells in vitro and in vivo. The cell poliferation was assessed with a MTT assay. Autophagy was evaluated by MDC staining and TEM analysis. Apoptosis was investigated using Annexin V-FITC/PI and DAPI staining. The antitumor effects were further evaluated in nude mice bearing HepG-2 xenografts, which received BMA-155Cl (10, 20 mg/kg, ip) for 18 days. Autophagy- and apoptosis-associated proteins and their mRNA levels were examined with Western blotting, immunohistochemistry, and RT-PCR. BMA-155Cl (2.5-20 µmol/L) inhibited the growth of HepG-2 cells with IC50 values of 16.62±1.34, 12.21±0.83, and 8.44±1.82 µmol/L at 24, 48, and 72 h, respectively. Furthermore, BMA-155Cl (5-20 µmol/L) dose-dependently induced autophagy and apoptosis in HepG-2 cells. The formation of autophagic vacuoles was induced by BMA-155Cl (10 µmol/L) at approximately 6 h and peaked at approximately 15 h. Pretreatment with 3-MA potentiated BMA-155Cl-mediated apoptotic cell death. This compound dose-dependently increased the mRNA and protein levels of Beclin-1, NF-κB p65, p53, and Bax, but decreased the expression of IκB and Bcl-2. Pretreatment with BAY 11-7082, a specific inhibitor of NF-κB p65, blocked BMA-155Cl-induced expression of autophagy- and apoptosis-associated proteins. BMA-155Cl administration effectively suppressed the growth of HepG-2 xenografts in vivo, and increased the protein expression levels of LC3B, Beclin-1, NF-κB p65, and Bax in vivo. We conclude that the NF-κB p65 pathway is involved in BMA-155Cl-triggered autophagy, followed by apoptosis in HepG-2 cells in vitro and in vivo. Hence, BMA-155Cl could be a promising pro-apoptotic candidate for developing as a novel anti-cancer drug.

[A comparative study of induction of remission and cost-effectiveness of enteral nutrition versus infliximab in moderate-to-severe Crohn's disease].

OBJECTIVE: To compare the induction of remission and cost-effectiveness of enteral nutrition (EN) and infliximab (IFX) in moderate-to-severe active Crohn's disease(CD). METHODS: Moderate-to-severe active CD patients were divided into IFX group and EN group. Remission rate, time to remission and treatment cost were compared between the two groups. Clinical remission was defined as Crohn's disease activity index (CDAI) < 150. The quality of life was evaluated by inflammatory bowel disease questionnaire of quality of life (IBDQ). RESULTS: A total of 100 patients were analyzed, including 48 patients in IFX group and 52 patients in EN group. IFX group had higher remission rate [87.5% (42/48) vs 67.3% (35/52) , P = 0.017] and shorter time to remission [(11.00 ± 8.35) days vs (33.94 ± 14.60) days, P < 0.001] than EN group. Treatment costs before remission were similar in two groups (P = 0.351) . The increase of IBDQ scores before and after treatment in IFX group was much higher than that of EN group (42.74 ± 27.50 vs 7.57 ± 22.77, P < 0.001) . Similarly, patients in EN group had greater increase of body mass index (BMI) than that of IFX group [(1.32 ± 0.29)kg/m(2) vs (0.51 ± 0.07) kg/m(2), P < 0.001]. For patients with CDAI < 280, remission rate was not significantly different [85.7% (24/28) vs 81.8% (18/22) , P = 0.718] between the two groups, while treatment cost in EN group was less than that of IFX group [(16.1 ± 5.9)×10(3) RMB vs (22.9 ± 11.9)×10(3) RMB, P = 0.021]. CONCLUSIONS: For patients with severe CD (CDAI ≥ 280), IFX has higher remission rate, shorter time to remission and comparable treatment cost than EN. But for patients with CDAI < 280, EN group has comparable remission rate to IFX group with lower cost.

[Enteral nutritional therapy in Crohn disease complicated with incomplete intestinal obstruction].

OBJECTIVE: To investigate the efficacy of enteral nutrition(EN) therapy for active Crohn disease(CD) complicated with incomplete intestinal obstruction. METHODS: Clinical data of 37 patients with active CD complicated with incomplete intestinal obstruction treated with EN(n=37) between January 2003 and September 2009 were retrospectively analyzed. CD activity index (CDAI) was between 150 and 450. The patients received total enteral nutrition (TEN) 125 kJ/kg by nasogastric tube or percutaneous endoscopic gastrostomy/jejunostomy(PEG/J) tube. Clinical response was defined as a decrease in CDAI≥70 from baseline since EN therapy, and clinical remission was defined as CDAI<150. Nutritional status, disease activity index, and side effects were recorded at the 0, 4th, and 12th week after EN therapy. RESULTS: Stricture or stenosis location included ileum in 8 (21.6%) patients, ileocolon in 19(51.4%), colon in 4(10.8%), jejunoileum in 5(13.5%), and duodenum in 1(2.7%). At 4 weeks after EN, CDAI significantly decreased(112.0±39.6 vs.174.6±34.7,P<0.05). The ratio of clinical response was 43.2%(16/37) and clinical remission was 72.9%(27/37). At 12 weeks, CDAI was 70.2±32.9, lower than that at week 4(P<0.05). The ratio of clinical response was 70.2%(26/37) and clinical remission was 78.4%(29/37). Other disease activity indexes such as C-reactive protein, erythrocyte sedimentation rate, and nutritional status such as BMI, serum albumin, prealbumin, transferrin and hemoglobin showed similar trend. During therapy, 7 cases had progressive intestinal obstruction resulting in bowel resection, 11 cases had diarrhea and/or abdominal distention due to inadequate infusion of home EN whose symptoms were improved after correction by the doctor. CONCLUSIONS: EN therapy can induce clinical response and remission in CD complicated with incomplete intestinal obstruction, relieve obstruction, alleviate the inflammatory response which plays positive role in the treatment of CD.

Triptolide ameliorates IL-10-deficient mice colitis by mechanisms involving suppression of IL-6/STAT3 signaling pathway and down-regulation of IL-17.

Triptolide is an active component of extracts derived from the medicinal vine Tripterygium Wilfordii Hook. f. (TWHF) whose extracts have been used to treat inflammatory bowel disease (IBD). We have reported that triptolide showed therapeutic activity in a murine IBD model, but the potential mechanism of action of this agent in IBD remains elusive. Accumulated data showed that both T-helper (Th) 1 and Th17 response may contribute to pathogenesis of human IBD and animal colitis. Interleukin (IL)-6/signal transducer and activator of transcription-3 (STAT3) signaling pathway play an important role in Th17 response as well as pathophysiology of IBD. We hypothesized that triptolide would attenuate the experimental colitis by repressing IL-17 and that this would involve down-regulation of IL-6/STAT3 signaling pathway. Histological examination demonstrated that triptolide significantly reduced the severity of colitis in C3H/HeJBir.IL-10-deficeint mice. Triptolide suppressed the IL-6/STAT3 signaling pathway, as well as repressed gene expression of IL-17 in vivo. In addition, triptolide (20ng/ml) in vitro was able to down-regulate the IL-6/STAT3 pathway and reduce IL-17 expression in cultured colonic explants from patients with Crohn's disease (CD).

[Effect of enteral supplement of arginine on intestinal adaptation and its mechanism in experimental rats with short bowel syndrome].

OBJECTIVE: To evaluate the effect of enteral supplement of arginine on intestinal adaptation in rats with short bowel syndrome (SBS) and to study its mechanism. METHODS: SD rats were randomly assigned to three groups: sham rats (Con), SBS rats (SB) and SBS rats supplemented with enteral arginine (SB-Arg). All the animals received isonitrogenic and isocaloric enteral nutrition, except that SB-Arg rats received enteral nutrition supplemented with arginine (300 mg kg(-1) d(-1)). Fat absorbability, plasma free fatty acids, parameters of intestinal adaptation, enterocytes proliferation and apoptosis were determined. RESULTS: After massive small bowel resection, rats had significant bowel adaptation. Compared with SB rats, SB-Arg rats demonstrated a significant increase in fat absorbability [(84.9+/-3.2)% vs [(81.3+/-3.9)%], plasma level of free fatty acids [(650.0+/-86.5) vs (289.5+/-76.9) mg/L], ileal mucosal weight [(18.0+/-3.5) vs (13.5+/-3.0) mg cm(-1) 100 g(-1)], ileal DNA content [(29.6+/-3.3) vs (26.0+/-2.6) microg cm(-1) 100 g(-1)], jejunal mucosal protein content [(65.5+/-7.3) vs (59.8+/-6.2) microg cm(-1) 100 g(-1)], ileal mucosal protein content[(39.2+/-2.3) vs(35.4+/-2.3) microg cm(-1) 100 g(-1)], jejunal mucosal proliferation index [31+/-4 vs 22+/-3] and ileal mucosal proliferation index [32+/-2 vs 25+/-3] (all P<0.05). Moreover, jejunal and ileal villus length, crypt depth and mucosal thickness in SBS-Arg rats were higher than those in SB rats (P<0.05). CONCLUSIONS: In rat SBS model, enteral supplement of arginine appears to stimulate intestinal structural and functional adaptation. The mechanism may be that arginine can stimulate enterocyte proliferation and inhibit enterocyte apoptosis.

[Therapeutic effects of combined enteral nutrition with Tripterygium Wilfordii poly-glycoside in remission induction of active adult Crohn's disease].

OBJECTIVE: To investigate the potential role of enteral nutrition (EN) combined with Tripterygium Wilfordii Poly-glycoside (TWP) for remission induction of active adult Crohn's disease (CD). METHODS: Clinical data of 62 adult patients with active CD treated with EN and TWP in combination (n = 42) or TWP alone (n = 20) from March 2001 to September 2008 were retrospectively analyzed. All the patients had a Crohn's Disease Activity Index (CDAI) > 150 and < 450. In TWP group, subjects received TWP tablets (1.0 - 1.5 mg x kg(-1) x d(-1)) with uncontrolled diets; while in the group of combination therapy, the patients were given total enteral nutrition (TEN) through tube feeding in addition to TWP tablets. Clinical response was defined by a decrease of at least 70 points in the CDAI from baseline after treatment, and clinical remission was defined as the absolute value of CDAI (less than 150). Patients' nutritional and disease activity index, such as CDAI score, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), were determined at 0, 4, and 12 weeks after treatment. RESULTS: The ratio of clinical response (78.6% vs. 40.0%, P = 0.003) and clinical remission (69.1% vs. 30.0%, P = 0.004) were both significantly higher in the combined treatment group than in those the TWP group at week 4. At week 12, the clinical response ratio was significantly higher in the combined treatment group (90.5% vs. 65.0%, P = 0.014); the remission ratio was also higher in the combined treatment group (76.2% vs. 55.0%, P = 0.091). The nutritional parameters improved from baseline at week 4 and 12 in the combined treatment group but not in TWP group. At week 4, blood albumin, prealbumin, and transferrin levels was higher in the combined treatment group than those in TWP group (P < 0.05); at week 12, patients in combined treatment group also had significantly higher body mass index (BMI), blood albumin, prealbumin, transferrin and hemoglobin levels (P < 0.05). CONCLUSIONS: Treatment with enteral nutrition and TWP in combination are superior to TWP alone for induction of clinical response and remission in adult Crohn's Disease. This strategy also improves patient's nutritional status and avoids the adverse effects of traditional therapy.

Cytotoxic and antioxidative phenolic compounds from the traditional Chinese medicinal plant, Myristica fragrans.

Two new phenolic compounds were isolated from the fruits of Myristica fragrans and their structures were elucidated as (-)-1-(2,6-dihydroxyphenyl)-9-[4-hydroxy-3-(p-menth-1-en-8-oxy)-phenyl]-1-nonanone ( 1) and (7 R,8 R)-7,8-dihydro-7-(3,4-dihydroxyphenyl)-3'-methoxy-8-methyl-1'-( E-propenyl)benzofuran (2). In addition, the absolute configuration of (+)-Delta8'-7-acetoxy-3,4,3',5'-tetramethoxy-8- O-4'-neolignan (3) was determined for the first time through spectroscopic and chemical methods. Their antioxidative activities against 2,2-diphenyl-1-picrylhydrazyl radical and cytotoxicity against K-562 cells were tested, and (7 S,8 S,7' R,8' S)-4,5'-dihydroxy-3,3'-dimethoxy-7,7'-epoxylignan (4) showed the corresponding activities with IC(50) values of 39.4 and 2.11 microM, respectively.

Cytotoxic macrocyclic diterpenoids from Euphorbia helioscopia.

A new cytotoxic macrocyclic diterpenoid, euphornin L (1), together with seven known analogues were isolated from the plant Euphorbia helioscopia L. The structure of 1 was elucidated by spectral data and X-ray crystallographic analysis. Euphornin L (1) and euphoscopin F (2) exhibited significant cytotoxicity against HL-60 cell lines with IC(50) values of 2.7 and 9.0 microM, respectively. The 13C-NMR data of euphoscopin F (2), epieuphoscopin B (3), euphoscopin B (5), and euphoscopin C (6) were also reported for the first time.

[Effect of Qingxin Kaiqiao fang on learning and memory ability and morphology of hippocampal nerve cells in AD mice].

OBJECTIVE: To study the effect of the Qingxin Kaiqiao fang on learning and memory ability and shape hippocampal nerve cells in Alzheimer disease (AD). METHOD: One handred and fifty mice were divid into five groups: blank group, model group, two groups of treatment by Qingxin Kaiqiao fang (14.82, 7.41 g x kg(-1)), piracetan comparison group (0.42 g x kg(-1)). The model group was orally given AlCl3 (200 mg x kg(-1)) every day. For Qingxin Kaiqiaofang and piracetan groups, AlCl3 treatment was given for 6 days at the beginning, followed by giving orally AlCl3 in the morning and drug in the afternoon for 8 weeks. Then, learning and memory aility, the contents of nitric oxide (NO), NO synthase (NOS) and acetylcholinesterase (AchE) in brain, and morphology of hippocampal nerve cells were investigated. RESULT: Learning and memory ability of Qingxin Kaiqiaofang groups was improved, compared with comparison group; the difference was significant (P < 0.05, P < 0.01). The drug could prevent hippocampal nerve cells from damaged obviously. The contents of NO, NOS and AchE in mice of treatment groups were lower than those of comparison group; the difference was significant (P < 0.05, P < 0.01). CONCLUSION: Qingxin Kaiqiaofang can improve learning and memory ability of AD mice, prote chippocampal nerve cells, and treat Alzheimer disease.

Minor furofurano lignans from the Tibetan herb, Lancea tibetica.

Four new furofurano lignans, lantibesides B - D ( 1 - 3) and lantibetin ( 4), along with nine known phenolic compounds were isolated from the EtOH extract of the traditional Tibetan medicinal plant, Lancea tibetica. By means of spectroscopic and chemical methods, the structures of the new compounds were elucidated as (1 R,2 S,5 R,6 S)-2-(3,4-methylenedioxyphenyl)-6-[(3-methoxy-4-beta- D-xylopyranosyloxy(1-->6)-beta- D-glucopyranosyloxy)phenyl]-3,7-dioxabicyclo[3.3.0]octane ( 1), (1 R,2 R,5 R,6 S)-2-(3,4-methylenedioxyphenyl)-6-[(3-methoxy-4-beta- D-xylopyranosyloxy(1-->6)-beta- D-glucopyranosyloxy)phenyl]-3,7-dioxabicyclo [3.3.0]octane ( 2), (1 R,2 R,5 R,6 S)-2-(3,4-methylenedioxyphenyl)-6-(3-methoxy-4-beta- D-glucopyranosyloxy)phenyl-3,7-dioxabicyclo[3.3.0]octane ( 3), and (1 R,2 R,5 R,6 S)-2-(3,4-dimethoxyphenyl)-6-(3,4-dihydroxyphenyl)-3,7-dioxabicyclo[3.3.0] octane ( 4). Compounds 2 and 3 showed weak cytotoxicity against the HL-60 cell line with IC (50) values of 61 and 99 microM, respectively.

[Observation on the transient analgesic effect of abdominal acupuncture TENS on pain of neck, shoulder, loin and legs].

OBJECTIVE: To observe on the transient analgesic effect of abdominal points transcutaneous electrical nerve stimulation (TENS) combined with abdominal acupuncture according to the holographic theory on pain of neck, shoulder, loin and legs. METHODS: One hundred and twenty cases of pain of neck, shoulder, loin and legs were randomly divided into 4 groups: abdominal acupuncture TENS group, acupoints TENS group, electroacupuneture (EA) group, non-abdominal acupuncture TENS group, 30 cases in each group. All the cases were treated by the same stimulation parameters, but different stimulation points. The VAS scores were recorded before and after treatment. RESULTS: The VAS scores were significantly different before and after treatment in abdominal acupuncture TENS group (P < 0.01); the total effective rate of the transient analgesic effec t was 96.7% in the abdominal acupuncture TENS group, 93.3% in the acupoints TENS group, 96.7% in the EA group with no significant difference among the 3 groups, but with a very significant difference between the abdominal acupuncture TENS group and the non-abdominal acupunctureTENS group (10.0%), P < 0.01. CONCLUSION: Abdominal acupuncture TENS has a better transient analgesic effect and can use less stimulation points to increase the analgesic effect.

Monoterpenoids and their glycosides from Winchia calophylla.

Three new monoterpenoid compounds have been isolated from extracts of the stem barks of Winchia calophylla A. DC. The new compounds include two cyclo-diglycosides, wincaloside A (2) and wincaloside B (3), and a derivative of tetrahydroxycyclohexane-carboxylic acid, winchiepoxide (1). Their structures have been elucidated by spectroscopic and chemical methods.

S-adenosylmethionine in treatment of cholestasis after total parenteral nutrition: laboratory investigation and clinical application.

OBJECTIVE: To observe the effects of S-adenosylmethionine (SAMe) in the treatment of cholestasis after total parenteral nutrition (TPN). METHODS: Thirty SD rats were randomly divided into control group, hypercalorie group, hypercalorie+SAMe group, sepsis group and sepsis+SAMe group to compare their states of cholestasis. Sixteen patients received SAMe because of cholestasis after prolonged TPN, and the therapeutic efficacy was observed. RESULTS: Bile flow was obviously decreased and the serum levels of total bile acid and gamma-glutamyl transpeptidase (gamma-G T) were markedly increased in the hypercalorie and sepsis groups. Meanwhile, hepatocyte fatty degeneration, dilatation of cholangioles, and bile sludge could be seen microscopically. SAMe administration in the hypercalorie+SAMe and sepsis+ SAMe groups could increase the bile flow, decrease the serum levels of total bile acid and gamma-G T, reduce the pathological damage to the liver, and clear the bile sludge in the cholangioles. Cholestasis and abnormal liver function were the main manifestations of the 16 patients before SAMe administration. After SAMe treatment for 3 weeks, serum levels of total bilirubin, alkaline phosphatase (AKP), gamma-G T, alanine amino transferase (ALT), and aspartate amino transferase (AST) were obviously decreased, and normalized in the 4th week. CONCLUSION: SAMe could prevent and treat cholestasis without discontinuation of TPN.