New approach of medicinal herbs and sulfasalazine mixture on ulcerative colitis induced by dextran sodium sulfate

BACKGROUND Sulfasalazine has been used as a standard-of-care in ulcerative colitis for decades,however,it results in severe adverse symptoms,such as hepatotoxicity,blood disorders,male infertility,and hypospermia.Accordingly,the new treatment strategy has to enhance pharmacological efficacy and stimultaneously minimize side effects.AIM To compare the anti-inflammatory action of sulfasalazine alone or in combination with herbal medicine for ulcerative colitis in a dextran sodium sulfate(DSS)-induced colitis mouse model.METHODS To induce ulcerative colitis,mice received 5%DSS in drinking water for 7 d.Animals were divided into five groups(n=9 each)for use as normal(non-DSS),DSS controls,DSS+sulfasalazine(30 mg/kg)-treatment experimentals,DSS+sulfasalazine(60 mg/kg)-treatment experimentals,DSS+sulfasalazine(30 mg/kg)+Citrus unshiu peel and Bupleuri radix mixture(30 mg/kg)(SCPB)-treatment experimentals.RESULTS The SCPB treatment showed an outstanding effectiveness in counteracting the ulcerative colitis,as evidenced by reduction in body weight,improvement in crypt morphology,increase in antioxidant defenses,down-regulation of proinflammatory proteins and cytokines,and inhibition of proteins related to apoptosis.CONCLUSIONSCPB may represent a promising alternative therapeutic against ulcerative colitis,without inducing adverse effects.

Effects of 5-fluouracil combined with sulfasalazine on human pancreatic carcinoma cell line BxPC-3 proliferation and apoptosis in vitro

BACKGROUND:Most pancreatic carcinomas are clinically insensitive to chemotherapeutics.The exact mechanisms of their apoptosis and multiple drug resistance are obscure at present.This study was undertaken to explore the influence of chemotherapy on anti-proliferation,apoptosis and the cell cycle,and lay a fundamental basis for further research into the apoptotic mechanisms and prevention of multiple drug resistance in pancreatic carcinoma. METHODS:The human pancreatic carcinoma cell line BxPC-3 was cultured in vitro.The growth inhibition rate,cell cycle and apoptotic rate of cells treated with 5-fluorouracil（5-FU）,sulfasalazine alone or a combination at different concentrations were evaluated with the MTT method and flow cytometry.Phase-contrast microscopy was used to observe morphological changes in the cells treated with 5-FU,sulfasalazine or both for 24 hours. RESULTS:The growth inhibition rate of the BxPC-3 cells treated with 5-FU and sulfasalazine significantly increased in a time-and dose-dependent manner.The growth inhibition rate of the cells treated with 5-FU gradually increased,but decreased at different concentrations of sulfasalazine for a prolonged period.The apoptotic rate of the BxPC-3 cells induced by sulfasalazine（200 mg/L）, 5-FU（100 mg/L）or both for 12 hours were（2.68±0.36）%, （6.59±0.90）%,and（10.52±0.55）%,respectively,compared with the corresponding control values were（3.17±0.08）%, （1.50±0.06）%,and（4.08±0.31）%[(t=2.33（P】0.05）,9.78 and 17.56（P【0.01）].It increased to（7.63±0.68）%,（40.43± 1.79）%,and（64.69±0.82）%for 48 hours,in comparison with the control that was（29.20±2.18）%,（5.61±0.13）%,and（12.02±0.52）%[t=17.06,33.66 and 94.51（P【0.01）]. The apoptotic rate,proportion of cells in S-phase and proliferative index rose after use of 5-FU（12.5,25,50,75, and 100 mg/L）alone for 24 hours.However,the apoptotic rate at augmented concentrations of sulfasalazine for 24 hours slowly increased from（1.47±0.08）%to（3.45± 0.28）%,the proportion of cells in G0/G1-phase increased from（35.13±0.32）%to（54.32±1.45）%,the proportion of cells in S-phase decreased from（45.37±1.48）%to（16.67± 2.73）%,and the proliferative index gradually lowered.The proportion of G0/G1-phase cells treated by 5-FU（100 mg/L） and sulfasalazine（200 mg/L）increased from（43.31±1.52）% （12 hours）to（85.05±0.24）%（48 hours）compared with the corresponding controls[t=7.93（12 hours）,21.30（48 hours）,P【0.01],and the proportion of cells in S-phase decreased from（11.63±1.11）%（12 hours）to（4.47±0.68）% （48 hours）in contrast to the controls[t=37.68（12 hours）, 8.60（48 hours）,P【0.01].Most cells after the combined use of the two agents for 24 hours displayed pyknosis and oval shape by phase-contrast microscopy.The cells treated with 5-FU（100 mg/L）for 24 hours were pyknotic and oval shaped.A few of cells in the group treated with sulfasalazine（200 mg/L）were pyknotic at 24 hours. CONCLUSIONS:Sulfasalazine may enhance the inhibitory proliferation and apoptosis effect on BxPC-3 cells induced by 5-FU,which is closely related to synergistically the cell cycle arrested in G0/G1-phase.

Current medical therapy of inflammatory bowel disease

INTRODUCTIONThe 1990’s have brought a significant promise and the hopefor a better and brighter future in the new millennium forpatients with inflammatory bowel disease(IBD).A betterunderstanding of the pathophysiology of IBD symptoms hasled to newer treatment modalities and streamlining oftherapy for specific subsets of patients.

Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review

BACKGROUND Despite the advent of biological drugs, conventional therapy continues to be used in moderate to severe inflammatory bowel disease(MS-IBD). This study hypothesized that as a standard of treatment and the primary alternative to biologics, conventional therapy should present robust effectiveness results in IBD outcomes.AIM To investigate the effectiveness of conventional therapy for MS-IBD.METHODS A systematic review with no time limit was conducted in July 2017 through the Cochrane Collaboration, MEDLINE, and LILACS databases. The inclusion criteria encompassed meta-analyses, systematic reviews, randomized clinical trials, observational and case-control studies concerning conventional therapy in adult patients with MS-IBD, including Crohn's disease(CD) and ulcerative colitis(UC). Corticosteroids(prednisone, hydrocortisone, budesonide, prednisolone,dexamethasone), 5-aminosalicylic acid(5-ASA) derivatives(mesalazine and sulfasalazine) and immunosuppressants [azathioprine(AZA), methotrexate(MTX), mycophenolate, cyclosporine, tacrolimus, 6-mercaptopurine(6-MP)] were considered conventional therapy. The exclusion criteria were sample size below50; narrative reviews; specific subpopulations(e.g., pregnant women,comorbidities); studies on postoperative IBD; and languages other than English,Spanish, French or Portuguese. The primary outcome measures were clinical remission(induction or maintenance), clinical response and mucosal healing. As secondary outcomes, fecal calprotectin, hospitalization, death, and surgeries were analyzed. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation criteria.RESULTS The search strategy identified 1995 citations, of which 27 were considered eligible(7 meta-analyses, 20 individual studies). For induction of clinical remission, four meta-analyses were selected(AZA and 6-MP showed no advantage over placebo,MTX or 5-ASA in CD; MTX showed no statistically significant difference versus placebo, 6-MP, or 5-ASA in UC; tacrolimus was superior to placebo for UC in two meta-analyses). Only one meta-analysis evaluated clinical remission maintenance, showing no statistically significant difference between MTX and placebo, 5-ASA, or 6-MP in UC. AZA and 6-MP had no advantage over placebo in induction of clinical response in CD. Three meta-analyses showed the superiority of tacrolimus vs placebo for induction of clinical response in UC. The clinical response rates for cyclosporine were 41.7% in randomized controlled trials(RCTs) and 55.4% in non-RCTs for UC. For induction of mucosal healing,one meta-analysis showed a favorable rate with tacrolimus versus placebo for UC. For secondary outcomes, no meta-analyses specifically evaluated fecal calprotectin, hospitalization or death. Two meta-analyses were retrieved evaluating colectomy rates for tacrolimus and cyclosporine in UC. Most of the twenty individual studies retrieved contained a low or very low quality of evidence.CONCLUSION High-quality evidence assessing conventional therapy in MS-IBD treatment is scarce, especially for remission maintenance, mucosal healing and fecal calprotectin.

Is non-biological treatment of rheumatoid arthritis as good as biologics?

The management of rheumatoid arthritis(RA) in the past three decades has undergone a paradigm shift from symptomatic relief to a "treat-to-target" approach. This has been possible through use of various conventional and biologic disease modifying anti-rheumatic drugs(DMARDs) which target disease pathogenesis at a molecular level. Cost and infection risk preclude regular use of biologics in resource-constrained settings. In therecent years, evidence has emerged that combination therapy with conventional DMARDs is not inferior to biologics in the management of RA and is a feasible cost-effective option.

Probiotic Medilac-S^(█) for the induction of clinical remission in a Chinese population with ulcerative colitis: A systematic review and meta-analysis

AIM To assess the effects of probiotic Medilac-S~ as adjunctive therapy for the induction of remission of ulcerative colitis(UC) in a Chinese population through a systematic review and meta-analysis. METHODS A systematic literature search was conducted to find randomized, controlled trials in a Chinese population with at least two study arms-a control arm which receives a conventional, oral aminosalicylate drug, and a treatment arm, which administers the same conventional drug in conjunction with the probiotic Medilac-S~ per os. Both English and Chinese databases were searched, including Pub Med, EMBASE, Google Scholar, Chinese National Knowledge Infrastructure, Wanfang Data, and VIP Search, and study data was extracted onto standardized abstraction sheets. Meta-analyses were conducted for primary and secondary outcomes of interest using a fixed or random effects model. The primary outcome was the induction of clinical remission and the secondary outcomes included changes in Sutherland index, endoscopic and histological scores, proportion of reported clinical symptoms and adverse events(AEs). For outcomes with sufficient data, the type of conventional drug therapy was also assessed to determine if the effects of combination therapy with Medilac-S~ was influenced by drug type. All tests were conducted using a type Ⅰ error rate of 0.05 and all confidence intervals(CI) were based on a 95% confidence level. Review protocol was uploaded to PROSPERO(CRD42018085658 upon completion).RESULTS Fifty-three clinical trials with a total of 3984 participants were identified and included in the review. Medilac-S~ adjunctive therapy significantly improved induction of clinical remission(RR = 1.21; 95%CI: 1.18-1.24; P < 0.0001) with the estimated likelihood of effective treatment, on average, 21% higher for those consuming the probiotic. Sutherland index scores showed the control mean was on average 3.10(CI: 2.41-3.78; P = 0.0428) units greater than the treatment mean, thereby demonstrating significant improvement in participants taking the probiotic. Similarly, a significant difference was seen between the overall reduction of endoscopic and histological scores of control and treatment arm participants, with score decreases in the control groups 0.71(CI: 0.3537-1.0742) and 1.1(CI: 0.9189-1.2300) units smaller than treatment group score decreases. The proportion of participants reporting clinical symptoms,(abdominal pain, tenesmus, blood and mucous in stool, and diarrhea) was significantly reduced after combination therapy with Medilac-S~(P < 0.0001) and estimated to be on average 44%(RR = 0.44, CI: 0.32-0.59), 53%(RR = 0.53, CI: 0.38-74), 40%(RR = 0.40, CI: 0.28-0.58) and 47%(RR = 0.47 CI: 0.36-0.42) respectively, of the proportion of individuals reporting the aforementioned symptoms after conventional therapy alone. The risk of AEs was also significantly reduced with adjunctive Medilac-S~ therapy. The proportion of individuals in the treatment groups reporting AEs was an estimated 72% of the proportion of individuals in the control groups reporting AEs(RR = 0.72, CI: 0.55-0.94, P = 0.0175). Upon comparing effect means for different drug types in conjunction with Medilac-S~, evidence of significant variability(P < 0.0001) was observed, and sulfasalazine was found to be the most effective drug in both primary and secondary outcomes. CONCLUSION Evidence suggests Medilac-S~ adjunctive therapy should be considered standard care for UC in a Chinese population because it aids in the induction of clinical remission, improves symptoms of the gastrointestinal tract and reduces risk of AEs.

Ferruginol alleviates inflammation in dextran sulfate sodium-induced colitis in mice through inhibiting COX-2, MMP-9 and NF-κB signaling

Objective:To assess the anti-inflammatory efficacy of ferruginol on dextran sulfate sodium(DSS)stimulated ulcerative colitis mice.Methods:Ulcerative colitis was induced in C57 BL/6 J mice by administering 2%of DSS through drinking water for 7 d.The mice in the treatment group were treated with DAA+50 mg/kg/day ferruginol orally.In the positive control group,sulfasalazine(50 mg/kg/day)was used alongside with DSS.After induction,the bodyweight,character of stool and feces occult blood were recorded daily,the disease activity index was calculated,and the colon length,colon weight,and spleen weight were recorded.The myeloperoxidase activity was assayed by spectrophotometry.Interleukin(IL)-6,IL-1β,and tumor necrosis factor-αwere determined by ELISA method,and nuclear factor-κB,cyclooxygenase-2,matrix metalloproteinases-9,and inducible nitric oxide synthase by Western blotting assays.Results:Ferruginol significantly increased the bodyweight,colon weight,colon length,and decreased disease activity index and spleen weight.It exhibited anti-inflammatory activity against DSS induced ulcerative colitis in mice by reducing the activities of myeloperoxidase,tumor necrosis factor-α,nuclear factor-κB,IL-1β,cyclooxygenase-2,matrix metalloproteinases-9,IL-6,and inducible nitric oxide synthase.Conclusions:Ferruginol could be used to treat ulcerative colitis by attenuating the inflammation in colon cells and maintaining colonic mucosal barrier integrity.

Expression of fibronectin and MMP-3 and its significance in the patients with ankylosing spondylitis

Objective: To observe the expression and significance of fibronectin and metalloproteinase-3(MMP-3) in patients with ankylosing spondylitis(AS). Methods: A total of 30 AS patients in our hospital and 30 healthy volunteers were selected in our study. Fibronectin and MMP-3 were measured and compared between these two groups. The AS group received sulfasalazine2 g daily for 3 months. Bath ankylosing spondylitis disease activity index, bath ankylosing spondylitis functional index, bath ankylosing spondylitis metrology index, erythrocyte sedimentation rate and C-reactive protein were compared before and after treatment.Pearson's linear-correlation analysis was used to determine relationships between parameters.Results: Totally 28 patients in the AS group completed the study. Fibronectin and MMP-3 in peripheral blood of AS patients were evidently higher than that in the normal control group(P<0.05). After treated by sulfasalazine, the level of expressing Fibronectin and MMP-3 significantly decreased compared with baseline values(P<0.05). Pearson's linear-correlation analysis showed that serum fibronectin and MMP-3 level had a positive correlation with bath ankylosing spondylitis disease activity index global assessment, spine pain, night pain, general pain, erythrocyte sedimentation rate and C-reactive protein(P<0.05). Conclusions: The expression of fibronectin and MMP-3 in AS patients were significantly higher than that in the normal control group, and they all decreased significantly after treatment. It indicated that both fibronectin and MMP-3 were correlated closely with the onset of AS.

Psoriasis treatment: Unconventional and non-standard modalities in the era of biologics

Psoriasis is a potentially debilitating inflammatory dermatosis affecting 0.2%-4.8% of the population worldwide causing a significant occupational, personal or psychosocial morbidity to these patients for life. The basic aim of psoriasis therapy is to control the disease to maximum possible extent and improve the patient's quality of life. Management of triggers for flareups, lifestyle modifications, and dietary supplements are often recommended. Intermittent or rotational therapy with frequent alterations in treatment options is usually needed to reduce toxicity of anti-psoriatic drugs in the absence of safer alternatives. Currently, several biological agents categorized as either T-cell targeted(e.g., Alefacept, Efalizumab) or cytokine modulating(e.g., Adalimumab, Infliximab, Etanercept) are available for treating severe psoriasis. However, their high cost is often precluding for most patients. The usefulness of systemic(methotrexate, cyclosporine, acitretin or several other therapeutic agents) or topical(tar, anthralin, corticosteroids or calcipotriol ointments, phototherapy with or without psoralens) therapies has been well established for the management of psoriasis. The literature is also replete with benefits of less used non-standard and unconventional treatment modalities(hydroxycarbamide, azathioprine, leflunomide, mycophenolate mofetil, isotretinoin, fumarates, topical calcineurin inhibitors, peroxisome proliferator-activated receptors agonists, statins, sulfasalazine, pentoxifylline, colchicine, grenz ray therapy, excimer laser, climatotherapy and balneophototherapy, peritoneal dialysis, tonsillectomy, ichthyotherapy, etc.). These can be used alternatively to treat psoriasis patients who have mild/minimal lesions, are intolerant to conventional drugs, have developed side effects or achieved recommended cumulative dose, where comorbidities pose unusual therapeutic challenges, or may be as intermittent, rotational or combination treatment alternatives.

Expression of C-Terminal Modified Serine Palmitoyltransferase-1 Alters Chemosensitivity of Inflammation-Associated Human Cancer Cell Lines

Background: The human serine palmitoyltransferase-1, SPTLC1, subunit is emerging as a stress responsive protein with putative role in modulating cellular stress response behavior. When compared to the parental cell line, recombinant Glioma cells expressing C-terminal modified SPTLC1 are found to show resistance to the cytotoxic effect of polycyclic hydrocarbons, PHs, including the environmental contaminant 3-methylcholanthrene. This novel functional association of SPTLC1 expression with proliferative capacity is thought to be due, in part, to its ability for crosstalk with protein regulators of different biological processes. Whether the effect of SPTLC1 on sensitivity to PHs extends to therapeutic drugs and the progression of the malignant phenotype is of research interest. Methods: In the current study, sub-cellular localization was by immunostaining for SPTLC1 in untreated and chemical treated cells and detection with confocal microscopy. The effect expressing C-terminal modified SPTLC1, in cancer cell lines of the inflammation-associated type, has on chemosensitivity and gene expression was also assessed. Parent Glioma LN18 and SKN-SH cells and their SPTLC1 recombinants were each treated with Glutamate, an excitatory neurotransmitter that can participate in both neuronal and excitotoxic signaling. In addition to the Glioma and SKN-SH cells, the PC3 prostate cancer and 647V bladder cancer cell lines were also treated with Celecoxib, a potent inhibitor of cyclooxygenase 2, COX-2, and an anti-inflammatory drug recently found to have anti-neoplastic activity against several malignancies. Results: Confocal microscopy revealed that Celecoxib mediates both rapid and enhanced redistribution of SPTLC1 and COX-2, to focal adhesion sites. In cell viability assay, SPTLC1 recombinant cells exhibited differential but dose-dependent resistance to excitotoxic levels of Glutamate. Drug co-treatment with a non-lethal dose of the potent kinase inhibitor, Sulfasalazine, increased the anti-proliferation effect of Celecoxib in a dose-dependent manner for all the cell lines tested. Conclusions: The effect of SPTLC1 expression on cellular chemosensitivity seen in the present study further highlights possible role of a C-terminal modified SPTLC1 variant in the biologic modulation of cellular behavior in response to therapeutic anticancer drugs.

Clinical features and management of Crohn' s disease in Chinese patients

Background An increasing incidence of Crohn' s disease has been found in China in recent years. Our study has been focused on evaluating the diversity of the clinical manifestations of Crohn' s disease in order to improve early diagnostic accuracy and therapeutic efficacy.Methods Thirty patients with active Crohn's disease were enrolled and their clinical data, including diagnostic and therapeutic results, were analyzed. Endoscopy combined with histological examination of biopsy specimens provided characteristic features of the disease. Transabdominal bowel sonography (TABS) was used for detecting intestinal complications. Nutritional supportive therapy was given to 20 subjects with active cases of the disease.Results Most patients were young adults with a higher proportion of females to males (ratio: 1.14: 1). The disease affects any segment or a combination of segments along with the alimentary tract (from the mouth to the anus). In this study, the colon and small bowel were the major sites involved. Recurrent episodes of abdominal pain in the right lower quadrant and watery diarrhea were the most common symptoms. Granulomas were identifiable in nearly one-third (30.8%) of all biopsy specimens. In moderate cases of the disease, remission was achieved more quickly through the use of oral prednisone therapy than with SASP or 5-ASA. Beneficial effects on the host's nutritional status were observed. Immunosuppressives were used on an individual basis and showed variable therapeutic effects. Sixteen patients had surgery due to intestinal obstruction or failure to respond to drug therapies. Rapid improvement after surgery was reported.Conclusion Endoscopy (with biopsy) and TABS were both crucial procedures for diagnosis. SASP (or 5-ASA) and prednisone were effective as inductive therapies. Azathioprine has demonstrable benefits after induction therapy with prednisone. Surgery, as an alternative treatment, provided another effective choice in selected patients.

Therapeutic Observation on Heat-sensitive Moxibustion plus Acupoint Injection for Ankylosing Spondylitis

Objective: To observe the clinical efficacy of heat-sensitive moxibustion plus acupoint injection in treating ankylosing spondylitis (AS). Methods: Totally 116 subjects with AS were randomized into a treatment group and a control group, 58 each. The treatment group was intervened by heat-sensitive moxibustion plus acupoint injection, and the control was by oral medication. Therapeutic efficacy was evaluated after 3 treatment courses. Results: The markedly effective rate was 38.9% and the total effective rate was 96.6% in the treatment group versus 11.9% and 67.8% in the control group. The markedly effective rate and total effective rate in the treatment group were significantly higher than those in the control group (P<0.05). Conclusion: Heat-sensitive moxibustion combining with acupoint injection has better therapeutic efficacy than oral medication in treating AS, and it's easy-to-operate without adverse reactions.

The Efficacy and Safety of Jitongning Capsule(脊痛宁胶囊) in Patients with Ankylosing Spondylitis

Objective： To confirm the efficacy and safety of Jitongning Capsule （脊痛宁胶囊） in the treatment of ankylosing spondylitis （AS）. Methods： A total of 120 AS patients with early-intermediate were randomly and equally assigned to Jitongning Capsule group and sulfasalazine group. Jitongning Capsule was orally taken 4.5 g per day and sulfasalazine was orally taken 2 g daily for 12 months. The primary endpoint was the proportion of patients achieving the Assessment in Ank＇ylosing Spondylitis 20 （ASAS 20）, secondary end points included Bath Ankylosing Spondylitis Disease Activity Index （BASDAI）, Bath Ankylosing Spondylitis Functional Index （BASFI）, Bath Ankylosing Spondylitis Metrology Index （BASMI）, patient＇s global assessment by VAS rating, spinal pain, general pain and night pain, erythrocyte sedimentation rate （ESR） and C-reactive protein （CRP）. Tumor necrosis factor-α （TNF-α）, interferen- γ （IFN-γ） and interleukin-4 （IL-4） in the peripheral blood mononuclear cells （PBMC） of AS patients were measured. Results： A total of 111 patients completed the study. There were 58 patients in Jitongning group and 53 patients in suffasalazine group. Both drugs showed mild and occasional side effects. After treated by Jitongning Capsule and sulfasalazine, the proportion of ASAS20 responders at 12 month was 72.41% （42/58） and 67.92% （36/53） respectively. Both Jitongning Capsule and sulfasalazine treatment induced significant decrease in the proportion of CD4＋-F cell and CD8＋T cell expressing TNF-γ and IFN-γ at 12-month of treatment compared with baseline values （P〈0.05）. Conclusion： Jitongning Capsule are effective in a setting close to real-life medical care with a sustained improvement in signs and symptoms of AS, and reduce cytokine levels in PBMC, It showed comparable effects to sulfasalazine.