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Frontiers in Pharmacology 2024Ulcerative colitis (UC) is marked by recurring inflammation. Existing treatments are ineffective and may have toxic side effects. Thus, new therapeutic agents are...
INTRODUCTION
Ulcerative colitis (UC) is marked by recurring inflammation. Existing treatments are ineffective and may have toxic side effects. Thus, new therapeutic agents are urgently needed. We studied the botanical formula "Li-Hong Tang (LHT)", which contains two main ingredients, R. Br and (Hook. f. et Thoms.) H. Ohba. In this study, we aimed to identify the effects of LHT on UC and explore its potential mechanism.
METHODS
LHT was analyzed using a mass spectrometer (MS). DSS at a dose of 2.5% was utilized to develop UC in mice. The administered groups received low, medium, and high dosages (0.32 g/kg, 0.64 g/kg, and 1.28 g/kg) of LHT and the positive medication, sulfasalazine (0.2 g/kg), respectively. Body weight, disease activity index (DAI) score, colon length, spleen index, serum myeloperoxidase (MPO), nitric oxide (NO), superoxide dismutase (SOD) and inflammatory factor concentrations were monitored. The expression of NRF2 and HO-1 in colonic tissues was evaluated by immunohistochemistry. 16S rDNA sequencing was employed to investigate alterations in the gut microbiota of the mice, aiming to elucidate the extent of LHT's impact.
RESULTS
LHT may ameliorate DSS-induced colitis in mice by lowering inflammation, reducing oxidative stress, restoring the intestinal barrier, and influencing the NRF2/HO-1 pathway. Moreover, LHT treatment exhibited a regulatory effect on the gut microbiota, characterized by elevated levels of Patescibacteria, Verrucomicrobiota, , , and levels while decreasing and r levels. Further study indicated that MPO, NO, and inflammatory factors were positively correlated with , , , , and negatively with , , and Patescibacteria. Furthermore, colony network analysis revealed that was negatively associated with and , whereas was positively related to .
CONCLUSION
LHT protects against DSS-induced mice by inhibiting the inflammatory response, oxidative stress, and mucosal injury. The protective role may involve regulating the NRF2/HO-1 signaling pathway and gut microbiota.
PubMed: 38873425
DOI: 10.3389/fphar.2024.1413666 -
Biomedicine & Pharmacotherapy =... Jun 2024Berberine (BBR) is a compound derived from Chinese herbal medicine, known for its anticancer properties through multiple signaling pathways. However, whether BBR can...
Berberine (BBR) is a compound derived from Chinese herbal medicine, known for its anticancer properties through multiple signaling pathways. However, whether BBR can inhibit tumor growth by participating in ferroptosis remains unconfirmed. In this study, we demonstrated that berberine synergistically inhibited NSCLC in combination with multiple ferroptosis inducers, and this combination synergistically down-regulated the mRNA and protein expression of SLC7A11, GPX4, and NRF2, resulting in ferroptosis accompanied by significant depletion of GSH, and aberrant accumulation of reactive oxygen species and malondialdehyde. In a lung cancer allograft model, the combination treatment exhibited enhanced anticancer effects compared to using either drug alone. Notably, p53 is critical in determining the ferroptosis sensitivity. We found that the combination treatment did not elicit a synergistic anticancer effect in cells with a p53 mutation or with exogenous expression of mutant p53. These findings provide insight into the mechanism by which combination induces ferroptosis and the regulatory role of p53 in this process. It may guide the development of new strategies for treating NSCLC, offering great medical potential for personal diagnosis and treatment.
PubMed: 38850659
DOI: 10.1016/j.biopha.2024.116832 -
Therapeutic Advances in Musculoskeletal... 2024The aim of the Severe Psoriatic arthritis - Early intervEntion to control Disease trial is to compare outcomes in psoriatic arthritis (PsA) patients with poor prognostic...
The protocol of a clinical effectiveness trial comparing standard step-up care, early combination DMARD therapy and early use of TNF inhibitors for the treatment of moderate to severe psoriatic arthritis: the 3-arm parallel group SPEED randomized controlled trial.
OBJECTIVES
The aim of the Severe Psoriatic arthritis - Early intervEntion to control Disease trial is to compare outcomes in psoriatic arthritis (PsA) patients with poor prognostic factors treated with standard step-up conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), combination csDMARDs or a course of early biologics.
DESIGN
This multicentre UK trial was embedded within the MONITOR-PsA cohort, which uses a trial within cohort design.
METHODS AND ANALYSIS
Patients with newly diagnosed PsA and at least one poor prognostic factor (polyarthritis, C-reactive protein >5 mg/dL, health assessment questionnaire >1, radiographic erosions) were randomized equally and open-label to either standard care with 'step-up' csDMARD therapy, initial therapy with combination csDMARDs (methotrexate with either sulfasalazine or leflunomide) or to early biologics induction therapy (adalimumab plus methotrexate). The primary outcome is the PsA disease activity score at week 24.
ETHICS
Ethical approval for the study was granted by the South Central Research Ethics Committee (ref 18/SC/0107).
DISCUSSION
Treatment recommendations for PsA suggest more intensive therapy for those with poor prognostic factors but there are no studies that have previously used prognostic factors to guide therapy. Applying initial intensive therapy has shown improved outcomes in other inflammatory arthritides but has never been tried in PsA. Combination csDMARDs have shown some superiority over single therapies but there are limited data and concerns about side effects. Early use of biologics has also been shown to be superior to methotrexate but these drugs are costly and not usually funded first line. However, if a short course of biologics can rapidly suppress inflammation allowing treatment to be withdrawn and response maintained on methotrexate, this may be a cost-effective model for early use.
TRIAL REGISTRATION
ClinicalTrials.gov (NCT03739853) and EudraCT (2017-004542-24).
PubMed: 38826570
DOI: 10.1177/1759720X241240913 -
Clinical and Experimental... 2024Inflammatory bowel disease (IBD) affects young adults of reproductive age, and questions related to pregnancy and breastfeeding are common in clinical practice. Most...
BACKGROUND
Inflammatory bowel disease (IBD) affects young adults of reproductive age, and questions related to pregnancy and breastfeeding are common in clinical practice. Most medications used to treat IBD are considered safe during pregnancy, except methotrexate and small molecules such as tofacitinib. Despite few studies regarding vedolizumab (VDZ) safety, it appears to be safe during pregnancy. Therefore, this study aimed to report the management of ulcerative colitis in pregnant patient refractory to anti-tumor necrosis factor (TNF) agents using VDZ.
CASE REPORT
A female, 38 years old, with ulcerative colitis was refractory to conventional treatment with mesalazine, sulfasalazine, and azathioprine. She was hospitalized at six weeks of gestation with severe acute colitis requiring the use of infliximab (IFX) to induce remission. She had a spontaneous abortion at nine weeks of gestation after the second dose of IFX. Since there was no endoscopic improvement after six months of IFX treatment, VDZ treatment was initiated. During the VDZ infusion period, the patient discovered that she was pregnant with twins, leading to the discussion of the risks and benefits of continuing the VDZ. The patient presented with disease clinical remission with the use of VDZ, and the babies were born at 34 weeks of gestation without complications. Breastfeeding was also performed without complications.
CONCLUSION
Continued VDZ medication is safe during pregnancy and breastfeeding, with adverse events similar to anti-TNF therapy.
PubMed: 38799766
DOI: 10.2147/CEG.S457256 -
Archives of Biochemistry and Biophysics Jul 2024Drug metabolism by human gut microbes is often exemplified by azo bond reduction in the anticolitic prodrug sulfasalazine. Azoreductase activity is often found in...
Drug metabolism by human gut microbes is often exemplified by azo bond reduction in the anticolitic prodrug sulfasalazine. Azoreductase activity is often found in incubations with cell cultures or ex vivo gut microbiome samples and contributes to the xenobiotic metabolism of drugs and food additives. Applying metagenomic studies to personalized medicine requires knowledge of the genes responsible for sulfasalazine and other drug metabolism, and candidate genes and proteins for drug modifications are understudied. A representative gut-abundant azoreductase from Anaerotignum lactatifermentan DSM 14214 efficiently reduces sulfasalazine and another drug, phenazopyridine, but could not reduce all azo-bonded drugs in this class. We used enzyme kinetics to characterize this enzyme for its NADH-dependent reduction of these drugs and food additives and performed computational docking to provide the groundwork for understanding substrate specificity in this family. We performed an analysis of the Flavodoxin-like fold InterPro family (IPR003680) by computing a sequence similarity network to classify distinct subgroups of the family and then performed chemically-guided functional profiling to identify proteins that are abundant in the NIH Human Microbiome Project dataset. This strategy aims to reduce the number of unique azoreductases needed to characterize one protein family in the diverse set of potential drug- and dye-modifying activities found in the human gut microbiome.
Topics: Humans; Nitroreductases; Gastrointestinal Microbiome; NADH, NADPH Oxidoreductases; Coloring Agents; Molecular Docking Simulation; Substrate Specificity; Sulfasalazine; Bacterial Proteins; Kinetics; Clostridiales; Azo Compounds
PubMed: 38740275
DOI: 10.1016/j.abb.2024.110025 -
Pediatric Rheumatology Online Journal May 2024Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used... (Randomized Controlled Trial)
Randomized Controlled Trial
Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis: does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial.
BACKGROUND
Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial.
METHODS
92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m/week.
RESULTS
32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4-10), median 10 months (7-16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6-9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group.
CONCLUSIONS
Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety.
TRIAL REGISTRATION
Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585 .
Topics: Humans; Arthritis, Juvenile; Etanercept; Female; Male; Child; Antirheumatic Agents; Methotrexate; Drug Therapy, Combination; Child, Preschool; Dose-Response Relationship, Drug; Treatment Outcome; Prednisolone; Sulfasalazine
PubMed: 38730442
DOI: 10.1186/s12969-024-00989-x -
Journal of Neuroinflammation May 2024Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated...
BACKGROUND
Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity in patient management is largely attributed to an incomplete understanding of the underlying pathological mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent inflammation and heightened excitatory transmission within pain pathways, stands as a significant contributor to persistent pain. Considering the role of the cystine/glutamate exchanger (also designated as system x) in modulating glutamate transmission and in supporting neuroinflammatory responses, we investigated the contribution of this exchanger in the development of neuropathic pain.
METHODS
We examined the implication of system x by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system x (using mice lacking the system x specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers.
RESULTS
The sciatic nerve lesion was found to upregulate system x at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system x had an analgesic effect in lesioned mice.
CONCLUSION
Together, these observations provide evidence for a role of system x in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system x. These findings suggest that drugs targeting system x could contribute to prevent or reduce neuropathic pain.
Topics: Animals; Mice; Neuralgia; Neuroinflammatory Diseases; Mice, Inbred C57BL; Male; Spinal Cord; Amino Acid Transport System y+; Disease Models, Animal; Mice, Knockout; Sulfasalazine; Hyperalgesia; Mice, Transgenic
PubMed: 38715127
DOI: 10.1186/s12974-024-03112-9 -
Biomedicine & Pharmacotherapy =... Jun 2024Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes...
Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes ameliorates clinical symptoms and morphological manifestations of IBD. Herein, we examined the roles of NLRP3 activation in IBD and modulation of NLRP3 by sulforaphane (SFN), a compound with multiple pharmacological activities that is extracted from cruciferous plants. To simulate human IBD, we established a mouse colitis model by administering dextran sodium sulfate in the drinking water. SFN (25, 50 mg·kg·d, ig) or the positive control sulfasalazine (500 mg/kg, ig) was administered to colitis-affected mice for 7 days. Model mice displayed pathological alterations in colon tissue as well as classic symptoms of colitis beyond substantial tissue inflammation. Expression of NLRP3, ASC, and caspase-1 was significantly elevated in the colonic epithelium. The expression of NLRP3 inflammasomes led to activation of downstream proteins and increases in the cytokines IL-18 and IL-1β. SFN administration either fully or partially reversed these changes, thus restoring IL-18 and IL-1β, substantially inhibiting NLRP3 activation, and decreasing inflammation. SFN alleviated the inflammation induced by LPS and NLRP3 agonists in RAW264.7 cells by decreasing the levels of reactive oxygen species. In summary, our results revealed the pathological roles of oxidative stress and NLRP3 in colitis, and indicated that SFN might serve as a natural NLRP3 inhibitor, thereby providing a new strategy for alternative colitis treatment.
Topics: Animals; Isothiocyanates; NLR Family, Pyrin Domain-Containing 3 Protein; Sulfoxides; Oxidative Stress; Colitis, Ulcerative; Inflammasomes; Disease Models, Animal; Mice; Mice, Inbred C57BL; Male; Dextran Sulfate; Colon; RAW 264.7 Cells
PubMed: 38713944
DOI: 10.1016/j.biopha.2024.116706 -
Clinical Case Reports May 2024This case demonstrated the complex pathophysiology of DRESS syndrome presenting with latent human herpes virus infection reactivation due to exposure to sulfasalazine...
This case demonstrated the complex pathophysiology of DRESS syndrome presenting with latent human herpes virus infection reactivation due to exposure to sulfasalazine and/or hydroxychloroquine. Patients who do not initially fulfill the diagnostic criteria on admission may evolve and eventually fulfill the criteria. Steroid dose tapering is required to prevent flaring.
PubMed: 38711841
DOI: 10.1002/ccr3.8905 -
Frontiers in Immunology 2024Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is characterized by a widespread maculopapular rash, lymphadenopathy, fever, and multisystem involvement....
Sulfasalazine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) coinfected with COVID-19 complicated by hemophagocytic lymphohistiocytosis: a case report.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is characterized by a widespread maculopapular rash, lymphadenopathy, fever, and multisystem involvement. Conversely, hemophagocytic lymphohistiocytosis (HLH) is an infrequent yet critical condition presenting with fever, hepatosplenomegaly, cytopenias, coagulation abnormalities, and elevated inflammatory markers. The overlapping clinical and laboratory features between DRESS and HLH poses a significant diagnostic challenge. Secondary HLH (sHLH) typically occurs in adults triggered by viral infections, malignancies, rheumatologic diseases, or immune deficiencies. Recently, COVID-19 has also been identified as one of the triggers for sHLH. Herein, we present a case of Sulfasalazine-induced DRESS coinfected with COVID-19 that subsequently progressed into HLH. Our patient exhibited common hepatorenal and splenic involvement along with rare cholecystitis and appendicitis. However, a significant improvement was observed upon the addition of etoposide and azathioprine. We hypothesize that excessive activation of the immune system and cytokine storm due to DRESS combined with COVID-19 infection led to more extensive systemic damage resulting in HLH development. This highlights the potential for severe consequences when DRESS coincides with HLH during a COVID-19 infection.
Topics: Humans; Lymphohistiocytosis, Hemophagocytic; COVID-19; Drug Hypersensitivity Syndrome; Sulfasalazine; SARS-CoV-2; Coinfection; Male; Middle Aged; Female
PubMed: 38686382
DOI: 10.3389/fimmu.2024.1371490