Risk-stratified monitoring for sulfasalazine toxicity: prognostic model development and validation.

BACKGROUND: Sulfasalazine-induced cytopenia, nephrotoxicity and hepatotoxicity is uncommon during long-term treatment. Some guidelines recommend 3 monthly monitoring blood tests indefinitely during long-term treatment while others recommend stopping monitoring after 1 year. To rationalise monitoring, we developed and validated a prognostic model for clinically significant blood, liver or kidney toxicity during established sulfasalazine treatment. DESIGN: Retrospective cohort study. SETTING: UK primary care. Data from Clinical Practice Research Datalink Gold and Aurum formed independent development and validation cohorts. PARTICIPANTS: Age ≥18 years, new diagnosis of an inflammatory condition and sulfasalazine prescription. STUDY PERIOD: 1 January 2007 to 31 December 2019. OUTCOME: Sulfasalazine discontinuation with abnormal monitoring blood-test result. ANALYSIS: Patients were followed up from 6 months after first primary care prescription to the earliest of outcome, drug discontinuation, death, 5 years or 31 December 2019. Penalised Cox regression was performed to develop the risk equation. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination. RESULTS: 8936 participants were included in the development cohort (473 events, 23 299 person-years) and 5203 participants were included in the validation cohort (280 events, 12 867 person-years). Nine candidate predictors were included. The optimism adjusted R2 D and Royston D statistic in the development data were 0.13 and 0.79, respectively. The calibration slope (95% CI) and Royston D statistic (95% CI) in validation cohort was 1.19 (0.96 to 1.43) and 0.87 (0.67 to 1.07), respectively. CONCLUSION: This prognostic model for sulfasalazine toxicity uses readily available data and should be used to risk-stratify blood-test monitoring during established sulfasalazine treatment.

Factors associated with acute anterior uveitis history in patients with axial spondyloarthritis: Results of a longitudinal study.

BACKGROUNDS: Acute anterior uveitis (AAU) is the most common extra-musculoskeletal manifestation in axial spondyloarthritis (axSpA). OBJECTIVES: The aim of the study is to evaluate the factors associated with AAU attacks in patients with axSpA during a 36-month follow-up period. METHODS: In total, 469 patients with axSpA were included in this observational study. Demographic data, clinical characteristics, disease activity measurements, and treatment patterns were compared between patients with and without a history of AAU. The development of AAU and its related factors were investigated using generalized estimating equations, which is a technique for longitudinal data analysis. RESULTS: Overall, 99 (21%) out of 469 patients experienced at least one AAU attack, with 77 patients (78%) having a history of AAU and 53 patients (58% of whom had a history of AAU) experiencing AAU attacks during the follow-up period. At baseline, patients with a history of AAU were found to be older (p = .001), be more likely to have peripheral arthritis (p < .001), have higher serum CRP levels (p = .016), have a higher frequency of sulfasalazine (SLZ) and tumor necrosis factor inhibitors (TNFi) use (p < .001 and p < .001, respectively). In the longitudinal analysis, having a history of AAU was identified as the only independent determinant of the development of AAU. CONCLUSIONS: AAU history might be a risk factor for the development of AAU attacks in patients with axSpA. Although TNFi and SLZ were prescribed more frequently to patients with a history of AAU, the effectiveness of these agents in preventing further AAU attacks was not demonstrated.

Effect of sulfasalazine on ferroptosis during intestinal injury in rats after liver transplantation.

Using a rat autologous orthotopic liver transplantation (AOLT) model and liver cold ischemia-reperfusion (I/R)-induced intestinal injury, we clarified whether ferroptosis occurred in rat AOLT cold I/R-induced intestinal injury. Additionally, the role and possible mechanism of the ferroptosis activator sulfasalazine (SAS) in intestinal injury-induced ferroptosis in rats with AOLT liver cold I/R were investigated. Sixty specific pathogen free (SPF)-grade adult male Sprague‒Dawley (SD) rats were randomly divided into 5 groups using the random number table method (n = 12). Six rats were randomly selected at 6 hour (h) and 24 h after I/R. Inferior vena cava blood specimens were collected from the portal vein (PV) opening at 6 h and 24 h. The concentrations of serum malondialdehyde (MDA), serum interleukin 6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA). Ileal tissue was obtained from the PV opening in rats in each group at 6 h and 24 h, and ileal tissue sections were observed under light microscopy. The contents of intestinal MDA, superoxide dismutase (SOD), glutathione(GSH), glutathione peroxidase 4 (GPX4), and tissue iron were determined by ELISA, and the expression of GPX4 and the cysteine glutamate reverse transporter light chain protein (xCT) was determined by Western blot. The experimental results show that ferroptosis is involved in the pathophysiological process of intestinal injury induced by cold hepatic ischemia-reperfusion in AOLT rats. In addition, SAS (500 mg/kg) may inhibit the cystine/glutamate antiporters (System Xc¯)/GSH/GPX4 signal axis in intestinal injury induced by cold I/R in rat AOLT liver, or iron overload after reperfusion, causing a massive accumulation of L-ROS and activating cellular ferroptosis, further aggravate the intestinal injury.

Unravelling pH/pKa influence on pH-responsive drug carriers: Insights from ibuprofen-silica interactions and comparative analysis with carbon nanotubes, sulfasalazine, and alendronate.

This study employs density functional theory to explore the interaction between ibuprofen (IBU) and silica, emphasizing the influence of the trimethylsilyl (TMS) functional group for designing pH-responsive drug carriers. The surface (S) and drug (D) molecules' neutral (0) or deprotonated (-1) states were taken into consideration during the investigation. The likelihood of these states was determined based on the pKa values and the desired pH conditions. To calculate the pH-dependent interaction energy (EintpH), four different situations have been identified: S0D0, S0D-1, S-1D0, and S-1D-1.The electrostatic component of interaction energy aligns favorably with its theoretical value in both the Debye-Hückel and Grahame models. The investigation has gathered first-hand experimental data on the drug loading and release of pH-responsive mesoporous silica nanoparticles. Effective drug loading was observed in the acidic environment of the stomach (pH 2-5), followed by a release in the slightly basic to neutral pH of the small intestine (pH 7.4), These findings align with existing literature. The results revealed horizontal drug adherence on silica surfaces, improving binding capabilities. Comparisons were made with combinations involving carboxylated carbon nanotubes and ibuprofen, silica, and sulfasalazine, and silica and alendronate, exploring drug loading/release dynamics associated with positive/negative interaction energies. The investigation, supported by experimental data, contributes valuable insights into pH-responsive mesoporous silica nanoparticles, offering new design possibilities for drug carriers.

Sulfasalazine promotes ferroptosis through AKT-ERK1/2 and P53-SLC7A11 in rheumatoid arthritis.

OBJECTIVE: Ferroptosis has been reported to play a role in rheumatoid arthritis (RA). Sulfasalazine, a common clinical treatment for ankylosing spondylitis, also exerts pathological influence on the progression of rheumatoid arthritis including the induced ferroptosis of fibroblast-like synoviocytes (FLSs), which result in the perturbated downstream signaling and the development of RA. The aim of this study was to investigate the underlying mechanism so as to provide novel insight for the treatment of RA. METHODS: CCK-8 and Western blotting were used to assess the effect of sulfasalazine on FLSs. A collagen-induced arthritis mouse model was constructed by the injection of collagen and Freund's adjuvant, and then, mice were treated with sulfasalazine from day 21 after modeling. The synovium was extracted and ferroptosis was assessed by Western blotting and immunofluorescence staining. RESULTS: The results revealed that sulfasalazine promotes ferroptosis. Compared with the control group, the expression levels of ferroptosis-related proteins such as glutathione peroxidase 4, ferritin heavy chain 1, and solute carrier family 7, member 11 (SLC7A11) were lower in the experimental group. Furthermore, deferoxamine inhibited ferroptosis induced by sulfasalazine. Sulfasalazine-promoted ferroptosis was related to a decrease in ERK1/2 and the increase of P53. CONCLUSIONS: Sulfasalazine promoted ferroptosis of FLSs in rheumatoid arthritis, and the PI3K-AKT-ERK1/2 pathway and P53-SLC7A11 pathway play an important role in this process.

Labetalol Ameliorates Experimental Colitis in Rat Possibly Through its Effect on Proinflammatory Mediators and Oxidative Stress.

BACKGROUND: Members of beta blockers drugs possess significant antioxidant activities. The current research is to assess the effect of the labetalol on acetic acid (AA-induced) colitis in rat model. METHODS: Forty adult Wistar rats were separated into 4 groups, including the negative control group, AA group, AA + sulfasalazine (100 mg/kg/day) group, and AA + labetalol (300 mg/kg/day) group. Colitis was induced in rats by the interrectal installation of 2 mL of 4% (v/v) AA. Sulfasalazine and labetalol were administered orally for 7 days after 2 hours of induction. The following parameters were measured: disease activity index (DAI), histopa-thological changes and colon tissue homogenate concentrations of proinflammatory mediators IL-1ß, adhesion molecules ICAM-1, and oxidative stress marker myeloperoxidase (MPO). RESULTS: The treatment with labetalol significantly reduced DAI and histopathological changes induced by AA. Also, labetalol markedly decreased the concentrations of IL-1ß, ICAM-1, and MPO in colonic tissue that were increased by AA. The effects of labetalol were significantly lower than that produced by sulfasalazine as standard drug. CONCLUSIONS: Labetalol exerts ameliorative effects on disease activity and histopathological features of AA-induced colitis in rats possibly through antioxidant effects and inhibition of inflammatory mediators.

Treatment of non-systemic juvenile idiopathic arthritis.

In the past two decades, the treatment of juvenile idiopathic arthritis (JIA) has evolved markedly, owing to the availability of a growing number of novel, potent and relatively safe therapeutic agents and the shift of management strategies towards early achievement of disease remission. However, JIA encompasses a heterogeneous group of diseases that require distinct treatment approaches. Furthermore, some old drugs, such as methotrexate, sulfasalazine and intraarticular glucocorticoids, still maintain an important therapeutic role. In the past 5 years, information on the efficacy and safety of drug therapies for JIA has been further enriched through the accomplishment of several randomized controlled trials of newer biologic and synthetic targeted DMARDs. In addition, a more rational therapeutic approach has been fostered by the promulgation of therapeutic recommendations and guidelines. A multinational collaborative effort has led to the development of the recommendations for the treat-to-target strategy in JIA. There is currently increasing interest in establishing the optimal time and modality for discontinuation of treatment in children with JIA who achieve sustained clinical remission. The aim of this Review is to summarize the current evidence and discuss the therapeutic approaches to the management of non-systemic phenotypes of JIA, including oligoarthritis, polyarthritis, enthesitis-related arthritis and psoriatic arthritis.

The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis.

Sulfasalazine is a prodrug known to be effective for the treatment of inflammatory bowel disease (IBD)-associated peripheral spondyloarthritis (pSpA), but the mechanistic role for the gut microbiome in regulating its clinical efficacy is not well understood. Here, treatment of 22 IBD-pSpA subjects with sulfasalazine identifies clinical responders with a gut microbiome enriched in Faecalibacterium prausnitzii and the capacity for butyrate production. Sulfapyridine promotes butyrate production and transcription of the butyrate synthesis gene but in F. prausnitzii in vitro, which is suppressed by excess folate. Sulfasalazine therapy enhances fecal butyrate production and limits colitis in wild-type and gnotobiotic mice colonized with responder, but not non-responder, microbiomes. F. prausnitzii is sufficient to restore sulfasalazine protection from colitis in gnotobiotic mice colonized with non-responder microbiomes. These findings reveal a mechanistic link between the efficacy of sulfasalazine therapy and the gut microbiome with the potential to guide diagnostic and therapeutic approaches for IBD-pSpA.

Prevalence of positive tuberculin skin test in a Brazilian sample of rheumatoid arthritis and spondylarthritis patients.

OBJECTIVE: Patients with rheumatic diseases have an increased risk of infections, especially tuberculosis. In this study, we aimed to recognize the positivity rate of tuberculosis skin test in patients with rheumatoid arthritis and spondyloarthritis and the characteristics of the patients with positive results. METHODS: Retrospective study of tuberculosis skin test results in patients followed from 2004 to 2021 in a single rheumatology unit. Data related to clinical and epidemiological features, along with treatment information referring to the period in which the tuberculosis skin test was performed, were collected from patients' charts. RESULTS: A total of 723 tests were identified (448 tests in 269 rheumatoid arthritis patients and 275 in 174 spondyloarthritis patients). In the rheumatoid arthritis sample, 31/275 (11.5%) individuals had positive tests, and in the spondyloarthritis, 38/174 (21.8%) had positive tests. In the rheumatoid arthritis sample, patients with positive tuberculosis skin tests used a higher dose of methotrexate than those with negative results (median of 25 mg/week versus median of 20 mg/week respectively; p=0.02). In the spondyloarthritis sample, tuberculosis skin test positivity was associated with alcohol ingestion (13.1% versus 2.9% in users and non-users respectively; p=0.02) and sulfasalazine use (15.7% of positivity in users versus 5% in non-users; p=0.01). CONCLUSION: The tuberculosis skin test-positive prevalence in rheumatoid arthritis was lower than in the spondyloarthritis sample. Patients with rheumatoid arthritis using a higher dosage of methotrexate or with spondyloarthritis using sulfasalazine had more frequency of tuberculosis skin test positivity and should be carefully followed by the attending physician in order to avoid the appearance of full-blown tuberculosis.

Sulfasalazine ameliorates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress and nuclear factor-kappaB pathways.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has a high mortality rate and incidence of complications. The pathophysiology of ALI/ARDS is still not fully understood. The lipopolysaccharide (LPS)-induced mouse model of ALI has been widely used to study human ALI/ARDS. Sulfasalazine (SASP) has antibacterial and anti-inflammatory effects and is used for treating inflammatory bowel and rheumatic diseases. However, the effect of SASP on LPS-induced ALI in mice has not yet been reported. Therefore, we aimed to investigate the effect of SASP on LPS-induced ALI in mice. Mice were intraperitoneally injected with SASP 2 h before or 4 h after LPS modeling. Pulmonary pathological damage was measured based on inflammatory factor expression (malondialdehyde and superoxide dismutase levels) in the lung tissue homogenate and alveolar lavage fluid. The production of inflammatory cytokines and occurrence of oxidative stress in the lungs induced by LPS were significantly mitigated after the prophylactic and long-term therapeutic administration of SASP, which ameliorated ALI caused by LPS. SASP reduced both the production of inflammatory cytokines and occurrence of oxidative stress in RAW264.7 cells, which respond to LPS. Moreover, its mechanism contributed to the suppression of NF-κB and nuclear translocation. In summary, SASP treatment ameliorates LPS-induced ALI by mediating anti-inflammatory and antioxidant effects, which may be attributed to the inhibition of NF-κB activation and promotion of antioxidant defenses. Thus, SASP may be a promising pharmacologic agent for ALI therapy.

Regulatory network of ferroptosis and autophagy by targeting oxidative stress defense using sulfasalazine in triple-negative breast cancer.

AIMS: The cellular defense system against oxidative stress is important for the survival ability and sensitization in chemotherapy; however, the regulatory mechanisms remain unknown in triple-negative breast cancer (TNBC) cells. This study aimed to investigate the relationship between ferroptosis and autophagy by targeting the defense of oxidative stress through the cystine transporter (xCT) using sulfasalazine (SASP), which is a widely employed xCT inhibitor. MAIN METHODS: We analyzed the cell death process of SASP in human TNBC cells, and examined the effects of SASP on tumor progression by using xenograft mouse model. KEY FINDINGS: TNBC cells demonstrated a high defense capacity against reactive oxidative species through xCT. SASP significantly attenuated oxidative stress resistance in MDA-MB-231, which is a generally used model cell as TNBC, through decreased glutathione levels, causing a marked iron-dependent ferroptotic cell death induction. Moreover, autophagy was required to trigger efficient SASP-induced ferroptosis at the early stage of cell death. Tamoxifen, which is currently in clinical use as the gold standard for endocrine therapy of estrogen receptor-positive breast cancer, was a beneficial tool as an autophagy regulator under ferroptotic cell death by SASP. Additionally, SASP suppressed tumor growth and metastasis progression through total glutathione reduction in the primary tumor, indicating high anticancer activity against TNBC without liver injury in vivo. SIGNIFICANCE: We revealed that SASP can efficiently induce ferroptosis associated with autophagy and that an understanding of the mechanism of cell death regulation by SASP is a promising new strategy for TNBC therapy and drug repositioning.

Qingchang suppositry induced remission in patients with mild-to-moderate ulcerative proctitis: a multicenter, prospective, randomized, parallel-controlled clinical trial.

OBJECTIVE: To evaluate the efficacy and safety of Qingchang suppository (, QCS), a preparation of Chinese herbal medicine, in the induction of remission in patients with mild-to-moderate ulcerative proctitis (UP). METHODS: We performed a multicenter, prospective, randomized, parallel-controlled trial to evaluate the efficacy of QCS induction therapy in 140 adult patients with mild-to-moderate UP and TCM syndrome of dampness-heat in large intestine. The patients were randomized to receive QCS (study group) or Salicylazosulfapyridine (SASP) suppository (control group) one piece each time, twice a day, per anum for 12 weeks. Mayo score and main symptoms score were evaluated at weeks 0, 2, 4, 8 and 12, rectosigmoidscopy was taken at weeks 0, 4, 8 and 12, Geboes score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and safety indexes were assessed at weeks 0 and 12. The primary efficacy endpoint is clinical remission rate, the secondary efficacy endpoints are clinical response rate, mucosa healing rate, Geboes score, the remission rates of the main symptoms, the median day to the remission of the symptom, etc. RESULTS: There were no statistical difference in the clinical remission rates, the clinical response rates, the mucosa healing rates, Geboes score, ESR and CRP between the two groups. The remission rates of tenesmus and anal burning sensation of the study group were significantly higher than those of the control group (76.5% vs 25.0%, P = 0.009; 74.51% vs 29.63%, P = 0.003). The median day to the remission of purulent bloody stool of the study group was significantly less than that of control group [11 (1, 64) vs 19 (2, 67), P = 0.007]. The patients receiving QCS had a significantly higher mucosa healing rate at week 4 than the patients receiving SASP suppository (71.42% vs 52.85%, P = 0.023). No adverse event occurred in the study group while the adverse events incidence of the control group was 5.7% (P = 0.049). CONCLUSIONS: QCS could induce the remission of UP as effectively and safely as SASP suppository, and was superior to SASP suppository in relieving the symptoms of tenesmus, anal burning sensation and purulent bloody stool and the time to reach mucosa healing.

Propolis alleviates ulcerative colitis injury by inhibiting the protein kinase C - transient receptor potential cation channel subfamily V member 1 - calcitonin gene-related peptide/substance P (PKC-TRPV1-CGRP/SP) signaling axis.

This study investigated the protective effect of water-soluble propolis (WSP) on colonic tissues in ulcerative colitis (UC) and the role of the protein kinase C - transient receptor potential cation channel subfamily V member 1 - calcitonin gene-related peptide/substance P (PKC-TRPV1-CGRP/SP) signaling pathway. Male SD rats were divided into a control group, a UC model group, various WSP groups (Low-WSP, Medium-WSP, and High-WSP) with UC, and a salazosulfapyridine (SASP) positive control group with UC. After UC was established, the WSP and SASP groups were treated with WSP or SASP, respectively, for 7 d. Each day, body weight measurements were obtained, and the disease activity index (DAI) was recorded by observing fecal characteristics and blood in the stool. After the experiment, hematoxylin and eosin (HE) colonic tissue staining was performed to observe pathological changes, western blotting and immunohistochemistry were performed to detect PKC, TRPV1, CGRP, and SP expression in colonic tissues, and laser confocal microscopy was performed to observe the fluorescence colocalization of PKC/TRPV1, TRPV1/CGRP, and TRPV1/SP. HE staining showed significant colonic tissue structure disruption and inflammatory infiltration in the UC group. Western blotting and immunohistochemistry showed that the expression of PKC, TRPV1, CGRP, and SP in the colonic tissues of the UC group increased significantly compared with that of the control group. Compared with the UC group, the expression of PKC, TRPV1, CGRP, and SP in colonic tissues was significantly reduced in the High-WSP, Medium-WSP, and SASP groups. Immunofluorescence showed the colocalized expression of PKC/TRPV1, TRPV1/CGRP, and TRPV1/SP proteins in the colon tissue of the UC group was significantly reduced after WSP and SASP interventions compared with that of the control group. The results suggest that the mechanism of UC alleviation by propolis may inhibit the PKC-TRPV1-CGRP/SP signaling pathway and the release of inflammatory mediators, thus alleviating inflammation.

The nonessential amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia.

ABSTRACT: Cysteine is a nonessential amino acid required for protein synthesis, the generation of the antioxidant glutathione, and for synthesizing the nonproteinogenic amino acid taurine. Here, we highlight the broad sensitivity of leukemic stem and progenitor cells to cysteine depletion. By CRISPR/CRISPR-associated protein 9-mediated knockout of cystathionine-γ-lyase, the cystathionine-to-cysteine converting enzyme, and by metabolite supplementation studies upstream of cysteine, we functionally prove that cysteine is not synthesized from methionine in acute myeloid leukemia (AML) cells. Therefore, although perhaps nutritionally nonessential, cysteine must be imported for survival of these specific cell types. Depletion of cyst(e)ine increased reactive oxygen species (ROS) levels, and cell death was induced predominantly as a consequence of glutathione deprivation. nicotinamide adenine dinucleotide phosphate hydrogen oxidase inhibition strongly rescued viability after cysteine depletion, highlighting this as an important source of ROS in AML. ROS-induced cell death was mediated via ferroptosis, and inhibition of glutathione peroxidase 4 (GPX4), which functions in reducing lipid peroxides, was also highly toxic. We therefore propose that GPX4 is likely key in mediating the antioxidant activity of glutathione. In line, inhibition of the ROS scavenger thioredoxin reductase with auranofin also impaired cell viability, whereby we find that oxidative phosphorylation-driven AML subtypes, in particular, are highly dependent on thioredoxin-mediated protection against ferroptosis. Although inhibition of the cystine-glutamine antiporter by sulfasalazine was ineffective as a monotherapy, its combination with L-buthionine-sulfoximine (BSO) further improved AML ferroptosis induction. We propose the combination of either sulfasalazine or antioxidant machinery inhibitors along with ROS inducers such as BSO or chemotherapy for further preclinical testing.

Morphology and ultrastructure of digestive system in pre-zoea and zoea I larvae of red king crab, Paralithodes camtschaticus (Tilesius, 1815).

The digestive system structure in pre-zoea and zoea I larvae of the red king crab Paralithodes camtschaticus has been examined. During this development period, the digestive system consists of an esophagus, a stomach, a midgut (where the hepatopancreas ducts open), and a hindgut. The esophagus begins from the oral slit on the animal's ventral side and extends vertically up to the junction with the cardiac stomach. The latter is followed by the pyloric stomach. At the stages under study, crabs have a cardiac-pyloric valve and a pyloric filter in the stomach already developed. The midgut begins with an expansion in the cephalothorax, enters the pleon, grows narrower there, and extends to somite 3 of pleon. The hepatopancreas is represented by a symmetrical paired gland which occupies almost the entire cephalothorax space and opens with its ducts at the junction of the pyloric stomach with the midgut. The hepatopancreas is divided into the anterior and posterior lobes. At the pre-zoea stage, the anterior lobes are large and filled with yolk. At the zoea I stage, the anterior lobes are smaller relative to the entire hepatopancreas, and the posterior lobes increase and form tubular outgrowths. It has been shown that during the transition from pre-zoea to zoea I, the number of mitochondria in enterocytes increases and a peritrophic membrane forms in the midgut. These changes are probably associated with the transition to independent living and feeding.

Smart Multivariate Spectrophotometric Determination of Two Co-Administered Autoimmune Drugs; Sulfasalazine and Pentoxifylline; in Bulk and Spiked Human Plasma.

BACKGROUND: Sulfasalazine and pentoxifylline are co-prescribed together to treat psoriasis and pemphigus vulgaris. Sulfasalazine is an anti-inflammatory, immunosuppressant, and antibiotic drug, while pentoxifylline is a vasodilator and immunosuppressant. The spectra of the two drugs and plasma suffer from severe overlap. OBJECTIVE: This work aims to simultaneously determine sulfasalazine and pentoxifylline in their binary mixture and spiked human plasma by the assessment of their UV spectral data. METHODS: Two model updated chemometric methods were established using principal component regression and partial least-squares regression models. The two models were validated in accordance with the U.S. Food and Drug Administration guidelines for bioanalysis and were applied for the determination of both drugs in synthetic mixtures or spiked human plasma. RESULTS: Accuracy and precision were within the accepted limits. In addition, three different assessment methods were used to evaluate the environmental greenness of the proposed models. CONCLUSION: The two updated models are simple, rapid, sensitive, and precise, and could be easily applied in QC laboratories for determination of sulfasalazine and pentoxifylline, without any preliminary separation steps or interference from plasma matrix. HIGHLIGHTS: Two updated chemometric models called principlal component regression and partial least-squares regression were established for determination of sulfasalazine and pentoxifylline in spiked human plasma using UV spectrophotometric data.

A polymeric iron oxide nanocomplex loaded with sulfasalazine: an approach for inducing ferritinophagy-assisted ferroptosis for anti-cancer therapy.

The approach of using ferroptosis to treat cancer has garnered attention due to its promising potential. However, the effectiveness of this therapy is often limited by the inherent redox system in cancer cells and the presence of ferritin as an iron ion storage molecule. To address this issue, we have designed a polymeric iron oxide nanocomplex loaded with sulfasalazine as a ferritinophagy-assisted ferroptosis inducing agent. The nanocomplex is based on a pH-responsive drug releasing platform that enables improved ferroptosis anti-cancer therapy. The nanocomplex was synthesized using polymerized phenylboronic acid decorated with iron oxide and further loaded with sulfasalazine by interacting with polymerized phenylboronic acid. Upon entering cancer cells, the nanocomplex releases sulfasalazine at the lysosomal acidic pH, which causes the complex to degrade into the labile iron ion (Fe2+). This process inhibits the production of GSH and reproduces the labile iron ion by degrading ferritin. As a result, an excess iron ion pool is formed, and the facilitated Fenton reaction induces an improved ferroptosis anti-cancer effect. Moreover, our research has demonstrated that the nanocomplex effectively regresses tumors, thereby representing significant inhibition of tumor growth using in vivo models. We believe that this ferritinophagy-assisted ferroptosis strategy using the nanocomplex provides a promising solution for iron-based anti-cancer therapy.

Gilaburu (Viburnum opulus L.) fruit extract has potential therapeutic and prophylactic role in a rat model of acetic acid-induced oxidant colonic damage.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) which has a global impact on the health care system with its recurrent and incompletely curable characteristics, affects the patients' quality of life. Gilaburu (GB; Viburnum opulus L.) is a fruit with rich polyphenol ingredient which is used ethnobotanically in Türkiye for medicinal purposes (for example, to pass kidney stones, to treat stomach, heart, and liver diseases, hemorrhages, hypertension, ulcers, common cold, tuberculosis, rheumatic and menstrual pain, and diabetes). On the other hand, the effects of GB in the experimental UC model have not been studied. AIM OF THE STUDY: This study aimed to explore the potential antioxidant and anti-inflammatory effects of GB fruit extract in improving acetic acid (AA)-induced UC. MATERIALS AND METHODS: Starting immediately after (AA + GB group) or 1 week before (GB + AA + GB group) the colitis induced by intrarectal AA (5%; v/v) administration, the rats orally received GB (100 mg/kg) once per day for 3 days. The control and AA groups were administered orally saline (1 ml), while the AA + SS group were administered sulfasalazine (SS; 100 mg/kg; orally) as a positive control once per day for 3 days. Distal colonic tissue specimens were obtained for the histological and biochemical [myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), chemiluminescence (CL), caspase-3, 8-hydroxy-2'-deoxyguanosine (8-OHdG), matrix metalloproteinase (MMP)-9, transforming growth factor (TGF)-ß1, smad-3 and cytokine (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, interferon (IFN)-γ), measurements] evaluations on the 3rd day. RESULTS: Elevated macroscopic and microscopic damage scores, high tissue wet weight values, increased tissue-associated MPO, MDA, CL, caspase-3, 8-OHdG, cytokines (TNF-α, IL-1ß, IL-6, IL-8), MMP-9, TGF-ß1, smad-3 levels, and decreased GSH values of the AA group were all reversed by GB treatments (AA + GB and GB + AA + GB groups) (p < 0.05-0.001). However, sulfasalazine treatment (AA + SS group) did not change the IL-8, 8-OHdG, MMP-9, and TGF-ß1 measurements significantly. CONCLUSIONS: Gilaburu shows both anti-inflammatory and antioxidant effects against AA-induced colonic damage by suppressing neutrophil infiltration, regulating inflammatory mediators, inhibiting reactive species production, lipid peroxidation, and apoptosis, conserving endogenous antioxidant glutathione, and ameliorating oxidative DNA damage. Since the current ulcerative colitis drugs display limited benefits and adverse side effects, potential therapeutic and/or prophylactic role of gilaburu can be evaluated in ulcerative colitis.

Folic Acid-Modified Long-Circulating Liposomes Loaded with Sulfasalazine For Targeted Induction of Ferroptosis in Melanoma.

Melanoma is a malignant tumor that originates from melanocytes. The incidence of melanoma is increasing worldwide, partially because of its insensitivity to radiotherapy or chemotherapy. Therefore, effective treatments for melanoma are urgently required. In this study, we employed folic acid-modified sulfasalazine long-circulating liposomes (FA-SSZ-Lips) to precisely target drug delivery to melanoma cells, eliciting ferroptosis effectively. The synthesized FA-SSZ-Lips were characterized as small spheres of a double-layer membrane, a particle size of 110.1 nm, and a ζ-potential of -22.8 ± 0.66 mV. FA-SSZ-Lips are effective drug carriers with SSZ-loading ratio and SSZ release rate of 6.2 ± 0.10%, and 72.63 ± 1.40%, respectively. The liposomes enhanced SSZ solubility, and the folic acid modifications increased the liposome targeting to melanoma cells. Compared with SSZ alone, FA-SSZ-Lips more strongly inhibited B16F10 cell growth, significantly disrupted the intracellular redox balance, and induced ferroptosis. After treatment, considerable differences were observed in the tumor volumes between FA-SSZ-Lips and phosphate-buffered saline control groups. The tumor growth-inhibition value of the FA-SSZ-Lips group reached 70.09%. Thus, FA-SSZ-Lips exhibited favorable antitumor effects in vitro and in vivo and are a promising strategy for melanoma treatment.