Polysulfonium: Unveiling a Bioactive Polymer to Induce Immunogenic Cell Death for Anticancer Therapy.

Here we report a brand-new bioactive polymer featuring sulfonium moieties that exhibits the capability of inducing immunogenic cell death (ICD) for anticancer therapy. The optimized polysulfonium presents a wide spectrum of potent anticancer activity and remarkable selectivity. In-depth mechanistic studies reveal that the polymer exerts its cytotoxic effects on cancer cells through a membrane-disrupting mechanism. This further initiates the release of a plethora of damage-associated molecular patterns, effectively triggering ICD and resulting in systemic anticancer immune responses. Notably, the compound demonstrated significant efficacy in suppressing tumor growth in the B16-F10 melanoma tumor model. Furthermore, it exhibits robust immune memory effects, effectively suppressing tumor recurrence and metastasis in both the rechallenge model and the lung metastatic tumor model. To the best of our knowledge, the study represents the pioneering exportation of cationic polysulfoniums, showcasing not only their remarkable safety and efficacy against primary tumors but also their unique ability in activating long-term immune memory.

Suplatast tosilate in patients with interstitial cystitis: Efficacy and treatment possibilities, with suggestions for future assessments.

OBJECTIVE: Suplatast tosilate, a Th2 cytokine inhibitor, was predicted to relieve interstitial cystitis symptoms. Four studies with suplatast tosilate in Japanese interstitial cystitis patients have been conducted: a single-arm clinical study, a phase II dose-ranging trial, a phase III trial with placebo, and a second phase PIII trial with placebo. Treatment efficacy was observed in the first two studies; however, in the phase PIII trials, no significant difference in interstitial cystitis symptom score changes was observed between suplatast tosilate and placebo. We summarized these four studies to investigate factors causing the difference in observed efficacy. METHODS: Placebo effects in the first two studies and differences regarding study design between the four studies were considered to be possible factors. Therefore, placebo effects were investigated by comparing interstitial cystitis symptom score changes, and the study designs were compared to investigate the effects on observed efficacy. RESULTS: Interstitial cystitis symptom score changes in the phase PII treatment groups increased in a dose-dependent manner and showed an almost linear relationship with interstitial cystitis symptom score changes observed in placebo groups of 2 phase PIII studies. A major difference regarding the phase PIII study design was the use of diagnostic hydrodistention. Diagnostic hydrodistention and its washout period were applied only in the phase PIII trials. CONCLUSIONS: Comparison of interstitial cystitis symptom score changes suggested that the placebo effect was very small. Use of diagnostic hydrodistention was considered to be a major difference in the population characteristics of the studies and may have resulted in different observed efficacies. Diagnostic hydrodistention, which potentially influences the treatment effect, is probably not essential for trials of suplatast in interstitial cystitis patients.

Sulfonium, an Underestimated Moiety for Structural Modification, Alters the Antibacterial Profile of Vancomycin Against Multidrug-Resistant Bacteria.

In the antibiotics arsenal, vancomycin is a last resort for the treatment of intractable infections. However, this situation is under threat because of the increasing appearance of vancomycin-resistant bacteria (VRB). Herein, we report a series of novel vancomycin derivatives carrying a sulfonium moiety. The sulfonium-vancomycin derivatives exhibited enhanced antibacterial activity against VRB both in vitro and in vivo. These derivatives also exhibited activity against some Gram-negative bacteria. The sulfonium modification enhanced the interaction of vancomycin with the bacterial cell membrane and disrupts membrane integrity. Furthermore, the in vivo pharmacokinetic profile, stability, and toxicity of these derivatives demonstrated good druggability of the sulfonium-vancomycin analogues. This work provides a promising strategy for combating drug-resistant bacterial infection, and advances the knowledge on sulfonium derivatives for structural optimization and drug development.

Suplatast tosilate alleviates nasal symptoms through the suppression of nuclear factor of activated T-cells-mediated IL-9 gene expression in toluene-2,4-diisocyanate-sensitized rats.

Histamine H1 receptor (H1R) gene is upregulated in patients with pollinosis; its expression level is highly correlated with the nasal symptom severity. Antihistamines are widely used as allergy treatments because they inhibit histamine signaling by blocking H1R or suppressing H1R signaling as inverse agonists. However, long-term treatment with antihistamines does not completely resolve toluene-2,4-diisocyanate (TDI)-induced nasal symptoms, although it can decrease H1R gene expression to the basal level, suggesting additional signaling is responsible for the pathogenesis of the allergic symptoms. Here, we show that treatment with suplatast tosilate in combination with antihistamines markedly alleviates nasal symptoms in TDI-sensitized rats. Suplatast suppressed TDI-induced upregulation of IL-9 gene expression. Suplatast also suppressed ionomycin/phorbol-12-myristate-13-acetate-induced upregulation of IL-2 gene expression in Jurkat cells, in which calcineurin (CN)/nuclear factor of activated T-cells (NFAT) signaling is known to be involved. Immunoblot analysis demonstrated that suplatast inhibited binding of NFAT to DNA. Furthermore, suplatast suppressed ionomycin-induced IL-9 mRNA upregulation in RBL-2H3 cells, in which CN/NFAT signaling is also involved. These data suggest that suplatast suppressed NFAT-mediated IL-9 gene expression in TDI-sensitized rats and this might be the underlying mechanism of the therapeutic effects of combined therapy of suplatast with antihistamine.

Suplatast tosilate for treating cutaneous mastocytosis.

Pediatric cutaneous mastocytosis is a rare disease caused by mast cell hyperplasia. We report the case of an infant diagnosed as cutaneous mastocytosis and seasonal allergies. The wheals, flushing, and pruritus of the mastocytosis were unresponsive to combination therapy with an antihistamine, a mast cell stabilizer (sodium cromoglycate), and a leukotriene antagonist. Addition of suplatast tosilate as a treatment for the seasonal allergy also dramatically improved his cutaneous symptoms and signs. Further trials of suplatast tosilate in selected cases of cutaneous mastocytosis are warranted.

Salacinol and related analogs: new leads for type 2 diabetes therapeutic candidates from the Thai traditional natural medicine Salacia chinensis.

The antidiabetic effect of a hot water extract of stems of Salacia chinensis (SCE) was evaluated in vivo in KK-Ay mice, a typical type 2 diabetes mellitus mice model. Administration of CE-2 dietary feed containing 0.25 and/or 0.50% of SCE for three weeks to KK-Ay mice significantly suppressed the elevation of both blood glucose and HbA1c levels without significant changes in body weight or food intake. Glucose tolerance was improved by administration to KK-Ay mice for 27 days of AIN93M purified dietary feed containing 0.12% of SCE. No suppressive effect with respect to HbA1c level was observed when AIN93M/Glc dietary feed in which all digestible glucides were replaced with glucose was administered with SCE. Thus, α-glucosidase inhibitory activity approved as the mechanism of action of the antidiabetic effect of SCE by in vitro investigation was reconfirmed also in in vivo studies. Evaluation of the α-glucosidase inhibitory activity of the active constituents, salacinol (1), kotalanol (3), and neokotalanol (4), by employing human α-glucosidases revealed that these compounds inhibited them as potently (IC50 = 3.9-4.9 µM for maltase) as they inhibited rat small intestinal α-glucosidase. The principal sulfonium constituents (1-4) were highly stable in an artificial gastric juice. In addition, 1-4 were hardly absorbed from the intestine in an experiment using the in situ rat ligated intestinal loop model. The results indicate that these sulfoniums are promising leads for a new type of anti-diabetic agents.

Novel antitussive effect of suplatast tosilate in guinea pigs.

We studied the antitussive effects of suplatast, a Th2 cytokine inhibitor, and compared them with the effects of codeine using an experimental cough model in guinea pigs. Suplatast and codeine dose-dependently inhibited cough caused by mechanical stimulation of the larynx, but they did not inhibit cough caused by mechanical stimulation of the bifurcation of the trachea. In guinea pigs with bronchitis, suplatast had an antitussive effect on cough caused by stimulation of the larynx, whereas codeine did not inhibit such cough. In SO2-exposed guinea pigs, suplatast tended to inhibit cough caused by mechanical stimulation of the tracheal bifurcation. Further, suplatast inhibited citric acid-induced cough augmented by pretreatment with an angiotensin-converting enzyme inhibitor, whereas codeine did not inhibit such cough. Suplatast also inhibited bradykinin-induced discharges of airway vagal afferent nerves and significantly inhibited 4-aminopyridine-induced discharges of airway vagal afferent nerves. These findings indicate that the antitussive effects of suplatast are mediated by a novel mechanism involving the peripheral nervous system.

[A case report of eosinophilic cystitis treated with oral suplatast tosilate].

A 61-year-old female was referred to our hospital presenting with micturition pain and urinary frequency, which was not relieved by antibiotics. A cystoscopic examination revealed an erosion, reddening and edematous lesion in the left bladder wall. Pathological examination of transurethral biopsy showed erosion and cystitis. After biopsy, micturition pain and urinary frequency became worse. The pathological examination was reviewed, and the diagnosis of eosinophilic cystitis was made. Administration of a corticosteroid had provided a short duration of relief, but her symptoms recurred within the five weeks of treatment. Therefore, she was treated with a combination of corticosteroid and suplatast tolilate, followed by monotherapy with suplatast tolilate. The relief of the symptoms by suplatast to lilate therapy continued for five months. However, the symptoms relapsed. Re-administration of steroidal agents was considered, but the patient suffered from uncontrolled diabetes. Therefore, she was treated with a combination of suplatast tosilate, anti-allergic drugs and mirabegron. Fourteen months after treatment with suplatast tosilate, no disease progression was noted.

A tertiary sulfonium compound, dimethylsulfoniopropionate in green sea algae, completely suppresses crucial Ehrlich ascites carcinoma in mice.

BACKGROUND/AIM: Dimethylsulfoniopropionate (DMSP) has been intensively studied in bacteria, plankton, algae and salt-resistant plants to investigate its metabolism and fate in the atmosphere. However, its effects on diseased terrestrial animals have not yet been examined. We have found that DMSP exerts a great healing effect for a variety of inflammatory disorders in rodents. In the present study, effects of single and high concentration of DMSP on terrible Ehrlich ascites carcinoma (EAC) bearing-mice with unavoidable-rapid death were examined. RESULTS: We found that high concentration of DMSP completely suppresses acute EAC, which has never been eradicated, and accumulates large amounts of activated macrophages with no inflammation on various viscera in the peritoneal cavity of normal mice. CONCLUSION: These results show that DMSP is a new and potent anticancer compound with no side-effects, most likely playing a vital role for cancer immune therapy.

[Effects of suplatast tosilate on airway inflammation and interleukin-5 in asthmatic rats].

OBJECTIVE: To study the effects of suplatast tosilate (IPD) on the airway inflammation and expression of interleukin-5 in asthmatic rats. METHODS: Fifty adult male Sprague-Dawley rats (4-week- old) were randomly assigned to five groups: placebo control, untreated asthma, budesonide(BUD)-treated asthma , early or late IPD intervention group (n=10 rats each). Asthmatic mode was prepared by ovalbumin sensitizion and challenge. Inflammatory cells and the percentage of EOS were detected in bronchoalveolar lavage fluid (BALF). The lung tissues were removed to detect the lung histomorphology. Gene expression of IL-5 was measured by reverse transcription-polymerase chain reaction (RT-PCR). Levels of interleukin 5 (IL-5) in BALF were measured using ELISA. RESULTS: The inflammatory cells and the percentage of EOS in BALF, IL-5 levels in BALF and IL-5 mRNA expression in the lung tissues were obviously higher in the untreated asthma group than the control group (P<0.05), while the parameters in the IPD or BUD-treated asthma groups were significantly lower than the untreated asthma group (P<0.05). CONCLUSIONS: IPD treatment can alleviate airway inflammation in asthmatic rats, possibly through inhibiting IL-5 mRNA transcripts.

Prophylactic effectiveness of suplatast tosilate in children with asthma symptoms in the autumn: a pilot study.

BACKGROUND: Exacerbations of bronchial asthma usually occur in the autumn. To our knowledge, however, the effectiveness of drugs for preventing exacerbations of asthma in the autumn has not been studied previously, except for leukotriene receptor antagonists and Omalizmab. METHODS: This study compared the prophylactic effectiveness of suplatast tosilate with that of mequitazine in children with asthma symptoms, which is usually exacerbated in the autumn. The study group comprised 27 children aged 2 to 15 years who required treatment for asthmatic attacks during the past year and tested positive at least for mite allergen in the preceding autumn. The subjects were randomly assigned to receive either suplatast or mequitazine. The primary endpoint of this study was the number of days without symptoms during the 8 weeks of treatment. In addition, the Japanese Pediatric Asthma Control Program (JPAC) scores were also recorded every 2 weeks in each group. RESULTS: Overall, 14 patients received suplatast, and 13 received mequitazine for 8 weeks from September through early October. During follow-up, the number of days without symptoms and the total JPAC scores did not differ significantly between the groups. However, as compared with weeks 1 to 2 of treatment, the mean number of days without symptoms during weeks 7 to 8 increased significantly in only the suplatast group (8.6 vs. 11.5 days; p = 0.004). CONCLUSIONS: Our results suggest that short-term additional treatment with suplatast is useful for preventing asthma symptoms in children with asthma, which is usually exacerbated in the autumn.

The effects of suplatast tosilate treatment and prophylaxis on lung histopathology in a mouse model of chronic asthma.

INTRODUCTION: Suplatast tosilate is a medication that inhibits TH2-type cytokines. We aimed to investigate the effects of suplatast tosilate treatment and prophylaxis on lung histopathology and cytokine levels in a mouse model of chronic asthma. MATERIALS AND METHODS: Forty-two BALB/c mice were divided into 6 groups: group I (control), group II (vehicle control), group III (dexamethasone), group IV (prophylaxis with suplatast tosilate), group V (treatment with suplatast tosilate), and group VI (prophylaxis and treatment with suplatast tosilate). All of the groups, except for the control and vehicle control groups, were sensitized and challenged with ovalbumin. The mice in the study groups, except those in the group receiving suplatast tosilate for prophylaxis only, were treated with study drugs. After the mice were killed, IL-4, IL-5, and interferon-γ levels were quantified in the lung tissue, which were examined histologically by light and electron microscopy. RESULTS: There were significant improvements in all histopathological parameters in the group treated with suplatast tosilate compared with the vehicle control group. Similar improvements were observed when the group receiving prophylaxis and treatment with suplatast tosilate was compared with the vehicle control as well. There were no significant differences between the group receiving only prophylaxis with suplatast tosilate and the vehicle control group. Cytokine levels were significantly higher in the vehicle control group when compared with the control group. Although all of the groups had lower cytokine levels than those of the vehicle control group, the differences were not statistically significant. CONCLUSIONS: Treatment with suplatast tosilate was effective in improving all histopathological parameters in a mouse model of chronic asthma. It was observed that the use of prophylactic suplatast tosilate was ineffective and had no additional effects when administered together with treatment.

Usefulness of suplatast tosilate, a Th2 cytokine inhibitor based on the Th1/Th2 ratio for allergic disease in children: a retrospective study.

BACKGROUND: Children with an atopic predisposition are presumed to have persistent Th2 dominance and thus develop allergic diseases. METHODS: A total of 45 children who fell to atopic dermatitis and/or intermittent asthma or mild persistent asthma between 2002 and 2007 were enrolled and retrospectively analyzed. Twenty-four children were administered oral treatment with the immunopharmacological drug suplatast tosilate (CAS 94055-76-2) at a dose of 3 mg/kg twice daily. Twenty-one of the control group were not administered oral suplatast tosilate but treated with other drugs. Blood was collected before and after administering suplatast tosilate or other drugs, and Th1 cells, Th2 cells, the Th1/Th2 ratio, the total IgE levels, and the eosinophil count were measured. RESULTS: In the suplatast tosilate group, Th1 cells increased to 7.9 (1.2-19.8) % from 5.5 (1.1-13.5) % (Wilcoxon P < 0.05), while the Th2 cells showed a decrease from 1.3 (0.5-6.5) % to 1.6 (0.4-2.9) %, but the differences were not significant. The Th1/Th2 ratio increased significantly from 4.1 (0.9-7.4) to 5.6 (1.3-15.5) (shifting to Th1 dominance) in the suplatast tosilate group (Wilcoxon P < 0.05), while it shifted to Th2 dominance in the control group (increased from 4.5 (2.2-12.2) to 5.7 (1.6-11.8)) but did not show significant difference. CONCLUSIONS: The Th1/Th2 ratio increased significantly after administration of suplatast tosilate, shifting to Th1 dominance. Therefore suplatast tosilate improves Th2 dominance and may inhibit subsequent progression of allergy over the long term.

Carcinoma infection and immune systems of Ehrlich ascites carcinoma-bearing mice treated with structurally similar sulfonium compounds.

The effects of intraperitoneal administration of dimethylsulfonioacetate (DMSA), dimethlsulfoniopropionate (DMSP), and methylmethionine (MeMet) solutions (10 mM each) on the body weights and the hematological parameters (red and white blood cells) of Ehrlich ascites carcinoma (EAC)-bearing mice were examined for up to 10 d. Body weights significantly increased in the EAC-bearing mice treated with and without MeMet in contrast to those with DMSA and DMSP. This increase was attributed to the increased amounts of ascitic fluid. EAC-bearing mice with and without MeMet both showed abnormal values of hematological parameters, while those with DMSA and DMSP exhibited almost normal levels on the 10th day.