Diffusive mediator feedbacks control the health-to-disease transition of skin inflammation.

The spatiotemporal dynamics of inflammation provide vital insights into the understanding of skin inflammation. Skin inflammation primarily depends on the regulatory feedback between pro- and anti-inflammatory mediators. Healthy skin exhibits fading erythema. In contrast, diseased skin exhibits expanding erythema with diverse patterns, which are clinically classified into five types: circular, annular, arcuate, gyrate, and polycyclic. Inflammatory diseases with expanding erythema are speculated to result from the overproduction of pro-inflammatory mediators. However, the mechanism by which feedback selectively drives the transition from a healthy fading erythema to each of the five types of diseased expanding erythema remains unclear. This study theoretically elucidates the imbalanced production between pro- and anti-inflammatory mediators and prospective treatment strategies for each expanding pattern. Our literature survey showed that eleven diseases exhibit some of the five expanding erythema, thereby suggesting a common spatiotemporal regulation underlying different patterns and diseases. Accordingly, a reaction-diffusion model incorporating mediator feedback reproduced the five observed types of diseased expanding and healthy fading patterns. Importantly, the fading pattern transitioned to the arcuate, gyrate, and polycyclic patterns when the productions of anti-inflammatory and pro-inflammatory mediators were lower and higher, respectively than in the healthy condition. Further depletion of anti-inflammatory mediators caused a circular pattern, whereas further overproduction of pro-inflammatory mediators caused an annular pattern. Mechanistically, the bistability due to stabilization of the diseased state exhibits circular and annular patterns, whereas the excitability exhibits the gyrate, polycyclic, arcuate, and fading patterns as the threshold of pro-inflammatory mediator concentration relative to the healthy state increases. These dynamic regulations of diffusive mediator feedback provide effective treatment strategies for mediator production wherein skins recover from each expanding pattern toward a fading pattern. Thus, these strategies can estimate disease severity and risk based on erythema patterns, paving the way for developing noninvasive and personalized treatments for inflammatory skin diseases.

Traveling wave of inflammatory response to regulate the expansion or shrinkage of skin erythema.

Many skin diseases show circular red lesions on the skin, called erythema. Erythema is characterized by the expansion of its circular area solely from local stimulation. A pathological inflammatory response caused by the stimulation persistently increases inflammatory mediators in the dermis, whereas a normal inflammatory response transiently increases mediators, resulting in the shrinkage of the erythema. Although the diffusion of mediators theoretically reproduces the expansion, how the inflammatory response expands or shrinks the erythema remains unknown. A possibility is positive feedback, which affects mediator production and can generate two distinct stable states (i.e., inflamed and noninflamed), referred to as bistability. Bistability causes a state transition either from the noninflamed to inflamed state or the reverse direction by suprathreshold stimulation. Additionally, the diffusion selectively causes state transition in either direction, resulting in spatial spread of the transited state, known as the traveling wave. Therefore, we hypothesize that the traveling wave of the inflammatory response can account for both the expansion and shrinkage. Using a reaction-diffusion model with bistability, we theoretically show a possible mechanism in which the circular inflamed area expands via the traveling wave from the noninflamed to the inflamed state. During the expansion, the boundary between the inflamed and noninflamed areas moves at a constant velocity while maintaining its concentration gradient. Moreover, when the positive feedback is weak, the traveling wave selectively occurs from the inflamed to noninflamed state, shrinking the inflamed area. Whether the inflamed area expands or shrinks is mainly controlled by the balance of mediator concentration between the noninflamed and inflamed states, relative to the threshold. The traveling wave of the inflammatory response provides an experimentally testable framework for erythema expansion and shrinkage, thereby contributing to the development of effective treatments, including probiotics.

The effect of lentinan combination therapy for unresectable advanced gastric cancer.

BACKGROUND: Developed as a biological response modifier (BRM), lentinan mitigates patients' symptoms by boosting the immune system. In combination with S-1 (tegafur, gimeracil, oteracil), lentinan is reported to mitigate adverse reactions to therapy for unresectable recurrent gastric cancer and prolong survival. However, there are few reports from actual clinical practice, and precise methods of using lentinan have not yet been established. This study retrospectively examined the usefulness of lentinan in patients. PATIENTS AND METHODS: The subjects of this study were 39 patients who were diagnosed with unresectable gastric cancer, based on preoperative examinations or findings at laparotomy in our Department. These patients underwent S-1/paclitaxel therapy. Nineteen of the patients received lentinan while 20 did not, and these two groups of patients were compared. RESULTS: There were no significant differences in patients' characteristics such as the male:female ratio, age at the start of chemotherapy, and staging classification of the 19 patients receiving lentinan and the 20 patients not receiving lentinan. Comparison of the two groups revealed no significant differences in overall survival time, but comparison of the duration of therapy revealed that therapy tended to be longer for the group taking lentinan than the group not taking lentinan. Adverse events were noted in 61.5% (24 patients) of the total patients group; such events tended to occur less frequently in the group receiving lentinan. CONCLUSION: Lentinan inclusion in therapy did not seem to prolong survival. Nevertheless, the duration of therapy tended to be longer for patients taking lentinan. This may be due to the fact that adverse events tended to occur less frequently in these patients during therapy. A decline in the incidence of adverse events increases the duration of therapy and improves the patients' quality of life (QOL); it may also prolong survival. Optimal methods of using lentinan need to be established.

Highly selective and simple method for determination of polythiols based on liquid chromatography with postcolumn excimer fluorescence derivatization.

An LC postcolumn derivatization method for determination of polythiols has been developed. This method involves separation using reversed-phase LC, postcolumn derivatization with N-(1-pyrenyl)maleimide, and excimer fluorescence detection. Analytes with a polythiol structure were converted into corresponding polypyrene-labeled derivatives, and the derivatives exhibited intramolecular excimer fluorescence (440-520 nm). In this study, dimercaprol and dithiothreitol were used as model polythiols. This polythiol analysis method is simple; it is also highly selective and sensitive and yields good calibration curves.

Liquid chromatographic determination of polythiols based on pre-column excimer fluorescence derivatization and its application to alpha-lipoic acid analysis.

We developed an LC method for the sensitive and selective fluorometric determination of polythiols. This method employs pre-column intramolecular excimer-forming fluorescence derivatization with N-(1-pyrene)iodoacetamide followed by LC separation. Polythiols were converted to the corresponding dipyrene-labeled derivatives, and the derivatives afforded intramolecular excimer fluorescence (440-540 nm). After the optimization using dithiothreitol and dimercaprol as model polythiols, alpha-lipoic acid (LA) and alpha-lipoamide were determined with high sensitivity and selectivity. The detection limits for polythiols were 0.6-3.5 fmol on column. Furthermore, this method could be successfully applied to the determination of LA in commercial dietary supplements and in human urine.