Development of a Customized Endoscopic Dual-Diffusing Optical Fiber Probe for Pancreatic Cancer Therapy: Toward Clinical Use.

Objective: We developed a dual-diffusing optical fiber probe (DDOFP), capable of uniformly illuminating the anatomical structure of pancreatic duct for photodynamic therapy (PDT) of pancreatic cancer in clinical settings. Background: Optical fiber presents a unique route for pancreatic PDT by enabling access to the pancreatic duct. For effective pancreatic PDT, the optical fiber should produce a uniform illumination covering of the pancreatic duct, while maintaining its transmission property under thermomechanical stresses in surgical environments. Methods: The transmission profiles of DDOFP were measured using a charge-coupled device (CCD) camera at two directions: front-spherical and side-cylindrical areas of the optical fiber. We simulated the change in transmission property by curved tube structures using optically transparent phantom. DDOFP was integrated with 19-gauge needle catheter that is commercially used as an optical guide to treat pancreatic cancer. The temperature of DDOFP was measured at the end face using a thermistor probe in the bovine tissue, while delivering laser energy of over 200 and 500 J. Results: DDOFP was customized to secure the inner diameter of the 19-gauge needle catheter of 686 µm to be integrated as a clinical device. The round ball lens fiber tip minimized the back-burn effect caused by blood carbonization during surgery and induced front-spherical diffusion. DDOFP produced uniform light illumination with intensity difference of <10%. When DDOFP was bent with a small curvature <15 mm, the transmission intensity was consistent. Under high-power laser transmission, DDOFP was found to be robust to cracking or deformation. Conclusions: DDOFP was customized for pancreatic PDT with superior thermomechanical property and uniform light illumination at both the front-spherical and side-cylindrical areas. This is the smallest clinically available optical fiber per our knowledge and officially approved by the Korea Food and Drug Administration (item approval number: 17-516). DDOFP can contribute immensely toward the efficient delivery of pancreatic PDT and photothermal therapy.

Identification of Sex Pheromone Components of Korean Dioryctria abietella (Lepidoptera: Pyralidae) Population and Synergism of Pheromone and Pine Cone Volatile Blends.

(9Z,11E)-tetradecadienyl acetate (9Z,11E-14:OAc) and (3Z,6Z,9Z,12Z,15Z)-pentacosapentaene (C25 pentaene), known as the sex pheromone of the European Dioryctria abietella population, were identified in the Korean D. abietella population. The ratio of 9Z,11E-14:OAc to C25 pentaene extracted from female pheromone glands was 1:23. The electroantennogram (EAG) response of male antennae to 9Z,11E-14:OAc was stronger than to C25 pentaene, whereas an opposite EAG response was observed in female antennae. Major volatile compounds in mature Korean pine cone (Pinus koraiensis), such as limonene, myrcene, and (-)-α-pinene, elicited dose-dependent EAG responses of male and female antennae. In field attraction testing, traps baited with 100:1,000, 100:2,000, and 100:3,000 ug of 9Z,11E-14:OAc to C25 pentaene were the most attractive to male D. abietella. More males were attracted to traps baited with 9Z,11E-14:OAc+C25 pentaene+limonene than traps baited with 9Z,11E-14:OAc+C25 pentaene. This showed that limonene acted as a synergist to sex pheromone. Delta traps, wing traps, and diamond traps were superior to bucket traps for capturing D. abietella males. This study showed that pheromone traps baited with 100:1,000 ~ 100:3,000 ug of 9Z,11E-14:OAc to C25 pentaene and limonene will be useful for the exact monitoring of D. abietella flight phenology in Pinus koraiensis Sieb. & Zucc. (Pinales: Pinaceae) forests.

Evaluation of thermal/acoustic performance to confirm the possibility of coffee waste in building materials in using bio-based microencapsulated PCM.

As the demand for coffee has increased, by-product disposal has become a challenge to solve. Many studies are being conducted on how to use coffee waste as building materials to recycle it. In this study, the thermal performance and acoustic performance of a composite developed using bio-based microencapsulated phase change material (MPCM) and coffee waste were evaluated, and the composite was applied as building material. The coffee waste was successfully degreased with ethanol to produce composites, and removal of contaminants and oils was confirmed via scanning electron microscopy. In the phase change process of MPCM, an appropriate amount of thermal energy is absorbed and stored, and the temperature is maintained. MPCM was used in the mixture and the improved thermal performance was evaluated via differential scanning calorimetry analysis, revealing a latent heat of 3.8 J/g for MPCM content of 10%. Further, thermal imaging cameras revealed that an increase in the proportion of MPCM leads to a slower decrease in temperature because of the heat preserved by MPCM over time. In an acoustic performance evaluation, impedance tube test results showed different aspects depending on low, mid, and high-frequency bands. Specifically, at medium frequencies, which correspond to the range of noise generated in cafes, specimens fabricated using MPCM were confirmed to exhibit a higher sound absorption coefficient and an improved acoustic performance. Hence, the composite can be considered an eco-friendly building material with promising thermal and acoustic performance.

Identification of the Female-Produced Sex Pheromone of the Dotted White Geometrid Naxa seriaria (Lepidoptera: Geometridae).

The dotted white geometrid moth, Naxa seriaria Motschulsky (Lepidoptera: Geometridae), is a pest of Oleaceae in Korea, Japan, and China. In this study, we identified (3Z,6Z,9Z,12Z,15Z)-heneicosapentaene (C-21 pentaene) as the only compound in extracts of the pheromone glands of female N. seriaria causing a response from receptors on the antennae of males in analyses by gas chromatography with electroantennographic detection. The synthetic sex pheromone elicited dose-dependent electrophysiological responses from antennae of male N. seriaria. In field tests, more male moths were captured in traps baited with synthetic C-21 pentaene than in unbaited traps, and increasing the loading of C-21 pentaene in the lure increased catches of male moths. Significantly more male N. seriaria moths were caught in delta traps than in bucket traps. Based on these results, C-21 pentaene is proposed to be the major, if not the only, component of the sex pheromone of N. seriaria.

Reactive oxygen species mediated-antifungal activity of cinnamon bark (Cinnamomum verum) and lemongrass (Cymbopogon citratus) essential oils and their constituents against two phytopathogenic fungi.

To find new and safe type of control agents against phytopathogenic fungi, the fumigant antifungal activity of 10 plant essential oils and constituents identified in cinnamon bark (Cinnamomum verum) and lemongrass (Cymbopogon citratus) essential oils was investigated against two phytopathogenic fungi, Raffaelea quercus-mongolicae and Rhizoctonia solani. Among plant essential oils, cinnamon bark and lemongrass essential oils showed 100% inhibition of R. quercus-mongolicae and R. solani at 5 mg/paper disc, respectively. Among test constituents, salicylaldehyde, eugenol, and hydrocinnamaldehyde showed 100% inhibition of growth of R. quercus-mongolicae at 2.5 mg/paper disc. Neral, geraniol, geranial, trans-cinnamaldehyde, methyl cinnamate, isoeugenol, and methyl eugenol exhibited >80% inhibition of growth of R. quercus-mongolicae at 2.5 mg/paper disc. Neral, geranial, trans-cinnamaldehyde, hydrocinnamaldehyde, and salicylaldehyde showed 100% inhibition of growth of R. solani at 2.5 mg/paper disc. A fumigant antifungal bioassay of artificial blends of the constituents identified in cinnamon bark and lemongrass essential oils indicated that trans-cinnamaldehyde and geranial were major contributors to the fumigant antifungal activity of the artificial blend. Confocal laser scanning microscopy images of fungi treated with cinnamon bark and lemongrass essential oils, trans-cinnamaldehyde, neral, and geranial revealed the reactive oxygen species (ROS) generation and cell membrane disruption.

Antibacterial mode of action of trans-cinnamaldehyde derived from cinnamon bark (Cinnamomum verum) essential oil against Agrobacterium tumefaciens.

The fumigant antibacterial activities of 50 plant essential oils belonging to 10 families were investigated against Agrobacterium tumefaciens. Among the test plant essential oils, Cinnamomum verum (cinnamon bark) essential oil showed the most potent fumigant antibacterial activity. When we investigated the antibacterial activities of compounds identified from cinnamon bark essential oil and 9 congeners of trans-cinnamaldehyde, lengths of inhibition zone of trans-cinnamaldehyde, salicylaldehyde and hydrocinnamaldehyde were 1.28, 1.73, and 1.24 cm at 0.625 mg/paper disc concentration, respectively. To determine the mode of action of trans-cinnamaldehyde and salicylaldehyde, intercellular reactive oxygen species (ROS) generation and cell membrane integrity were determined using a confocal laser scanning microscopy. Furthermore, we compared the up- and down-regulated gene expression of A. tumefaciens treated with trans-cinnamaldehyde and salicylaldehyde with that of untreated A. tumefaciens. With cutoffs of |log2FC| > 1 and FDR < 0.05, 29 and 43 down-regulated genes and 27 and 117 up-regulated genes were found in the treatment of trans-cinnamaldehyde and salicylaldehyde, respectively. Based on the ROS generation results, cell membrane integrity assay, and gene expression, we conclude that the antibacterial mode of action of trans-cinnamaldehyde and salicylaldehyde is ROS generation by the Fenton reaction caused by the down-regulation of an ATP synthesis-related gene cluster, corrupted iron ion homeostasis, and a corrupted ROS defense mechanism. The high concentration of ROS damaged the A. tumefaciens cell membrane, which caused cell death.

Circular reutilization of coffee waste for sound absorbing panels: A perspective on material recycling.

The increase in coffee consumption has led to increased production of coffee waste. Methods to recycle coffee waste are constantly being researched. Coffee powder is a porous material that can effectively be used to absorb sound. In this study, sound-absorbing panels were developed using coffee waste combined with resin. A sound absorption characterization of the new material was performed. Then, the noise reduction potential using coffee-waste sound absorbers was investigated in cafés. A café has several noise sources, such as coffee machines, music, and the voices of people. The noise reduction effect was evaluated using the ODEON simulation software together with the improvement in both the clarity and reverberation time in a case study café. In the investigated room, the acoustic definition (D50) increased up to 0.8, while the reverberation time (RT) reduced to 0.6 s. The results of this study demonstrate that the noise generated in the café was reduced by recycling the coffee waste produced as a by-product in the same building. Finally, this study presents a new construction material manufactured through coffee waste that is in turn applied to cafés where the coffee waste itself is produced.

Behavioral and Electrophysiological Effects of Ajowan (Trachyspermum ammi Sprague) (Apiales: Apiaceae) Essential Oil and Its Constituents on Nymphal and Adult Bean Bugs, Riptortus clavatus (Thunberg) (Hemiptera: Alydidae).

We investigated the repellent effect of 12 Apiaceae plant essential oils on nymphal and adult (male and female) forms of the bean bug, Riptortus clavatus (Thunberg) (Hemiptera: Alydidae), using a four-arm olfactometer. Among the essential oils tested, ajowan (Trachyspermum ammi Sprague) essential oil showed the strongest repellent activity against the nymphal and adult bean bugs. For female adults, the repellent activity was significantly different between an ajowan oil-treated chamber and an untreated chamber down to a concentration of 14.15 µg/cm2. We also investigated the repellent activity of individual ajowan essential oil constituents. Of the compounds examined, carvacrol and thymol showed the most potent repellent activity against the nymphal and adult bean bugs. Carvacrol and thymol exhibited 73.08% and 70.0% repellent activity for the bean bug nymph at 0.71 and 2.83 µg/cm2, respectively, and 82.6% and 80.7% at 5.66 and 11.32 µg/cm2, respectively, for male adults. Carvacrol and thymol exhibited strong repellent activity against female adult bean bugs down to a concentration of 2.83 µg/cm2. Ajowan essential oil, thymol and carvacrol elicited a negative electroantennogram (EAG) response from adult bean bugs. This could explain the repellent activity of ajowan essential oil and its constituents. Our results indicate that ajowan essential oil and its constituents carvacrol and thymol can be potential candidates as the 'push' component in a 'push-pull' strategy for bean bug control.

Fumigant Antifungal Activity via Reactive Oxygen Species of Thymus vulgaris and Satureja hortensis Essential Oils and Constituents against Raffaelea quercus-mongolicae and Rhizoctonia solani.

In this study, the fumigant antifungal activity of 10 Lamiaceae plant essential oils was evaluated against two phytopathogenic fungi, Raffaelea quercus-mongolicae, and Rhizoctonia solani. Among the tested essential oils, thyme white (Thymus vulgaris) and summer savory (Satureja hortensis) essential oils exhibited the strongest fumigant antifungal activity against the phytopathogenic fungi. We analyzed the chemical composition of two active essential oils and tested the fumigant antifungal activities of the identified compounds. Among the tested compounds, thymol and carvacrol had potent fumigant antifungal activity. We observed reactive oxygen species (ROS) generation in two fungi treated with thymol and carvacrol. Confocal laser scanning microscopy images of fungi stained with propidium iodide showed that thymol and carvacrol disrupted fungal cell membranes. Our results indicated that ROS generated by thymol and carvacrol damaged the cell membrane of R. querqus-mongolicae and R. solani, causing cell death.

Effects of Pheromone Dose and Trap Height on Capture of a Bast Scale of Pine, Matsucoccus thunbergianae (Hemiptera: Margarodidae) and Development of a New Synthesis Method.

Matsuone is a well-known sex pheromone of the genus Matsucoccus (Hemiptera: Margarodidae), including species Matsucoccus matsumurae (Kuwana), Matsucoccus resinosae Bean & Goldwin, and Matsucoccus thunbergianae Miller & Park. In this study, we investigated the effects of matsuone dose and trap height on the capture of M. thunbergianae and developed an alternative synthesis of racemic matsuone. In field trapping experiments, M. thunbergianae males showed dose-dependent attraction to (6R,10R/S)-matsuone from 100 µg up to an approximate saturation level of 1,600 µg per rubber septum lure. Traps baited with (6R,10R/S)-matsuone and installed 50 cm above ground level attracted more males than traps 100 and 150 cm above ground level. To reduce synthesis procedures, time, and labor, we developed a new synthetic route to racemic matsuone and conducted field experiments with the product. Although traps baited with the racemic matsuone were less attractive than traps baited with (6R,10R/S)-matsuone synthesized by a previously reported method, the new synthetic route could be an economically favorable alternative to the previous method used in production of lures for field application.

Imaging inflammation using an activated macrophage probe with Slc18b1 as the activation-selective gating target.

Activated macrophages have the potential to be ideal targets for imaging inflammation. However, probe selectivity over non-activated macrophages and probe delivery to target tissue have been challenging. Here, we report a small molecule probe specific for activated macrophages, called CDg16, and demonstrate its application to visualizing inflammatory atherosclerotic plaques in vivo. Through a systematic transporter screen using a CRISPR activation library, we identify the orphan transporter Slc18b1/SLC18B1 as the gating target of CDg16.

Identification of Aggregation-Sex Pheromone of the Korean Monochamus alternatus (Coleoptera: Cerambycidae) Population, the Main Vector of Pine Wood Nematode.

We confirmed an aggregation-sex pheromone of the Korean Monochamus alternatus Hope (Coleoptera: Cerambycidae) population, which primarily transmitted the pine wood nematode in Korea. Only the M. alternatus male emitted monochamol which has been previously reported in the Chinese M. alternatus population. In field attraction testing, the monochamol+α-pinene+ethanol combination attracted more M. alternatus adult beetles than traps containing only monochamol, ethanol, or α-pinene. The bark beetle aggregation pheromone compounds of ipsenol, ipsdienol, and ipsenol+ipsdienol, did not show synergistic effects with the monochamol+α-pinene+ethanol combination. No synergistic effects were observed when each host volatile compound of 3-carene, ß-caryophyllene, limonene, myrcene, and ß-pinene was added to traps containing monochamol+α-pinene+ethanol. The ratio of female beetles was much higher in traps containing the monochamol+α-pinene+ethanol combination than that of the natural population. Our results indicated that pheromone and synergists could be useful for managing the M. alternatus population.

Insecticidal Activity of Lamiaceae Plant Essential Oils and Their Constituents Against Blattella germanica L. Adult.

The insecticidal activities of 13 Lamiaceae plant oils and their components against adult German cockroaches, Blattella germanica L. (Blattodea: Blattellidae), were evaluated using fumigant and contact bioassay. Among the tested oils, basil, pennyroyal, and spearmint showed the strongest insecticidal activities against adult B. germanica. Insecticidal activity of pennyroyal was 100% against male B. germanica at 1.25 mg concentration in fumigant bioassay. Basil and spearmint revealed 100% and 100% insecticidal activity against male B. germanica at 5 mg concentration, but their activities reduced to 80% and 25% at 2.5 mg concentration, respectively. In contact, toxicity bioassay, basil, pennyroyal, and spearmint oils exhibited 100%, 100%, and 98% mortality against female B. germanica at 1 mg/♀, respectively. Among the constituents identified in basil, pennyroyal, and spearmint oils, insecticidal activity of pulegone was the strongest against male and female B. germanica.

Nematicidal Activity of 3-Acyltetramic Acid Analogues Against Pine Wood Nematode, Bursaphelenchus xylophilus.

Among 98 3-acyltetramic acid analogues, compounds 1c, 2c, 2f and 2g, showed >90% nematicidal activity against the pine wood nematode Bursaphelenchus xylophilus at a 10 µg/mL concentration. The nematicidal activities of compounds 1d, 1h, and 2k were a little lower at 88.0%, 85.8%, and 57.2% at a 10 µg/mL concentration, respectively. The nematicidal activity of emamection benzoate, widely used in Korea for the prevention of pine wilt disease, was 32.3% at a 10 µg/mL concentration. Other 3-acyltetramic acid analogues showed less than 30% nematicidal activity. A structure-activity relationship study indicated that the chain length of the C-acyl substituent was very important for high nematicidal activity. All active compounds had C13H27 or C11H23 acyl substituents, in two closely related groups with the common physicochemical properties of a polar surface area 57.6A², PSA (polar surface area) 7.8-8.6% and ClogP (calculated partition coefficient) 5.1-5.9 and a polar surface area 75-84A², PSA 11.1-11.6% and ClogP 4.7-5.1, respectively. Our study indicates that active 3-acyltetramic acid analogues could have potential as lead compounds for developing novel pine wood nematode control agents.

Identification of the Aggregation-sex Pheromone Produced by Male Monochamus saltuarius, a Major Insect Vector of the Pine Wood Nematode.

In this study, we isolated and identified an aggregation-sex pheromone from Monochamus saltuarius, the major insect vector of the pine wood nematode in Korea. Adult males of M. saltuarius produce 2-undecyloxy-1-ethanol, which is known as an aggregation-sex pheromone in other Monochamus species. We performed field experiments to determine the attractiveness of the pheromone and other synergists. More M. saltuarius adult beetles were attracted to traps baited with the pheromone than to unbaited traps. Ethanol and (-)-α-pinene interacted synergistically with the pheromone. Traps baited with the pheromone + (-)-α-pinene +ethanol were more attractive to M. saltuarius adults than traps baited with the pheromone, (-)-α-pinene, or ethanol alone. Ipsenol, ipsdienol, and limonene were also identified as synergists of the aggregation-sex pheromone for M. saltuarius adults. In field experiments, the proportion of females was much higher in the beetles caught in traps than among the beetles emerging from naturally-infested logs in the laboratory. Our results suggest that a combination of aggregation-sex pheromone and synergists could be very effective for monitoring and managing M. saltuarius.

Optical visualisation of thermogenesis in stimulated single-cell brown adipocytes.

The identification of brown adipose deposits in adults has led to significant interest in targeting this metabolically active tissue for treatment of obesity and diabetes. Improved methods for the direct measurement of heat production as the signature function of brown adipocytes (BAs), particularly at the single cell level, would be of substantial benefit to these ongoing efforts. Here, we report the first application of a small molecule-type thermosensitive fluorescent dye, ERthermAC, to monitor thermogenesis in BAs derived from murine brown fat precursors and in human brown fat cells differentiated from human neck brown preadipocytes. ERthermAC accumulated in the endoplasmic reticulum of BAs and displayed a marked change in fluorescence intensity in response to adrenergic stimulation of cells, which corresponded to temperature change. ERthermAC fluorescence intensity profiles were congruent with mitochondrial depolarisation events visualised by the JC-1 probe. Moreover, the averaged fluorescence intensity changes across a population of cells correlated well with dynamic changes such as thermal power, oxygen consumption, and extracellular acidification rates. These findings suggest ERthermAC as a promising new tool for studying thermogenic function in brown adipocytes of both murine and human origins.

APX-115, a first-in-class pan-NADPH oxidase (Nox) inhibitor, protects db/db mice from renal injury.

Recent studies have suggested that renal Nox is important in the progression of diabetic nephropathy. Therefore, we investigated the effect of a novel pan-NOX-inhibitor, APX-115, on diabetic nephropathy in type 2 diabetic mice. Eight- week-old db/m and db/db mice were treated with APX-115 for 12 weeks. APX-115 was administered by oral gavage at a dose of 60 mg/kg per day. To compare the effects of APX-115 with a dual Nox1/Nox4 inhibitor, db/db mice were treated with GKT137831 according to the same protocol. APX-115 significantly improved insulin resistance in diabetic mice, similar to GKT137831. Oxidative stress as measured by plasma 8-isoprostane level was decreased in the APX-115 group compared with diabetic controls. All lipid profiles, both in plasma and tissues improved with Nox inhibition. APX-115 treatment decreased Nox1, Nox2, and Nox4 protein expression in the kidney. APX-115 decreased urinary albumin excretion and preserved creatinine level. In diabetic kidneys, APX-115 significantly improved mesangial expansion, but GKT137831 did not. In addition, F4/80 infiltration in the adipose tissue and kidney decreased with APX-115 treatment. We also found that TGF-ß stimulated ROS generation in primary mouse mesangial cells (pMMCs) from wild-type, Nox1 KO, and Duox1 KO mice, but did not induce Nox activity in pMMCs from Nox2 knockout (KO), Nox4 KO, or Duox2 KO mice. These results indicate that activating Nox2, Nox4, or Duox2 in pMMCs is essential for TGF-ß-mediated ROS generation. Our findings suggest that APX-115 may be as effective or may provide better protection than the dual Nox1/Nox4 inhibitor, and pan-Nox inhibition with APX-115 might be a promising therapy for diabetic nephropathy.

Direct organelle thermometry with fluorescence lifetime imaging microscopy in single myotubes.

We describe organelle thermometry using an endoplasmic reticulum-targeting small molecule dye and cytosolic mCherry, whose fluorescence lifetimes reduce with increasing temperature and can be monitored by fluorescence lifetime imaging microscopy. The results show that heat production in single myotubes is highly localized and is coupled to a Ca(2+) burst.

A novel fluorescence-based assay for measuring A2E removal from human retinal pigment epithelial cells to screen for age-related macular degeneration inhibitors.

Age-related macular degeneration (AMD) is a common retinal disease that leads to irreversible central vision loss in the elderly population. Recent studies have identified many factors related to the development of dry AMD, such as aging, cigarette smoking, genetic predispositions, and oxidative stress, eventually inducing the accumulation of lipofuscin, which is one of the most critical risk factors. One of the major lipofuscins in retinal pigment epithelial (RPE) cells is N-retinylidene-N-retinylethanolamine (also known as A2E), a pyridinium bis-retinoid. Currently there is a lack of effective therapy to prevent or restore vision loss caused by dry AMD. Recent studies have shown that 430 nm blue light induces the oxidation of A2E and the activation of caspase-3 to subsequently cause the death of RPE cells, suggesting that removal of A2E from retinal pigment cells might be critical for preventing AMD. Here, we developed a fluorescence-labeled A2E analog (A2E-BDP) that functions similar to A2E in RPE cells, but is more sensitive to detection than A2E. A2E-BDP-based tracing of intracellular A2E will be helpful, not only for studying the accumulation and removal of A2E in human RPE cells but also for identifying possible inhibitors of AMD.

Suppression of the TRIF-dependent signaling pathway of Toll-like receptor by CDr10b in RAW264.7 macrophages.

Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns and play a critical role in innate immune responses. TLR signaling pathways can be largely classified as either myeloid differential factor 88 (MyD88)- or toll-interleukin-1 receptor domain-containing adapter inducing interferon-ß (TRIF)-dependent pathways. Compound of Designation red 10 binding (CDr10b) was synthesized to investigate its role in neuroinflammatory diseases. This study was conducted to determine whether CDr10b can affect TLR signaling pathways. CDr10b suppressed NF-κB activation as well as COX-2 and iNOS expression induced by TLR3 or TLR4 agonists. CDr10b also suppressed the activation of interferon regulatory factor 3 (IRF3) and the expression of interferon inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. These results indicate that CDr10b can modulate the TRIF-dependent pathway of TLRs and has the potential to become a new therapeutic drug for chronic inflammatory diseases.