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على الرغم من أن هجر الأراضي الزراعية والمستوطنات المصاحبة لها كان أمرا شائعا في الماضي إلا أنه أصبح أحد التهديدات الرئيسية للاستخدام المستدام للأراضي. ولقد توسعت الظاهرة لتشمل مختلف أنواع الأراضي المرتفعة والمنخفضة، كما غزت العديد من دول العالم بقاراته المختلفة. تدور معظم أسباب الهجر حول الأخطار الطبيعية المفاجئة والصراعات والرغبة في تغيير استعمالاتها لدوافع اقتصادية واجتماعية وبيئية. وفي سلطنة عمان يعتبر هجر المزارع من أبرز مظاهر التصحر وبخاصة في السهول الساحلية كسهل الباطنة والواحات الجبلية والصحراوية. تهدف الدراسة إلى التعرف على حالة الأراضي الزراعية المهجورة في قرية الرميس بولاية بركاء وأسباب هجرها، وإيضاح الآثار الاقتصادية والاجتماعية والبيئية. تعتمد الدراسة في منهجيتها على العمل الميداني وتسجيل الملاحظات المباشرة عن طبيعة الأراضي الزراعية المهجورة. لقد خلصت الدراسة إلى بروز مجموعة من الأسباب المحفزة لانتشار الأراضي المهجورة زراعيا في قرية الرميس لعل ابرزها: ارتفاع الأجور خارج نطاق الأنشطة الزراعية وارتفاع تكاليف العمل الزراعي بنسبة 87%، إضافة الى مجموعة من الآثار البيئية والاجتماعية والاقتصادية للأراضي المهجورة زراعيا على سكان المنطقة تمثلت في انتشار الحشرات السامة والثعابين بنسبة 89%، وموطنا لمكبات النفايات غير القانونية بنسبة 87%. ومن أبرز توصيات الدراسة: الرغبة في إثارة الموضوع على مستوى المجالس البلدية ومجلس الشورى وضرورة تبني الحكومة للمشاريع المتوسطة والصغيرة لإدارة وتشغيل الأراضي الزراعية المهجورة.

PDE4 inhibitors are expected to be anti-inflammatory agents based on their mechanism of action, but the application of this drug class is limited by a narrow therapeutic window due to adverse effects associated with gastrointestinal function. Difamilast, a novel selective phosphodiesterase 4 (PDE4) inhibitor, demonstrated significant efficacy without adverse reactions such as nausea and diarrhea in patients with atopic dermatitis (AD) and was recently approved in Japan. In this study, we investigated the pharmacological and pharmacokinetic properties of difamilast to provide nonclinical data to help understand the clinical effects. Difamilast selectively inhibited recombinant human PDE4 activity in assays. The IC 50 of difamilast against PDE4B, a PDE4 subtype that plays an important role in the inflammatory response, was 0.0112 μ M, representing a 6.6-fold decrease compared with the IC 50 against PDE4D (0.0738 μ M), a subtype that can trigger emesis. Difamilast inhibited TNF- α production in human (IC 50 = 0.0109 μ M) and mouse (IC 50 = 0.0035 μ M) peripheral blood mononuclear cells and improved skin inflammation in a mouse model of chronic allergic contact dermatitis. These effects of difamilast on TNF- α production and dermatitis were superior to those of other topical PDE4 inhibitors: CP-80633, cipamfylline, and crisaborole. In pharmacokinetic studies using miniature pigs and rats, the concentrations of difamilast in the blood and brain after topical application were not sufficient to support pharmacological activity. This nonclinical study contributes to explain the efficacy and safety of difamilast with a sufficient therapeutic window in the clinical trials. SIGNIFICANCE STATEMENT: This is the first report on the nonclinical pharmacological profile of difamilast ointment, a novel topical PDE4 inhibitor that demonstrated utility in clinical trials in patients with atopic dermatitis. Difamilast, which has high PDE4 selectivity (especially for the PDE4B subtype), ameliorated chronic allergic contact dermatitis in mice after topical application, with a pharmacokinetic profile in animals that suggests few systemic side effects; thus, difamilast is a promising new therapeutic treatment for atopic dermatitis., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Ephedra herb, a dried terrestrial stem of Ephedra sinica, is used in traditional Japanese medicine (Kampo) and Chinese medicine to treat the common cold, headaches, bronchial asthma, and nasal inflammation. E. sinica predominantly contains two ephedrine alkaloids-(-)-ephedrine and (+)-pseudoephedrine-which are crucial for its medicinal effects. This study aimed to reveal the influence of genetic and environmental factors on ephedrine alkaloids content using statistical genetic analyses. To evaluate the influence of genetic factors on ephedrine alkaloids content, 25 clonal lines were cultivated in Ibaraki and the broad-sense heritability of the traits was estimated. The heritabilities of (-)-ephedrine, (+)-pseudoephedrine, and "total alkaloids" (TA) content were 0.871, 0.969, and 0.865, respectively. The heritabilities of ephedrine alkaloids content were high. To evaluate the influence of environmental factors on ephedrine alkaloids content, four clonal lines which have different genotypes were cultivated in three locations (Ibaraki, Shizuoka, and Yamanashi prefectures). The effects of genotype (G), location (L), and genotype by environment (G × E) interactions on ephedrine alkaloids content were found to be significant (p < 0.05) by two-way ANOVA, and, in particular, the genotypic effects were found to be the largest. Our results indicate that the ephedrine alkaloids content in E. sinica is under relatively strong genetic control and remains stable under various environments. These findings suggest that E. sinica with a higher and stable ephedrine alkaloids content could be cultivated in different locations through selective breeding.

Under the hypothesis that olfactory neural epithelium gene expression profiles may be useful to look for disease-relevant neuronal signatures, we examined microarray gene expression in olfactory neuronal cells and underscored Notch-JAG pathway molecules in association with schizophrenia (SZ). The microarray profiling study underscored JAG1 as the most promising candidate. Combined with further validation with real-time PCR, downregulation of NOTCH1 was statistically significant. Accordingly, we reverse-translated the significant finding from a surrogate tissue for neurons, and studied the behavioral profile of Notch1 +/- mice. We found a specific impairment in social novelty recognition, whereas other behaviors, such as sociability, novel object recognition and olfaction of social odors, were normal. This social novelty recognition deficit was male-specific and was rescued by rapamycin treatment. Based on the results from the animal model, we next tested whether patients with psychosis might have male-specific alterations in social cognition in association with the expression of NOTCH1 or JAG1. In our first episode psychosis cohort, we observed a specific correlation between the expression of JAG1 and a face processing measure only in male patients. The expression of JAG1 was not correlated with any other cognitive and symptomatic scales in all subjects. Together, although we acknowledge the pioneering and exploratory nature, the present work that combines both human and animal studies in a reciprocal manner suggests a novel role for the Notch-JAG pathway in a behavioral dimension(s) related to social cognition in psychotic disorders in a male-specific manner., (© 2022. The Author(s).)

Gentle touch such as stroking of the skin produces a pleasant feeling, which is detected by a rare subset of sensory neurons that express Mas-related G protein-coupled receptor B4 (MrgprB4) in mice. We examined small populations of MrgprB4-positive neurons in the trigeminal ganglion and the dorsal root ganglion, and most of these were sensitive to transient receptor potential ankyrin 1 (TRPA1) agonist but not TRPV1, TRPM8, or TRPV4 agonists. Deficiency of MrgprB4 did not affect noxious pain or itch behaviors in the hairless plantar and hairy cheek. Although behavior related to acetone-induced cold sensing in the hind paw was not changed, unpleasant sensory behaviors in response to acetone application or sucrose splash to the cheek were significantly enhanced in Mrgprb4-knockout mice as well as in TRPA1-knockout mice. These results suggest that MrgprB4 in the trigeminal neurons produces pleasant sensations in cooperation with TRPA1, rather than noxious or cold sensations. Pleasant sensations may modulate unpleasant sensations on the cheek via MrgprB4., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Dried terrestrial stems of Ephedra sinica are called 'Ephedra herb,' whose pharmacological effects are due mainly to two major ingredients, (-)-ephedrine and (+)-pseudoephedrine (total alkaloids which are defined in Japanese Pharmacopoeia (TA)). Ephedra herb is an important crude drug in Japan. However, E. sinica is widely distributed in arid areas of northeastern China and Mongolia. Recently, E. sinica has started to be cultivated in Japan. This study aimed to assess the validity of selection breeding on TA content of E. sinica in several locations in Japan. In this experiment, we grew approximately 350 seedlings and divided them randomly into seven groups. Nearly fifty plants were cultivated at each of seven locations. In Ibaraki, Yamanashi, and Shizuoka, average TA content of whole samples satisfied the criteria for Ephedra herb defined in Japanese Pharmacopoeia (7.0 mg/g of dry weight (DW)). Plants with high and intermediate TA content at four locations were selected and transplanted to Ibaraki. There were significant differences in TA content between selected plants with high and intermediate TA content before and after transplanting (p < 0.05). TA content of high-TA plants was significantly higher than that of control plants cultivated continuously at Ibaraki (p < 0.05). These results suggest that the selection on content of ephedrine alkaloids in E. sinica under various locations in Japan is valid, and high- TA E. sinica plants can be selected at various locations.

Dried terrestrial stems of Ephedra sinica are known as 'Ephedra herb.' The pharmacological effects are mainly related to two major ingredients, (-)-ephedrine and (+)-pseudoephedrine (total alkaloids which are defined in Japanese Pharmacopoeia, TA). In this study, in order to aid in cultivation and breeding, the stability of TA content and stem dry weight of 46 E. sinica genets was evaluated from the first year of transplantation to the sixth year. TA content and composition ratio of these genets were stable after the second year, and dry weight was stable after the fourth year. These traits showed high inter-genet variability but low annual variability for each genet. Additionally, rank correlation coefficients of each trait among the genets were high. There was no significant correlation between these traits. Furthermore, to assess the reproducibility of these traits in clones, we evaluated TA content and dry weight of three clonal lines with high TA contents. TA content and composition ratio of the clonal lines were also stable after the second year of transplantation, and dry weight of the clonal lines was also stable after the fourth year. Moreover, TA content and composition ratio in each clonal line were comparable with those of each original genet after the second year. These results suggested that ephedrine alkaloids content and dry weight of E. sinica plants are stable, and that these traits are highly reproducible in clones. Therefore, selection breeding of E. sinica using vegetative propagation can be effective for high and stable quality of Ephedra herb.

Background Diabetic peripheral neuropathy is a common long-term complication of diabetes. Accumulating evidence suggests that vascular impairment plays important roles in the pathogenesis of diabetic peripheral neuropathy, while the mechanism remains unclear. We recently reported that transient receptor potential ankyrin 1 (TRPA1) is sensitized by hypoxia, which can contribute to cold hypersensitivity. In this study, we investigated the involvement of TRPA1 and vascular impairment in painful diabetic peripheral neuropathy using streptozotocin-induced diabetic model mice. Results Streptozotocin-induced diabetic model mice showed mechanical and cold hypersensitivity with a peak at two weeks after the streptozotocin administration, which were likely to be paralleled with the decrease in the skin blood flow of the hindpaw. Streptozotocin-induced cold hypersensitivity was significantly inhibited by an antagonist HC-030031 (100 mg/kg) or deficiency for TRPA1, whereas mechanical hypersensitivity was unaltered. Consistent with these results, the nocifensive behaviors evoked by an intraplantar injection of the TRPA1 agonist allyl isothiocyanate (AITC) were enhanced two weeks after the streptozotocin administration. Both streptozotocin-induced cold hypersensitivity and the enhanced AITC-evoked nocifensive behaviors were significantly inhibited by a vasodilator, tadalafil (10 mg/kg), with recovery of the decreased skin blood flow. Similarly, in a mouse model of hindlimb ischemia induced by the ligation of the external iliac artery, AITC-evoked nocifensive behaviors were significantly enhanced three and seven days after the ischemic operation, whereas mechanical hypersensitivity was unaltered in TRPA1-knockout mice. However, no difference was observed between wild-type and TRPA1-knockout mice in the hyposensitivity for current or mechanical stimulation or the deceased density of intraepidermal nerve fibers eight weeks after the streptozotocin administration. Conclusion These results suggest that TRPA1 sensitization during diabetic vascular impairment causes cold, but not mechanical, hypersensitivity in the early painful phase of diabetic peripheral neuropathy. However, TRPA1 may play little or no role in the progression of diabetic peripheral neuropathy.

Lysophosphatidic acid (LPA) plays an important role in a variety of cellular functions. In particular, LPA5 receptor is highly expressed in spinal cord and dorsal root ganglion, which are associated with pain. This fact prompted us to hypothesize that LPA5 antagonists show analgesic effects. To search for potent LPA5 antagonists with blood brain barrier (BBB) permeability, we conducted high throughput screening (HTS). In HTS campaign, we found a 2H-isoquinoline-1-one scaffold showing antagonistic activity against LPA5 and synthesized a series of 2H-isoquinoline-1-one derivatives and evaluated their LPA5 activities. Among these compounds, compound 7e showed potent LPA5 activity with an IC 50 value of 0.12 μM, and acceptable BBB permeability. Furthermore, it showed effective analgesic effect in a chronic constriction injury rat model. Therefore, 7e may have a potential as novel pain therapeutic approach., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and (2) the pharmacological effects of a novel LPA5 antagonist on intrathecal prostaglandin (PG)- and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced allodynia, and neuropathic and inflammatory pain in rodents. Intrathecal injection of a selective LPA5 agonist, geranylgeranyl diphosphate, and a non-selective agonist, LPA, induced allodynia in wild type, but not in LPA5 knockout mice. These novel results suggest that LPA5 is important for pain signal transmission in the spinal cord. AS2717638 (6,7-dimethoxy-2-(5-methyl-1,2-benzoxazol-3-yl)-4-(piperidin-1-ylcarbonyl)isoquinolin-1(2H)-one) bound to the LPA-binding site on LPA5 and selectively inhibited LPA-induced cyclic adenosine monophosphate accumulation in human LPA5-but not LPA1-, 2-, or 3-expressing cells. Further, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 also significantly improved PGE 2 -, PGF 2α -, and AMPA-induced allodynia, while both pregabalin and duloxetine alleviated only PGE 2 -induced allodynia in mice. Similarly, AS2717638 significantly ameliorated static mechanical allodynia and thermal hyperalgesia in rat models of chronic constriction injury (CCI)-induced neuropathic pain. AS2717638 also showed analgesic effects in a rat model of inflammatory pain. These findings suggest that LPA5 antagonists elicit broad analgesic effects against both neuropathic and inflammatory pain. Accordingly, pharmacological LPA5 antagonists are attractive development candidates for potential novel pain therapies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The Ephedra herb, which has been used in Kampo medicines, originates from terrestrial stems of Ephedra species. It is important to establish cultivation methods and cultivars to secure a stable supply of the Ephedra herb that would meet the quality standards for the ephedrine alkaloids content. In this study, we first grew Ephedra sinica plants derived from seeds in the field for 5 years. Then, for selective breeding of cultivars that could meet the quality standards for the ephedrine alkaloids content, we measured the content of total alkaloids (TAs), ephedrine (Eph), and pseudoephedrine (PEph) in individual plants derived from seedlings and grown for 4 years in the field. The range of the TA content in each individual plant was narrower than that among individual plants grown in the field. Therefore, individual plants were selected according to their TA content, Eph/PEph ratio, and stolon-formation capability. The selected individuals were propagated using stolons, and their TA content was studied for 2 years. In the second year, the TA content in terrestrial stems derived from stolons of the selected individuals was as high as that of their parents. Therefore, it was confirmed that the selected individuals that were propagated using stolons could produce TA reproducibly. This study suggested that selective breeding using stolon propagation is effective for stabilizing Ephedra herb TA content.

Background: Acute postoperative pain is induced by most incisional surgeries and usually resolves with wound repair. However, many patients experience moderate to severe pain despite receiving currently available postoperative pain relief. Accumulating evidence suggests that inflammatory cells, neutrophils, and macrophages infiltrating the wound site contribute to the acute inflammation, pain, and subsequent wound repair. Colchicine is commonly used to relieve pain in gout by inhibiting the infiltration of granulocytes and other motile cells. In this study, we examined the effects of colchicine on acute postoperative pain and wound repair by correlating the infiltration of neutrophils and macrophages in a mouse model of postoperative pain induced by plantar incision. Furthermore, these effects of colchicine were compared with clodronate liposomes, which selectively deplete circulating macrophages., Results: Plantar incision induced mechanical hypersensitivity in the ipsilateral hind paw that peaked one day and lasted for three days after the surgery. Treatment with colchicine significantly attenuated the early infiltration of Gr1-positive cells (neutrophils) around the incision site and mechanical hypersensitivity, which was accompanied with inhibition of the subsequent infiltration of Iba1-positive cells (macrophages) and macrophage polarization toward the proinflammatory M1 phenotype. By contrast, an intravenous injection of clodronate liposomes significantly inhibited the infiltration of macrophages around the incision site but had little effect on the infiltration of neutrophils or mechanical hypersensitivity. Importantly, colchicine treatment significantly delayed wound closure after the incisional surgery, whereas clodronate liposome administration had no effect on wound closure., Conclusion: These results suggest that colchicine can alleviate acute postoperative pain and also enhance the risk of delayed wound repair, which are associated with the suppression of neutrophil and subsequent proinflammatory M1 macrophage infiltration around the incision site, while the involvement of macrophages may be limited.