Suppression of glucose-6-phosphate-isomerase induced arthritis by oral administration of transgenic rice seeds expressing altered peptide ligands of glucose-6-phosphate-isomerase

Objective: To investigate the effects of transgenic rice seeds expressing the altered peptide ligand (APL) of human glucose-6-phosphate-isomerase (hGPI_325–339) in mice model of GPI-induced arthritis (GIA).

Methods: We generated transgenic rice expressing T-cell epitope of hGPI_325–339 and APL12 contained in the seed endosperm. The transgenic rice seeds were orally administered prophylactically before the induction of GIA. The severity of arthritis and titers of serum anti-GPI antibodies were evaluated. We examined for IL-17 production in splenocytes and inguinal lymph node (iLN) cells, and analyzed the expression levels of functional molecules in splenocytes.

Results: Prophylactic treatment of GIA mice with APL12 transgenic (APL12-TG) rice seeds significantly reduced the severity of arthritis and titers of serum anti-GPI antibodies compared with non-transgenic (Non-TG) rice-treated mice. APL12-TG and hGPI_325–339 transgenic (hGPI_325–339-TG) rice seeds improved the histopathological arthritis scores and decreased IL-17 production compared with non-TG rice-treated mice. APL12-TG rice-treated GIA mice showed upregulation of Foxp3 and GITR protein in CD4?⁺?CD25?⁺?Foxp3^+?cells in the spleen compared with non-TG rice- and hGPI_325–339-TG rice-treated mice.

Conclusion: APL12-TG rice seeds improved the severity of GIA through a decrease in production of IL-17 and anti-GPI antibodies via upregulation of Foxp3 and GITR expression on Treg cells in spleen.     

Efficacy and safety of systemic methotrexate vs. acitretin in psoriasis patients with significant palmoplantar involvement: a prospective,randomized study

Background Palmoplantar psoriasis (PP) is a chronic, inflammatory and proliferative dermatosis of the palms and/or soles with significant morbidity. It is notoriously difficult to treat and unresponsive to traditional topical agents. Material and methods This was a prospective, randomized study involving 111 patients of psoriasis with significant palmoplantar disease. Patients meeting the eligibility criteria were randomly assigned to one of the two treatment groups. Patients in Group I received methotrexate in doses of 0.4 mg/kg weekly, and patients in Group II received acitretin in doses of 0.5 mg/kg daily. Patients were evaluated by modified PPPASI (m‐PPPASI) score for palm and sole involvement at baseline, at two weekly intervals for the first 4 weeks and then four weekly for next 8 weeks. Treatment protocol was continued for a period till patient achieved 75% reduction in m‐PPPASI from baseline or 12 weeks whichever was earlier. Results There was a statistically significant difference in reduction of m‐PPPASI of patients on methotrexate at weeks 8 and 12. The mean m‐PPPASI at week 8 was 15.38 ± 6.08 in methotrexate group and 17.23 ± 5.25 in acitretin group (P = 0.04). The mean m‐PPPASI at week 12 was 10.30 ± 5.97 in methotrexate group and 12.40 ± 5.31 in acitretin group (P = 0.03). Marked improvement (m‐PPPASI 75) was achieved in 12 (24%) patients in methotrexate group compared with 4 (8%) in acitretin group which was statistically significant (P = 0.029). Adverse events were generally mild and were seen in 14 patients in methotrexate group and 15 patients in acitretin group (P = 0.080). Conclusion Methotrexate is relatively inexpensive, safe and efficacious drug for the treatment of psoriasis patients with significant palmoplantar involvement. Acitretin can be used as an alternative therapy and with a good safety profile.     

Effects of arotinolol on exercise capacity and humoral factors during exercise in normal subjects

Summary A placebo-controlled, double-blind crossover study was undertaken in 10 normal subjects to examine the effects of arotinolol (10 mg bid), a nonselective beta blocker with alpha-blocking activity, on exercise capacity and hormone levels during exercise after a 2-week treatment period. Maximal oxygen uptake (VO₂ max) and blood lactic acid concentration (LA) were measured during progressive exercise testing. An exercise intensity equivalent to 4 mmol/l of LA was used for the constant workload exercise test. Humoral factors were measured after 20 minutes of constant workload exercise. The administration of arotinolol significantly decreased systolic blood pressure and heart rate at rest and during exercise, but diastolic blood pressure did not change. No significant difference was found between arotinolol and placebo with regard to VO₂ max and maximal workload. Plasma renin activity (PRA), aldosterone (PAC), and norepinephrine (NE) levels at rest and during exercise did not differ between the two treatments. In contrast, plasma epinephrine (EN) levels at rest and during exercise were significantly greater with arotinolol. Atrial natriuretic peptide (ANP) at rest did not differ between the two treatments. However, exercise caused a significant increase in ANP after arotinolol treatment. These findings suggest that arotinolol decreases blood pressure and heart rate without affecting exercise capacity.     

Immunoneutralization of glycoprotein Ibalpha attenuates endotoxin-induced interactions of platelets and leukocytes with rat venular endothelium in vivo

This study aimed to examine molecular mechanisms for endotoxin-induced adhesive changes in platelets in vivo. Platelets labeled with carboxyfluorescein diacetate succinimidyl ester were visualized in rat mesenteric venules through intravital microscopy assisted by a high-speed fluorescence video imager at 1000 frames per second or by a normal-speed intensifier under monitoring of erythrocyte velocity. Leukocyte rolling was examined by normal-speed transmission video images. The velocity of platelets traveling along the centerline of venules followed that of erythrocytes, whereas that measured at the periendothelial space was significantly smaller than the erythrocyte velocity; a majority of these cells exhibited transient but notable rolling with endothelium. Administration of endotoxin increased the density of periendothelial platelets and reduced the rolling velocities of platelets and leukocytes in venules: All events were attenuated by anti-rat P-selectin monoclonal antibody s789G or by anti-human glycoprotein (GP) Ibalpha monoclonal antibody GUR83/35, which blocks ristocetin-induced aggregation of rat platelets. Isolated rat platelets injected into endotoxin-pretreated rats were able to roll on the venules. This event was attenuated by pretreatment of platelets in vitro with GUR83/35 but not with s789G, suggesting involvement of endothelial P-selectin and platelet GP Ibalpha in the endotoxin-induced responses. Furthermore, isolated human platelets showed similar rolling interactions with endotoxin-preexposed rat venules, and pretreatment of the platelets with GUR83/35, but not with s789G, significantly reduced such interactions. Our results provide the first evidence for involvement of GP Ibalpha in endotoxin-induced microvascular rolling of platelets and leukocytes, and this system serves as a potentially useful tool to examine GP Ibalpha-associated function of human platelets in vivo.