Spermidine activates RIP1 deubiquitination to inhibit TNF-α-induced NF-κB/p65 signaling pathway in osteoarthritis.

Spermidine has been known to inhibit the production of pro-inflammatory cytokines. However, there are no reports about anti-inflammatory effects of spermidine on osteoarthritis (OA). Herein, we examined whether OA progression could be delayed by intraperitoneal injection (i.p.) of spermidine in the anterior cruciate ligament transection (ACLT) and TNF-α induced arthritis (TIA) mouse models. During the process, human FLS cells (H-FLS) were used to investigate the potential ubiquitination mechanism of spermidine-mediated RIP1 in TNF-α-induced NF-κB/p65 signaling. We found that spermidine attenuated synovitis, cartilage degeneration and osteophyte formation, resulting in substantially lower OARSI scores and TNF-α scores in spermidine-treated ACLT and TIA mice. In terms of the mechanism, 9 µM spermidine did not affect the viability, proliferation, cell cycle and apoptosis of H-FLS, and exerted inhibitory effects by activating CYLD-mediated RIP1 deubiquitination on TNF-α-induced NF-κB/p65 signaling in H-FLS. From these data, we can conclude that spermidine attenuates OA progression by the inhibition of TNF-α-induced NF-κB pathway via the deubiquitination of RIP1 in FLS. Therefore, intake of spermidine could be a potential therapy for preventing OA.

Multicenter Study on Observation of Acute-phase Responses After Infusion of Zoledronic Acid 5 mg in Chinese Women with Postmenopausal Osteoporosis.

OBJECTIVE: It has been reported that acute-phase reactions (APR) after infusion of 5 mg zoledronic acid for the first time is common. This study surveyed the incidence and characteristics of APR in Chinese postmenopausal women receiving 5 mg zoledronic acid intravenously for osteoporosis and to evaluate the efficacy of non-steroidal anti-inflammatory drugs (NSAID) in preventing or alleviating APR following the first 5 mg zoledronic acid infusion. METHODS: A total of 2601 patients with an average age of 68.14 ± 9.89 years and a mean body mass index of 22.90 ± 3.24 kg/m2 from 62 centers in China were treated with 5 mg zoledronic acid intravenously for the first time. The incidence of fever and pain were observed in these patients, and the time of fever or pain onset and duration, and the intensity of fever and grade of pain were also recorded. The dosage, duration, and efficacy of NSAID and safety outcomes were also documented. RESULTS: At the end of the study, 18 patients are eliminated due to incomplete records of temperature. The incidence of fever was 28.65% (740/2583) within 7 days following zoledronic acid infusion; 98.34% (727/740) occurred at 1.03 ± 0.66 days after infusion and lasted 1.72 ± 0.93 days. A total of 456 (17.53%) patients had newly onset pain (312 of 1187, 26.28%) or experienced pain aggravation (144 of 1414, 10.18%), which mostly occurred within 3 days after zoledronic acid infusion. A total of 1246 (47.6%) patients had received NSAID for a median time of 2.63 ± 2.45 days. Using NSAID for at least 2 days could decrease body temperature by 0.54 ± 0.86°C, increase the percentage of pain-free patients by 6.17%, and reduce the percentage of patients with moderate to severe pain by 8.7%. CONCLUSIONS: Compared with Western populations, Chinese patients had a higher rate of fever and pain after their first zoledronic acid infusion. These symptoms were often mild to moderate in intensity and transient in duration. NSAID could effectively reduce the incidence and severity of such APR.

Decreased anandamide transporter activity and calcitonin gene-related peptide production in spontaneously hypertensive rats: role of angiotensin II.

In the present study, we investigated the role of angiotensin II in regulating the anandamide transporter activity and resultant calcitonin gene-related peptide (CGRP) production in spontaneously hypertensive rats (SHRs). Systolic blood pressure, plasma levels of anandamide, angiotensin II and CGRP, CGRP mRNA expression in dorsal root ganglion and anandamide transporter activity in peripheral blood lymphocytes were measured in SHRs treated with selective angiotensin II type 1 receptor antagonist losartan. Rat peripheral blood lymphocytes were isolated to examine the effect of exogenous angiotensin II on anandamide-induced CGRP mRNA expression, anandamide transporter activity and intracellular reactive oxygen species production in presence or absence of losartan and antioxidant n-acetyl-cysteine. In SHRs, the plasma level of angiotensin II and anandamide was elevated, but the anandamide transporter activity was attenuated concomitantly with decreased CGRP production. Treatment with losartan for 2weeks produced depressor effect, restored the reduced anandamide transporter activity, decreased the plasma anandamide level and increased the plasma level and mRNA expression of CGRP in SHRs. In cultured lymphocytes, up-regulation of CGRP mRNA expression by exogenous administration of anandamide was inhibited by anandamide transporter blocker and angiotensin II. Angiotensin II also inhibited the anandamide transporter activity concentration-dependently while increased intracellular reactive oxygen species production, which was reversed by pretreatment with losartan or n-acetyl-cysteine. The present findings suggest that angiotensin II plays a critical role in mediating the decrease in anandamide transporter activity and CGRP production in SHRs, which is likely due to activation angiotensin II type 1 receptor and resultant reactive oxygen species production.

Demethylbellidifolin prevents nitroglycerin tolerance via improved aldehyde dehydrogenase 2 activity.

The aim of this study was to investigate the effect of demethylbellidifolin (DMB), a major xanthone compound of Swertia davidi franch, on nitroglycerin (NTG) tolerance. In the in vivo portion of the study, pretreatment of Sprague-Dawley rats with NTG (10 mg/kg) for 8 days caused tolerance to the depressor effect of NTG. This was evident because the depressor effect of NTG (150 microg/kg, I. V.) was almost completely abolished in the tolerant rats. The tolerance could be diminished by treatment with DMB. In the in vitro study, the exposure of aortic rings of Sprague-Dawley rats to NTG (10 microM) for 30 min caused tolerance to the vasodilating effect of NTG. The tolerance is evident because of a substantial right shift of the NTG concentration-relaxation curves. This shift was reduced by pretreatment of the aortic rings with DMB. In cultured human umbilical vein endothelial cells (HUVECs), incubation of NTG for 16 h increased reactive oxygen species (ROS) production, attenuated cyclic guanosine monophosphate (cGMP) levels and decreased the activity of aldehyde dehydrogenase 2 (ALDH-2), the main enzyme responsible for NTG bioactivation. All the effects mentioned above were prevented by co-incubation with DMB. In conclusion, DMB prevents NTG tolerance via increasing ALDH-2 activity through decreasing ROS production.