Protectin Conjugates in Tissue Regeneration 1 Inhibits Macrophage Pyroptosis by Restricting NLRP3 Inflammasome Assembly to Mitigate Sepsis via the cAMP-PKA Pathway.

Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel anti-inflammatory and proresolving lipid mediator biosynthesized from docosahexaenoic acid. Excessive activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome and consequent pyroptosis are involved in diverse inflammatory diseases. However, how PCTR1 affects NLRP3 inflammasome activation and pyroptosis are still unclear. Here, we demonstrated that PCTR1 inhibited NLRP3 inflammasome activation and pyroptosis. These results show that PCTR1 dose-dependently inhibited gasdermin D cleavage in lipopolysaccharide (LPS)-primed murine primary macrophages upon nigericin stimulation. Additionally, PCTR1 treatment after LPS priming inhibited caspase-1 activation and subsequent mature interleukin-1ß release independent of the nuclear factor-kappa B pathway. PCTR1 exerted its inhibitory effects by blocking NLRP3-apoptosis-associated speck-like protein containing a CARD (ASC) interaction and ASC oligomerization, thereby restricting NLRP3 inflammasome assembly. However, the inhibitory effect of PCTR1 could be reversed by KH7 and H89, which are the inhibitors of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway. Moreover, PCTR1 treatment alleviated lung tissue damage and improved mouse survival in LPS-induced sepsis. Our study unveils the molecular mechanism of negative regulation of NLRP3 inflammasome activation and pyroptosis by a novel lipid mediator and suggests that PCTR1 may serve as a potential treatment option for NLRP3-inflammasome driven diseases.

Protectin DX increases alveolar fluid clearance in rats with lipopolysaccharide-induced acute lung injury.

Acute respiratory distress syndrome is a life-threatening critical syndrome resulting largely from the accumulation of and the inability to clear pulmonary edema. Protectin DX, an endogenously produced lipid mediator, is believed to exert anti-inflammatory and pro-resolution effects. Protectin DX (5 µg/kg) was injected i.v. 8 h after LPS (14 mg/kg) administration, and alveolar fluid clearance was measured in live rats (n = 8). In primary rat ATII epithelial cells, protectin DX (3.605 × 10-3 mg/l) was added to the culture medium with LPS for 6 h. Protectin DX improved alveolar fluid clearance (9.65 ± 1.60 vs. 15.85 ± 1.49, p < 0.0001) and decreased pulmonary edema and lung injury in LPS-induced lung injury in rats. Protectin DX markedly regulated alveolar fluid clearance by upregulating sodium channel and Na, K-ATPase protein expression levels in vivo and in vitro. Protectin DX also increased the activity of Na, K-ATPase and upregulated P-Akt via inhibiting Nedd4-2 in vivo. In addition, protectin DX enhanced the subcellular distribution of sodium channels and Na, K-ATPase, which were specifically localized to the apical and basal membranes of primary rat ATII cells. Furthermore, BOC-2, Rp-cAMP, and LY294002 blocked the increased alveolar fluid clearance in response to protectin DX. Protectin DX stimulates alveolar fluid clearance through a mechanism partly dependent on alveolar epithelial sodium channel and Na, K-ATPase activation via the ALX/PI3K/Nedd4-2 signaling pathway.

Saikosaponin a Inhibits Cigarette Smoke-Induced Oxidant Stress and Inflammatory Responses by Activation of Nrf2.

Saikosaponin a (SSa), a triterpenoid saponin, has numerous pharmacological properties, including anti-inflammatory and antioxidant effects. The purpose of this study was to investigate whether and how SSa protected against cigarette smoke (CS)-induced lung inflammation in mice. The mice were exposed to CS and SSa was administered by an intraperitoneal (i.p.) injection 1 h before CS treatment for 5 consecutive days. The results showed that SSa significantly inhibited CS-induced inflammatory cell infiltration, NO, TNF-α, and IL-1ß production in BALF. SSa also inhibited CS-induced MPO and MDA contents in lung tissues. Furthermore, SSa significantly inhibited CS-induced NF-κB and upregulated the expression of Nrf2 and HO-1. In conclusion, these results support a therapeutic potential for SSa in CS-induced lung inflammation.

[Effect of Curcumin on Cerebral Ischemia-reperfusion Injury in Rats].

OBJECTIVE: To investigate the effect of curcumin on cerebral ischemia-reperfusion injury in rats and its mechanism. METHODS: 250 male SD rats were randomly divided into five groups:sham group (Sham group), ischemia-reperfusion group (I/R group), curcumin groups with dosage of 30 mg/kg (Cur30 group), 100 mg/kg (Cur100 group) and 300 mg/kg (Cur300 group). The brain tissue damage degree, leukocyte cells infiltration, levels of TNF-α and MMP-9 expressions, and blood-brain barrier permeability were detected. RESULTS: At the same time point,the score of brain tissue injury,number of leukocyte, expression of MMP-9 and TNF-α, and Evans blue dye of I/R group and Curs group were higher than those of Sham group (P < 0.05). The score of brain tissue damage degree, number of leukocyte, expression of MMP-9 and TNF-α, and Evans blue dye of Cur groups were lower than those of I/R group (P < 0.05). The Cur100 group had the best effect. CONCLUSION: Curcumin can decrease cerebral ischemia reperfusion pathological damage significantly and suppressed the expression of MMP-9 and TNF-α, and Evans blue dye, brain tissue damage, leukocyte infiltration, which may be involved in protective mechanisms of curcumin.

[Three-dimensional finite element analysis of maxillary canine during the tooth translation movement].

OBJECTIVE: To find the characteristic of the stress distribution in the periodontal tissue during maxillary canine distal translation. METHODS: The model was implemented numerically by means of the 3-dimensional finite element method (FEM) and was used to simulate orthodontic tooth translation movements. The finite element model was loaded with defined force systems. And the stresses at 0, 7, 14, and 21 days of loaded distal force and moment in maxillary canine were calculated. RESULTS: During the whole distal translation of canine, 1. the stress in alveolar bone was higher than that in peridontal ligament; 2. the stresses in the cervical region were higher than those in the apical region of the alveolar bone and periodontal tissues; 3. the stresses in the cervical, medium and apical regions of periodontal tissue were on the decline, and the stress in cervical region declined faster than that in apical region. On the 21st day the stresses in the cervical, medium and apical regions were similar. CONCLUSION: The 3-D FEM analysis revealed that alveolar bone loss could be most likely to happen during the initial stage of the tooth movement, and the data from this study mihgt be helpful to orthodontists in selecting an appropriate device of force systems to control the initial loading during orthodontic treatment.

[A comparative study of the bracket bond failure between adults and adolescents receiving fixed orthodontic therapy].

OBJECTIVE: To evaluate the bracket bond failure and its causes between adult and adolescent patients during fixed orthodontic therapy. METHODS: Bracket bond failure data of 30 adults and 30 adolescents, receiving fixed orthodontic therapy, have been collected within the first 12 visits, respectively. The compliance has been analyzed with survival analyse between the two groups. RESULT: The general bracket bond failure rate in the adult group is lower than that of the adolescent group and the difference is significant (p < 0.05). In the adolescent group, the failure rate for mandibular anterior teeth is highest and different from that of the adult group (p < 0.05). The failure rate resulted from biting hard food is ranked No. 1. CONCLUSIONS: The compliance of the adults receiving fixed orthodontic therapy is better than that of the adolescents. The investigation of bracket bond failure causes is beneficial in helping orthodontists improve orthodontic practice and raise clinical efficiency. The survival analysis is effective in evaluating the bond failure.