Keratin7 and Desmoplakin are involved in acute lung injury induced by sepsis through RAGE.

Keratin 7 (Krt7) is a member of the keratin family and is primarily involved in cytoskeleton composition. It has been shown that Krt7 is able to influence its own remodeling and interactions with other signaling molecules via phosphorylation at specific sites unique to Krt7. However, its molecular mechanism in acute lung injury (ALI) remains unclear. In this study, differential proteomics was used to analyze lung samples from the receptor for advanced glycation end products (RAGE)-deficient and (wild-type)WT-septic mice. We screened for the target protein Krt7 and identified Ser53 as the phosphorylation site using mass spectrometry (MS), and this phosphorylation further triggered the deformation and disintegration of Desmoplakin (Dsp), ultimately leading to epithelial barrier dysfunction. Furthermore, we demonstrated that in sepsis, mDia1/Cdc42/p38 MAPK signaling activation plays a role in septic lung injury. We also explored the mechanism of alveolar dysfunction of the Krt7-Dsp complex in the epithelial cell barrier. In summary, the present findings increase our understanding of the pathogenesis of septic acute lung injury.

ATR and BRCA2 Simultaneous Mutation in a ccRCC With Sarcomatoid Differentiation and Extensive Metastases: A Case Report.

The genomic landscape and driver-gene mutations differ significantly among diverse histological subtypes of clear cell renal cell carcinoma (ccRCC) due to the intratumoral heterogeneity. Frequent mutations in canonical DNA damage response genes, such as BRCA1/2 or ATR serine/threonine kinase (ATR) haven't been reported even in large-scale genomic profiling of ccRCC researches. Herein, we reported a rare ccRCC harboring ATR and BRCA2 simultaneous mutation with complicated morphologies and extensive metastases. Our case indicates that the deleterious alteration of DNA damage response genes, increasing CD8+ TILs, high PD1/PD-L1 expression and high TMB might contribute to this patient's tumor metastasis and aggressive biological behavior.

[Effects of Moxibustion on Expression of STAT 1, SOCS mRNA in Synovium of Rats with Rheumatoid Arthritis].

OBJECTIVE: To observe the effect of moxibustion on mRNA expression of signal transducers and activators of transcription 1 (STAT 1), suppressors of cytokine signaling (SOCS) in synovium of rheumatoid arthritis (RA) rats, and to investigate its mechanism for relieving RA. METHODS: 40 Wistar rats were equally and randomly divided into control, model, moxibustion, acupuncture and infrared groups (n = 8 in each group). RA model was developed by putting rats in windy, cold and damp room and injection of Freund's complete adjuvant. Bilateral "Shenshu" (BL 23) were stimulated by the respective means for 20 min in duration, once every other day, ten times in total. The swelling degree of voix pedis (perimeter) of rats was measured. The contents of serum interleukin-1 (IL-1) and interleukin-2(IL-2) were detected by radioimmunoassay, and expression of STAT 1, SOCS mRNA in synovium were assessed by RT-PCR. RESULTS: Rats in model group had acute and severe swelling of voix pedis, together with the increase of serum IL-1 content and decrease of IL-2 content, and down-regulation of mRNA expression of both STAT 1 and SOCS in synovium(all P<0. 01). All three modalities of treatment alleviated the swelling and reversed the relevant changes(P<0. 05, P<0. 01) , however, moxibustion produced greater effects than acupuncture or infrared in elevating IL-2 content and up-regulating mRNA expression of both STAT 1 and SOCS. CONCLUSION: Moxibustion achieves the effects of anti-inflammation and joint swelling reduction of RA via decrease of IL-1, increase of IL-2 in serum and up-regulation of STAT 1, SOCS mRNA expression in synovium.

[Influence of Moxibustion on TLR 4-MyD 88-NF-KB Signal Transduction Pathway of Synovial Tissue in Rheumatoid Arthritis Rats].

OBJECTIVE: To observe the effect of moxibustion intervention on the expression of toll-like receptor-4 (TLR 4), myeloid differentiation factor 88(MyD 88), and nuclear factor kappa B p 65 (NF-κB p 65) genes of knee-joint synovial cells in rheumatoid arthritis (RA) rats, so as to explore its molecular mechanism underlying improving RA. METHODS: Forty SD rats were randomly divided into normal control, RA model, moxibustion and medication groups (n = 10). The RA model was duplicated by raising the rats in a windy, cold and wet environment, followed by injecting Freund's complete adjuvant (0. 15 mL) into the rat's foot. Moxibustion was applied to "Shenshu" (BL 23) and "Zusanli" (ST 36) for 20 min, once daily for 15 days. Rats of the medication group were treated by intragastric administration of tripterygium wilfordii (8. 75 mL/kg), once daily for 15 days. Pathological changes of the synovial tissues were detected by H. E. stain, the contents of serum TNF-α and IL-1 detected by radioimmunoassay, and the expression levels of TLR 4 mRNA, MyD 88 mRNA and TRAF-6 mRNA of synovial tissue were analyzed by real time-PCR, and the NF-κB p 65 immunoactivity was assayed by immunohistochemistry. RESULTS: In comparison with the normal control group, the synovial tissue of the knee-joint was impaired remarkably and infiltrated by numerous inflammatory cells, and the synovial surface got thickening because of hyperplasia in the model group. Following moxibustion and medication, these situations such as synovial infiltration of inflammatory, synovial cell proliferation were alleviated. The serum TNF-α and IL-1 contents and synovial TLR 4 mRNA, MyD 88 mRNA, TRAF-6 mRNA and NF-κB p 65 expression levels were remarkably higher in the model group than in the control group(P<0. 01). After moxibustion and medication, the contents of serum TNF-α and IL-1, the expression levels of TLR 4 mRNA, MyD 88 mRNA, TRAF-6 mRNA and NF-κB p 65 were significantly down-regulated(P<0. 01, P<0. 05). CONCLUSION: Moxibustion intervention can improve pathological changes of the knee-joint synovial membrane tissue in RA rats, which may be related with its effect in inhibiting abnormal activation of TLR 4-MyD 88-NF-κB pathway in synovial tissue.

[Effect of moxibustion on ultrastructure of synovial cells in rheumatoid arthritis rats].

OBJECTIVE: To observe the influence of moxibustion of "Shenshu"(BL 23) and "Zusanli" (ST 36) on the microstructure of synovial cells in the knee-joint in rheumatoidarthritis (RA) rats so as to study its underlying mechanism in anti-inflammatory immune effect. METHODS: A total of 120 Wistar rats were randomized into normal control, model, acupuncture, moxibustion, CO2-laser and medication groups (n = 20/group). RA model was duplicated by raising the rats in a windy (electro-fan blowing), cold [(6 +/- 2) degrees] and wet (80%-90%) environment for 12 h/d and 20 days, followed by injecting Freund's complete adjuvant (0.15 mL) into the rat's ankle. Moxibustion or acupuncture or CO2 laser (10.6 microm) irradiation was applied to "Shenshu" (BL 23) and "Zusanli" (ST 36) for 20 min, once daily for 15 days. Intragastric perfusion of Leigongteng (Tripterygium Wilfordii Hook.f.) was given to medication group, 8 mg/kg, once daily for 15 days. The thoracic gland index [weight of the thoracic gland (mg)/ body weight (g) x 100%] and spleen index [weight of the spleen (mg)/body weight (g) x 100%] were calculated after killing the rats under anesthesia. The ultrastructure of synovial cells of the knee-joint was observed by using transmission electron microscopy. RESULTS: In comparison with the normal control group, the thoracic gland index in the model group was decreased significantly (P < 0.01), while the spleen index of the model group increased considerably (P < 0.05). In comparison with the model group, the thoracic gland indexes in the acupuncture, moxibustion, CO-laser and medication groups were increased significantly (P < 0.05, P < 0.01), whereas the spleen indexes in the four groups decreased evidently (P < 0.05). No significant differences were found among the acupuncture, moxibustion, CO2-laser and medication groups in up-regulating the thoracic gland index and down-regulating the spleen index (P > 0.05). After modeling, the synoviocytes of the knee-joint were impaired remarkably, exhibiting incomplete cellular membrane, some prolapsed organelles, marginalized stained granules in the cellular nucleus, vague nuclear membrane, enlarged rough endoplasmic reticulum, reduction in the number of mitochondria with vacuolization degeneration and multiple lysosomes. But, the pathological changes of the ultrastructure of most synoviocytes in the acupuncture, moxibustion, CO2-laser and medication groups were relatively milder. CONCLUSION: Moxibustion can protect the immune organs (thoracic gland and spleen) from injury and improve pathological changes of the ultrastructure of local synoviocytes in RA rats.