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Axon regeneration requires actomyosin interaction, which generates contractile force and pulls the regenerating axon forward. In Caenorhabditis elegans, TLN-1/talin promotes axon regeneration through multiple down-stream events. One is the activation of the PAT-3/integrin-RHO-1/RhoA GTPase-LET-502/ROCK (Rho-associated coiled-coil kinase)-regulatory non-muscle myosin light-chain (MLC) phosphorylation signaling pathway, which is dependent on the MLC scaffolding protein ALP-1/ALP-Enigma. The other is mediated by the F-actin-binding protein DEB-1/vinculin and is independent of the MLC phosphorylation pathway. In this study, we identified the svh-7/rtkn-1 gene, encoding a homolog of the RhoA-binding protein Rhotekin, as a regulator of axon regeneration in motor neurons. However, we found that RTKN-1 does not function in the RhoA-ROCK-MLC phosphorylation pathway in the regulation of axon regeneration. We show that RTKN-1 interacts with ALP-1 and the vinculin-binding protein SORB-1/vinexin, and that SORB-1 acts with DEB-1 to promote axon regeneration. Thus, RTKN-1 links the DEB-1-SORB-1 complex to ALP-1 and physically connects phosphorylated MLC on ALP-1 to the actin cytoskeleton. These results suggest that TLN-1 signaling pathways coordinate MLC phosphorylation and recruitment of phosphorylated MLC to the actin cytoskeleton during axon regeneration., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sakai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Axon regeneration is an evolutionarily conserved process essential for restoring the function of damaged neurons. In Caenorhabditis elegans hermaphrodites, initiation of axon regeneration is regulated by the RhoA GTPase-ROCK (Rho-associated coiled-coil kinase)-regulatory nonmuscle myosin light-chain phosphorylation signaling pathway. However, the upstream mechanism that activates the RhoA pathway remains unknown. Here, we show that axon injury activates TLN-1/talin via the cAMP-Epac (exchange protein directly activated by cAMP)-Rap GTPase cascade and that TLN-1 induces multiple downstream events, one of which is integrin inside-out activation, leading to the activation of the RhoA-ROCK signaling pathway. We found that the nonreceptor tyrosine kinase Src, a key mediator of integrin signaling, activates the Rho guanine nucleotide exchange factor EPHX-1/ephexin by phosphorylating the Tyr-568 residue in the autoinhibitory domain. Our results suggest that the C. elegans integrin signaling network regulates axon regeneration via the Src-RhoGEF-RhoA axis. SIGNIFICANCE STATEMENT The ability of axons to regenerate after injury is governed by cell-intrinsic regeneration pathways. We have previously demonstrated that the Caenorhabditis elegans RhoA GTPase-ROCK (Rho-associated coiled-coil kinase) pathway promotes axon regeneration by inducing MLC-4 phosphorylation. In this study, we found that axon injury activates TLN-1/talin through the cAMP-Epac (exchange protein directly activated by cAMP)-Rap GTPase cascade, leading to integrin inside-out activation, which promotes axonal regeneration by activating the RhoA signaling pathway. In this pathway, SRC-1/Src acts downstream of integrin activation and subsequently activates EPHX-1/ephexin RhoGEF by phosphorylating the Tyr-568 residue in the autoinhibitory domain. Our results suggest that the C. elegans integrin signaling network regulates axon regeneration via the Src-RhoGEF-RhoA axis., (Copyright © 2021 Sakai et al.)

The GHIJKL fragment of gymnocin-B was synthesized using the oxiranyl anion strategy. The first highlight of the synthesis is the bromoketone cyclization reaction on the oxepane ring to construct the fused bisoxepane GH ring. The second key step is the introduction of the trans -4-hydroxy-3-methyloxepane J ring via addition of trimethylaluminum to a conjugated oxonium moiety, followed by diastereoselective epoxidation and regioselective reduction.

Owing to an outstanding wide antitumor spectrum and excellent anti-tumor effect cisplatin has been used in chemotherapy for malignant tumor. However, cisplatin has strong side effects such as renal injury. Taurine has been found to protect against inflammatory tissue damage in a variety of experimental models. The aim of the present study was to investigate the effect of taurine against iNOS dependent DNA damage in cisplatin-induced renal injury in rats. With the help of a rat model of drug-induced kidney damage, we have assessed the nephrotoxic effects of different doses of cisplatin in the presence and absence of taurine. Immunohistochemical methods were used to examine the distribution of arginine, iNOS, citrulline and 8-nitroguanine in renal tissue. The expression levels of citrulline, iNOS, and 8-nitroguanine immunoreactivities were found to increase as a function of the dose of cisplatin used, and to decrease in the presence of taurine. The expression level of arginine immunoreactivity was reduced as a function of the dose of cisplatin used. On the other hand, iNOS, 8-nitroguanine and citrulline immunohistochemical staining showed an intense immunoreactivity in the renal tubule of cisplatin-treated animals; and arginine immunoreactivity was localized in the renal tubule of taurine-treated animals. We also confirmed the decrease of citrulline and iNOS expression in the renal tubule after taurine administration as well as the expression level of 8-nitroguanine, a nitrative stress marker in the same animals. The present results support the concept that taurine may have a protective role in the formation of cisplatin-related DNA lesions arising through iNOS-mediated nitrative stress.

Cisplatin (CDDP) is one of the most effective chemotherapeutic agent used in the treatment of many kind of solid tumors. Its primary side effect is nephrotoxicity. The aim of this study to investigate the effects of taurine on cisplatin-induced acute nephrotoxicity. A single intraperitoneal injection of CDDP (15 mg/kg, or 25 mg/kg) deteriorated the kidney functions as reflected by histopathological changes. Histopathological changes were observed in all cisplatin groups. In the cisplatin group, oxidative stress was evident in the cisplatin group by observing an increase in 8-OHdG expression, an indicator of oxidative DNA damage. CDDP also resulted to an increase in CD68 expression in the renal tissues of CDDP groups. Taurine transporter (TauT) was down-regulated, and p53 was up-regulated in renal tissues as indicated by immunohistochemical analysis. Administration with taurine prior to a cisplatin injection was able to protect against deterioration of kidney function, to abrogate the decline in anti-oxidants and to suppress the increase in DNA damage. Moreover, taurine inhibited p53 activation and improved the pathological changes induced by cisplatin. This study demonstrates the protective effects of taurine in attenuating the expression of pro-inflammatory mediators and in improving antioxidant capacity in the kidney of cisplatin-injected rats. Thus, taurine could be a beneficial dietary supplement to attenuate cisplatin induced nephrotoxicity.