The Role of Resveratrol on Spinal Cord Injury: from Bench to Bedside.

Spinal cord injury (SCI) is a severe and disabling injury of the central nervous system, with complex pathological mechanisms leading to sensory and motor dysfunction. Pathological processes, such as oxidative stress, inflammatory response, apoptosis, and glial scarring are important factors that aggravate SCI. Therefore, the inhibition of these pathological processes may contribute to the treatment of SCI. Currently, the pathogenesis of SCI remains under investigation as SCI treatment has not progressed considerably. Resveratrol, a natural polyphenol with anti-inflammatory and antioxidant properties, is considered a potential therapeutic drug for various diseases and plays a beneficial role in nerve damage. Preclinical studies have confirmed that signaling pathways are closely related to the pathological processes in SCI, and resveratrol is believed to exert therapeutic effects in SCI by activating the related signaling pathways. Based on current research on the pathways of resveratrol and its role in SCI, resveratrol may be a potentially effective treatment for SCI. This review summarizes the role of resveratrol in promoting the recovery of nerve function by regulating oxidative stress, inflammation, apoptosis, and glial scar formation in SCI through various mechanisms and pathways, as well as the deficiency of resveratrol in SCI research and the current and anticipated research trends of resveratrol. In addition, this review provides a background for further studies on the molecular mechanisms of SCI and the development of potential therapeutic agents. This information could also help clinicians understand the known mechanisms of action of resveratrol and provide better treatment options for patients with SCI.

Targeted Therapy of Spinal Cord Injury: Inhibition of Apoptosis Is a Promising Therapeutic Strategy.

Spinal cord injury (SCI) is a serious disabling central nervous system injury that can lead to motor, sensory, and autonomic dysfunction below the injury level. SCI can be divided into primary injury and secondary injury according to pathological process. Primary injury is mostly irreversible, while secondary injury is a dynamic regulatory process. Apoptosis is an important pathological event of secondary injury and has a significant effect on the recovery of nerve function after SCI. Nerve cell death can further aggravate the microenvironment of the injured site, leading to neurological dysfunction and thus affect the clinical outcome of patients. Therefore, apoptosis plays a crucial role in the pathological progression of secondary SCI, while inhibiting apoptosis may be a promising therapeutic strategy for SCI. This review will summarize and explore the factors that lead to cell death after SCI, the influence of cross talk between signaling pathways and pathways involved in apoptosis and discuss the influence of apoptosis on SCI, and the therapeutic significance of targeting apoptosis on SCI. This review helps us to understand the role of apoptosis in secondary SCI and provides a theoretical basis for the treatment of SCI based on apoptosis.

Highly dispersed NiS2 quantum dots as a promising cocatalyst bridged by acetylene black significantly improved the photocatalytic H2 evolution performance of g-C3N4 nanosheets.

In this work, ternary nanocomposite (CNs-AB/NiS2) as a novel efficient H2 evolution photocatalyst without the use of noble metals was successfully synthesized by depositing acetylene black (AB) and ultra-fine NiS2 nanoparticles on the surface of CNs (g-C3N4) through ultrasonic dispersion and chemical vapor deposition methods, respectively. It was revealed that the loaded AB and NiS2 nanoparticles have significantly improved the photocatalytic H2 evolution efficiency of the CNs by improving the photogenerated electron-hole pair separation, visible light absorption and hydrogen evolution kinetics. Besides acting as a cocatalyst, AB served as a conductive electron bridge between CNs and NiS2, which accelerated the effective transfer of electrons from CNs to NiS2 and improved the H2 evolution kinetics of the NiS2 cocatalyst. The H2 evolution experiments revealed that the ternary photocatalyst CNs-AB/NiS210 displayed a H2 evolution rate of up to 2434.85 µmoL g-1 h-1, which was a 1.41 times enhancement compared to that of the binary composite CNs-NiS210 and was 12.43 times higher than that of the pure CNs. Moreover, the ternary photocatalyst CNs-AB/NiS210 not only exhibited excellent photocatalytic activity and stability in the tests, but provided a novel idea for the development of high-efficiency catalysts free of noble metals as well.

Multifunctional nanoplatform based on g-C3N4, loaded with MnO2 and CuS nanoparticals for oxygen self-generation photodynamic/photothermal synergistic therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) are both promising therapeutic approaches for cancer. Unfortunately, the anticancer efficiency of PDT is restricted by the hypoxic tumor microenvironment and the performance of the photosensitizer (PS) while the efficiency of PTT is limited by the penetration depth of NIR light, making it difficult to further improve the efficiency of the treatment. In this paper, we strategically proposed a multifunctional nano-platform based on g-C3N4 and loaded with CuS and MnO2 nanoparticals. Interestingly, the obtained F127@CNs-CuS/MnO2 nano-platform with high singlet oxygen quantum yield and excellent photothermal performance were used in synergistic PTT and PDT therapy to cope with the limitation of single mode cancer treatment under irradiation and has greatly improved the treatment effect. Additionally, MnO2 nanoparticles loaded on the CNs surface could not only generate oxygen to ameliorate hypoxia in the tumor environment by reacting with H2O2 in tumor cells, but also react with the over-expressed reduced glutathione (GSH) in cancer cells to further improve the synergistic therapeutic effect. In the in vitro hepatocarcinoma cell inactivation experiment, the maximum cell inactivation efficiency of the PDT, PTT and PDT/PTT synergistic treatment group reached at 65% (F127@CNs-MnO2), 69.2% (CNs-MnO2) and 88.6% (F127@CNs-MnO2) respectively, which means that the F127@CNs-CuS/MnO2-mediated PTT/PDT synergy anticancer treatment was more effective than single mode therapy. In summary, the innovative multifunctional nanoplatform F127@CNs-CuS/MnO2 used for synergistic PTT and PDT treatment has greatly improved the inactivation efficiency of cancer cells and has provided a new scheme for the treatment of hypoxic tumors.

The role of aquaporin 4 (AQP4) in spinal cord injury.

Aquaporin-4 (AQP-4) is an aquaporin composed of six helical transmembrane domains and two highly conserved ASN-pro-ALA (NPA) motifs. It is strongly expressed in rodent and human spinal cord tissues and plays a key role in the pathological process after SCI. After SCI, edema, glial scarring, and inflammation can accelerate the progression of injury and lead to deterioration of function. Many studies have reported that AQP-4 plays an important role in SCI. In particular, it plays an important role in secondary pathological processes (spinal cord edema, glial scar formation, and inflammatory response) after SCI. Loss of AQP-4 has been associated with reduced spinal edema and improved prognosis after SCI in mice. In addition, downregulation of AQP-4 reduces glial scar formation and the inflammatory response after SCI. There is a consensus from numerous studies that AQP-4 may be a potential target for SCI therapy, which guides the ongoing investigation for molecular therapy of SCI. Here, we review the structure of AQP-4, its expression in normal and damaged spinal cord, and its role in SCI, as well as discuss the theoretical basis for the treatment of SCI.

MDP-induced interleukin-1beta processing requires Nod2 and CIAS1/NALP3.

Nucleotide-binding oligomerization domain (Nod)2 is a sensor of muramyl dipeptides (MDP) derived from bacterial peptidoglycan. Nod2 also plays a role in some autoinflammatory diseases. Cold-induced autoinflammatory syndrome 1 (CIAS1)/NACHT domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NALP3) has been suggested to be sufficient for MDP-dependent release of mature IL-1beta, but the role of Nod2 in this process is unclear. Using mice bearing selective gene deletions, we provide in vitro and in vivo data showing that MDP-induced IL-1beta release requires Nod2 and CIAS1/NALP3 as well as receptor-interacting protein-2 (Rip2), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1. In contrast, MDP-dependent IL-6 production only requires Nod2 and Rip2. Together, our data provide a new understanding of this important pathway of IL-1beta production and allow for further studies of the role of these proteins within the broader context of inflammatory disease.

[Electromagnetic navigation interlocking intramedullary nail technology for treatment of femoral shaft fractures].

OBJECTIVE: To explore the value of electromagnetic navigation interlocking intramedullary nail in the treatment of femoral shaft fracture. METHODS: Between July 2012 and October 2013, 53 cases of femoral shaft fracture were treated. There were 40 males and 13 females, aged 16-52 years (mean, 38.3 years). The causes of injury were traffic accident in 28 cases, falling from height in 11 cases, falling in 7 cases, crush injury in 4 cases, and other in 3 cases. Of 53 cases, there were 3 cases of open fracture (Gustilo I degree) and 50 cases of closed fracture. Fracture was located in the proximal femur in 17 cases, middle femur in 29 cases, and distal femur in 7 cases. According to Winquist classification, 7 cases were rated as type I, 8 cases as type II, 22 cases as type III, and 16 cases as type IV; according to AO classification, 18 cases were rated as type 32-A, 28 cases as type 32-B, and 7 cases as type 32-C. The time from injury to operation was 3-11 days (mean, 5 days). Distal interlocking intramedullary nail was implanted using electromagnetic navigation. RESULTS: The distal locking nail operation with interlocking intramedullary nail was successfully completed under electromagnetic navigation; the one-time success rate of distal locking nail operation reached 100%; and the locking nail time was 5.0-9.5 minutes (mean, 7.0 minutes). Healing of incision by first intention was obtained after operation, and no complication of skin necrosis, infection, and sinus tract occurred. Fifty-three cases were all followed up 5-12 months (mean, 9 months). One case had hip pain and weaken middle gluteal muscle strength, and the symptoms disappeared after removing the nail. During the follow-up period, no broken nails, nail exit, infection, or re-fracture occurred. All fractures achieved clinical healing, and the healing time was 8-22 weeks (mean, 14.5 weeks). In 49 patients followed up 8 months, the Lysholm score was excellent in 44 cases, good in 4 cases, and acceptable in 1 case, with an excellent and good rate of 98%. CONCLUSION: Electromagnetic navigation system is safe and reliable, with the advantages of high positioning accuracy, short operation time, and no radiation, the clinical application of the system for distal locking nail operation can obtain excellent short-term effectiveness.

Cleavage of p65/RelA of the NF-kappaB pathway by Chlamydia.

Chlamydia trachomatis is a bacterial pathogen that infects the eyes and urogenital tract. Ocular infection by this organism is the leading cause of preventable blindness worldwide. The infection is also a leading cause of sexually transmitted disease in the United States. As obligate intracellular pathogens, chlamydiae have evolved sophisticated, yet undefined, mechanisms to maintain a favorable habitat for intracellular growth while avoiding harm to the host. We show here that chlamydiae have the ability to interfere with the NF-kappaB pathway of host inflammatory response. We found that Chlamydia infection did not promote IkappaBalpha degradation, a prerequisite for NF-kappaB nuclear translocation/activation, nor induce p65/RelA nuclear redistribution. Instead, it caused p65 cleavage into an N terminus-derived p40 fragment and a p22 of the C terminus. The activity was specific because no protein cleavage or degradation of NF-kappaB pathway components was detected. Moreover, murine p65 protein was resistant to cleavage by both human and mouse biovars. The chlamydial protein that selectively cleaved p65 was identified as a tail-specific protease (CT441). Importantly, expression of either this protease or the p40 cleavage product could block NF-kappaB activation. A hallmark of chlamydial STD is its asymptomatic nature, although inflammatory cellular response and chronic inflammation are among the underlying mechanisms. The data presented here demonstrate that chlamydiae have the ability to convert a regulatory molecule of host inflammatory response to a dominant negative inhibitor of the same pathway potentially to minimize inflammation.

Triad3A regulates ubiquitination and proteasomal degradation of RIP1 following disruption of Hsp90 binding.

Toll-like receptors (TLRs) play a crucial role in innate immunity by recognizing microbial pathogens. Triad3A is an E3 ubiquitin-protein ligase that interacts with the Toll/interleukin-1 receptor domain of TLRs and promotes their proteolytic degradation. In the present study, we further investigated its activity on signaling molecules downstream of TLRs and tumor necrosis factor (TNF) receptor 1. Triad3A promoted down-regulation of two TIR domain-containing adapter proteins, TIRAP and TRIF, as well as a RIP1 but had no effect on other adapter molecules in either the TLRs or TNF-alpha signaling pathways. Multiple sequence alignment analysis suggested that RIP1 contains a TIR homologous domain, and mutation of amino acid residues in this domain identified three residues critical for its interaction with Triad3A. Moreover, Triad3A acted as a negative regulator in TNF-alpha signaling. Reduction of Triad3A expression by small interference RNAs rendered cells hyperresponsive to TNF-alpha stimulation. Conversely, overexpression of Triad3A in cells blocked TNF-alpha-induced cell activation. This negative regulation was effected independently of changes in the cellular protein level of RIP1. Further studies indicated that RIP1 formed a complex with Triad3A and heat shock protein 90 (Hsp90), which is a chaperone protein capable of maintaining the stability of its client proteins. Treatment of cells with geldanamycin to disrupt the Hsp90 complex led to proteasomal degradation of RIP1. Depletion of Triad3A by small interference RNA treatment inhibited geldanamycin-activated ubiquitination and proteolytic degradation of RIP1. These results suggest that Triad3A is an E3 ubiquitin-protein ligase to RIP1 and that Hsp90 and Triad3A cooperatively maintain the homeostasis of RIP1.

NF-kappa B-inducing kinase regulates selected gene expression in the Nod2 signaling pathway.

The innate immune system surveys the extra- and intracellular environment for the presence of microbes. Among the intracellular sensors is a protein known as Nod2, a cytosolic protein containing a leucine-rich repeat domain. Nod2 is believed to play a role in determining host responses to invasive bacteria. A key element in upregulating host defense involves activation of the NF-kappaB pathway. It has been suggested through indirect studies that NF-kappaB-inducing kinase, or NIK, may be involved in Nod2 signaling. Here we have used macrophages derived from primary explants of bone marrow from wild-type mice and mice that either bear a mutation in NIK, rendering it inactive, or are derived from NIK-/- mice, in which the NIK gene has been deleted. We show that NIK binds to Nod2 and mediates induction of specific changes induced by the specific Nod2 activator, muramyl dipeptide, and that the role of NIK occurs in settings where both the Nod2 and TLR4 pathways are activated by their respective agonists. Specifically, we have linked NIK to the induction of the B-cell chemoattractant known as BLC and suggest that this chemokine may play a role in processes initiated by Nod2 activation that lead to improved host defense.

N-(3-oxo-acyl)homoserine lactones signal cell activation through a mechanism distinct from the canonical pathogen-associated molecular pattern recognition receptor pathways.

Innate immune system receptors function as sensors of infection and trigger the immune responses through ligand-specific signaling pathways. These ligands are pathogen-associated products, such as components of bacterial walls and viral nuclear acids. A common response to such ligands is the activation of mitogen-activated protein kinase p38, whereas double-stranded viral RNA additionally induces the phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha). Here we have shown that p38 and eIF2alpha phosphorylation represent two biochemical markers of the effects induced by N-(3-oxo-acyl)homoserine lactones, the secreted products of a number of Gram-negative bacteria, including the human opportunistic pathogen Pseudomonas aeruginosa. Furthermore, N-(3-oxo-dodecanoyl)homoserine lactone induced distension of mitochondria and the endoplasmic reticulum as well as c-jun gene transcription. These effects occurred in a wide variety of cell types including alveolar macrophages and bronchial epithelial cells, requiring the structural integrity of the lactone ring motif and its natural stereochemistry. These findings suggest that N-(3-oxo-acyl)homoserine lactones might be recognized by receptors of the innate immune system. However, we provide evidence that N-(3-oxo-dodecanoyl)homoserine lactone-mediated signaling does not require the presence of the canonical innate immune system receptors, Toll-like receptors, or two members of the NLR/Nod/Caterpillar family, Nod1 and Nod2. These data offer a new understanding of the effects of N-(3-oxo-dodecanoyl)homoserine lactone on host cells and its role in persistent airway infections caused by P. aeruginosa.

Functional analysis of the plant disease resistance gene Pto using DNA shuffling.

Pto is a serine/threonine kinase that mediates resistance in tomato to strains of Pseudomonas syringae pv. tomato expressing the (a)virulence proteins AvrPto or AvrPtoB. DNA shuffling was used as a combinatorial in vitro genetic approach to dissect the functional regions of Pto. The Pto gene was shuffled with four of its paralogs from a resistant haplotype to create a library of recombinant products that was screened for interaction with AvrPto in yeast. All interacting clones and a representative sample of noninteracting clones were sequenced, and their ability to signal downstream was tested by the elicitation of a hypersensitive response in an AvrPto-dependent or -independent manner in planta. Eight candidate regions important for binding to AvrPto or for downstream signaling were identified by statistical correlations between individual amino acid positions and phenotype. A subset of the regions had previously been identified as important for recognition, confirming the validity of the shuffling approach. Three novel regions important for Pto function were validated by site-directed mutagenesis. Several chimeras and point mutants exhibited a differential interaction with (a)virulence proteins in the AvrPto and VirPphA family, demonstrating distinct binding requirements for different ligands. Additionally, the identification of chimeras that are both constitutively active as well as capable of binding AvrPto indicates that elicitation of downstream signaling does not involve a conformational change that precludes binding of AvrPto, as previously hypothesized. The correlations between phenotypes and variation generated by DNA shuffling paralleled natural variation observed between orthologs of Pto from Lycopersicon spp.