The powerful potential of amino acid menthyl esters for anti-inflammatory and anti-obesity therapies.

Our newly developed menthyl esters of valine and isoleucine exhibit anti-inflammatory properties beyond those of the well-known menthol in macrophages stimulated by lipopolysaccharide (LPS) and in a mouse model of colitis induced by sodium dextran sulfate. Unlike menthol, which acts primarily through the cold-sensitive TRPM8 channel, these menthyl esters displayed unique mechanisms that operate independently of this receptor. They readily penetrated target cells and efficiently suppressed LPS-stimulated tumour necrosis factor-alpha (Tnf) expression mediated by liver X receptor (LXR), a key nuclear receptor that regulates intracellular cholesterol and lipid balance. The menthyl esters showed affinity for LXR and enhanced the transcriptional activity through their non-competitive and potentially synergistic agonistic effect. This effect can be attributed to the crucial involvement of SCD1, an enzyme regulated by LXR, which is central to lipid metabolism and plays a key role in the anti-inflammatory response. In addition, we discovered that the menthyl esters showed remarkable efficacy in suppressing adipogenesis in 3T3-L1 adipocytes at the mitotic clonal expansion stage in an LXR-independent manner as well as in mice subjected to diet-induced obesity. These multiple capabilities of our compounds establish them as formidable allies in the fight against inflammation and obesity, paving the way for a range of potential therapeutic applications.

Immune gene activation by NPR and TGA transcriptional regulators in the model monocot Brachypodium distachyon.

The nonexpressor of pathogenesis-related (NPR) gene family is well known to play a crucial role in transactivation of TGA transcription factors for salicylic acid (SA)-responsive genes, including pathogenesis-related protein 1 (PR1), during plants' immune response after pathogen attack in the model dicot Arabidopsis thaliana. However, little is known about NPR gene functions in monocots. We therefore explored the functions of NPRs in SA signaling in the model monocot Brachypodium distachyon. BdNPR1 and BdNPR2/3 share structural similarities with A. thaliana AtNPR1/2 and AtNPR3/4 subfamilies, respectively. The transcript level of BdNPR2 but not BdNPR1/3 appeared to be positively regulated in leaves in response to methyl salicylate. Reporter assays in protoplasts showed that BdNPR2 positively regulated BdTGA1-mediated activation of PR1. This transactivation occurred in an SA-dependent manner through SA binding at Arg468 of BdNPR2. In contrast, BdNPR1 functioned as a suppressor of BdNPR2/BdTGA1-mediated transcription of PR1. Collectively, our findings reveal that the TGA-promoted transcription of SA-inducible PR1 is orchestrated by the activator BdNPR2 and the repressor BdNPR1, which function competitively in B. distachyon.

Partial tibial nerve transfer for iatrogenic peroneal nerve palsy after endovenous laser ablation for varicose veins of the lower extremity: A case report.

Postprocedural peroneal nerve palsy after endovenous laser ablation (EVLA) for varicose veins is rare and is associated with poor functional recovery. There have been no reports using tibial nerve transfer for iatrogenic peroneal nerve palsy after EVLA. Herein, we present a case with peroneal nerve injury after EVLA, which was successfully treated by partial tibial nerve transfer for the first time. A 75-year-old female presented with a right foot drop immediately after EVLA of the lesser saphenous vein. The ankle and toe dorsiflexion had a muscle grade of M0 on the British Medical Research Council muscle scale, without voluntary motor unit action potentials (MUAP) in the tibialis anterior (TA) muscle on the needle electromyography. Three months after the injury, surgical nerve exploration revealed a damaged common peroneal nerve with discoloration and scarring at the fibular head. Intraoperative deep peroneal nerve stimulation confirmed the absence of compound muscle action potentials in the TA. The best functioning motor fascicles of the tibial nerve were transferred to the deep peroneal main trunk involving motor branches of the TA, extensor digitorum longus, and extensor hallucis longus (EHL) through the interosseous membrane. The postoperative course was uneventful, with no complications. After 3 months of surgery, nascent MUAP appeared in the TA. After 24 months, the patient regained the TA and EHL muscle function and ambulation without an ankle-foot orthosis and tibial nerve deficits. Thus, our procedure may serve as an alternative to nerve grafting, tendon transfer, and orthoses for better management of the major neural complications associated with EVLA.

Nerve-End Capping Treatment with a Polyglycolic Acid Conduit for Rat Sciatic Neuroma: A Preliminary Report.

BACKGROUND: The treatment of painful neuroma remains challenging. Recently, a nerve-end capping technique using a bioabsorbable nerve conduit was newly introduced to treat amputation neuroma. A collagen-coated polyglycolic acid (PGA) conduit has been commercially available for the reconstruction of peripheral nerve defects, yielding successful clinical outcomes. However, no experimental research has been conducted using this PGA nerve conduit as capping device for treating amputation neuroma. The purpose of this study was to investigate nerve-end capping treatment with the PGA conduit in the rat sciatic nerve amputation model, focusing on histological scar formation and neuroinflammation. METHODS: Forty-seven rats were divided into two groups: no capping (transected nerve stump without capping; n = 25) and capping (nerve-end capping with collagen-coated PGA nerve conduit; n = 22). Twelve weeks after sciatic neurectomy, neuropathic pain was evaluated using the autotomy score. Stump neuromas were histologically evaluated or perineural scar and neuroinflammation. RESULTS: While autotomy scores gradually exacerbated in both groups, they were consistently lower in the capping group at 4, 8, and 12 weeks postprocedure. Twelve weeks after surgery, the transected nerve stumps in the no-capping group had formed macroscopic bulbous neuromas strongly adhering to surrounding tissues, whereas they remained wrapped with the PGA nerve conduits loosely adhering to surrounding tissues in the capping group. Histologically, distal axonal fibers were expanded radially and formed neuromas in the no-capping group, while they were terminated within the PGA conduit in the capping group. Perineural scars and neuroinflammation were widely found surrounding the randomly sprouting nerve end in the no-capping group. In capped counterparts, scars and inflammation were limited to closely around the terminated nerve end. CONCLUSION: Nerve-end capping with a collagen-coated PGA conduit after rat sciatic neurectomy might prevent neuroma formation by suppressing perineural scar formation and neuroinflammation around the nerve stump, potentially relieving neuropathic pain.

Phytohormone-dependent plant defense signaling orchestrated by oral bacteria of the herbivore Spodoptera litura.

A vast array of herbivorous arthropods live with symbiotic microorganisms. However, little is known about the nature and functional mechanism of bacterial effects on plant defense responses towards herbivores. We explored the role of microbes present in extracts of oral secretion (OS) isolated from larvae of Spodoptera litura, a generalist herbivore, in phytohormone signaling-dependent defense responses in Arabidopsis thaliana (Arabidopsis). In response to mechanical damage (MD) with application of bacteria-free OS (OS- ) prepared by sterilization or filtration of OS, Arabidopsis leaves exhibited enhanced de novo synthesis of oxylipins, and induction of transcript abundance of the responsible genes, in comparison to those in leaves with MD + nonsterilized OS (OS+ ), indicating that OS bacteria serve as suppressors of these genes. By contrast, de novo synthesis/signaling of salicylic acid and signaling of abscisic acid were enhanced by OS bacteria. These signaling networks were cross-regulated by each other. Meta-analysis of OS bacteria identified 70 bacterial strains. Among them was Staphylococcus epidermidis, an anaerobic staphylococcus that was shown to contribute to the suppression/manipulation of phytohormone-dependent plant defense signaling. The presence of OS bacteria was consequently beneficial for S. litura larvae hosted by Brassicaceae.

Posttraumatic triggering of the extensor pollicis brevis tendon in de Quervain's disease successfully diagnosed with ultrasonography: A case report.

Triggering due to de Quervain's disease is exceedingly rare. This is the first successfully diagnosed case of the snapping phenomenon of the extensor pollicis brevis (EPB) tendon in de Quervain's disease evaluated with preoperative dynamic ultrasonography, clearly demonstrated in an intraoperative video, and treated with decompression of EPB subcompartment only under a wide-awake surgery. Dynamic ultrasonographic images identified snapping caused by unsmooth excursion of an enlarged EPB tendon in a separate subcompartment. In snapping de Quervain's disease, ultrasonographic evaluations and wide-awake surgery are essential to exactly diagnose and successfully treat the snapping condition of the EPB and/or APL tendons.

The Ring-Type E3 Ubiquitin Ligase JUL1 Targets the VQ-Motif Protein JAV1 to Coordinate Jasmonate Signaling.

Jasmonates regulate plant defense and development. In Arabidopsis (Arabidopsis thaliana), JASMONATE-ASSOCIATED VQ-MOTIF GENE1 (JAV1/VQ22) is a repressor of jasmonate-mediated defense responses and is degraded through the ubiquitin-26S proteasome system after herbivory. We found that JAV1-ASSOCIATED UBIQUITIN LIGASE1 (JUL1), a RING-type E3 ubiquitin ligase, interacted with JAV1. JUL1 interacted with JAV1 in the nucleus to ubiquitinate JAV1, leading to proteasomal degradation of JAV1. The transcript levels of JUL1 and JAV1 were coordinately and positively regulated by the CORONATINE INSENSITIVE1-dependent signaling pathway in the jasmonate signaling network, but in a manner that was not dependent on CORONATINE INSENSITIVE1-mediated signaling upon herbivory by Spodoptera litura Gain or loss of function of JUL1 modulated the expression levels of the defensin gene PDF1.2 in leaves, conferring on the plants various defense properties against the generalist herbivore S. litura Because neither the JUL1 mutant nor overexpression lines showed any obvious developmental defects, we concluded that the JAV1/JUL1 system functions as a specific coordinator of reprogramming of plant defense responses. Altogether, our findings offer insight into the mechanisms by which the JAV1/JUL1 system acts specifically to coordinate plant defense responses without interfering with plant development or growth.

Traumatic index extensor tendon attenuation mimicking closed tendon rupture: two case reports.

BACKGROUND: While some traumatic closed index extensor tendon ruptures at the musclotendinous junction have been previously reported, closed index extensor tendon pseudorupture due to intertendinous attenuation is exceedingly rare with only one case report of a gymnastics-related sports injury in the English literature. Herein, we report two non-sports injury related cases of traumatic index extensor tendon attenuation mimicking closed tendon rupture, including the pathological findings and intraoperative video of the attenuated extensor indicis proprius tendon. CASE PRESENTATION: A 28-year-old man and a 30-year-old man caught their hands in a high-speed drill and lathe, respectively, which caused a sudden forced flexion of their wrists. They could not actively extend the metacarpophalangeal joints of their index fingers. Intraoperatively, although the extensor indicis proprius and index extensor digitorum communes tendons were in continuity without ruptures, both tendons were attenuated and stretched. The attenuated index extensor tendons were reconstructed either with shortening by plication or step-cut when the tendon damage was less severe or, in severely attenuated tendons, with tendon grafting (ipsilateral palmaris longus) or tendon transfer. Six months after the operation, the active extension of the index metacarpophalangeal joints had recovered well. CONCLUSIONS: Two cases of traumatic index extensor tendon attenuation were treated successfully by shortening the attenuated tendon in combination with tendon graft or transfer. We recommend WALANT (wide-awake local anesthesia and no tourniquet) in the reconstruction surgery of index extensor tendon attenuation to determine the appropriate amount of tendon shortening or optimal tension for tendon grafting or transfer. Intraoperative voluntary finger movement is essential, as it is otherwise difficult to judge the stretch length of intratendinous elongation and extent of traumatic intramuscular damage affecting tendon excursion.

Evaluation of dual release of stromal cell-derived factor-1 and basic fibroblast growth factor with nerve conduit for peripheral nerve regeneration: An experimental study in mice.

BACKGROUND: The development of drug delivery systems has enabled the release of multiple bioactive molecules. The efficacy of nerve conduits coated with dual controlled release of stromal cell-derived factor-1 (SDF-1) and basic fibroblast growth factor (bFGF) for peripheral nerve regeneration was investigated. MATERIALS AND METHODS: Sixty-two C57BL6 mice were used for peripheral nerve regeneration with a nerve conduit (inner diameter, 1 mm, and length, 7 mm) and an autograft. The mice were randomized into five groups based on the different repairs of nerve defects. In the group of repair with conduits alone (n = 9), a 5-mm sciatic nerve defect was repaired by the nerve conduit. In the group of repair with conduits coated with bFGF (n = 10), SDF-1 (n = 10), and SDF-1/bFGF (n = 10), it was repaired by the nerve conduit with bFGF gelatin, SDF-1 gelatin, and SDF-1/bFGF gelatin, respectively. In the group of repair with autografts (n = 10), it was repaired by the resected nerve itself. The functional recovery, nerve regeneration, angiogenesis, and TGF-ß1 gene expression were assessed. RESULTS: In the conduits coated with SDF-1/bFGF group, the mean sciatic functional index value (-88.68 ± 10.64, p = .034) and the axon number (218.8 ± 111.1, p = .049) were significantly higher than the conduit alone group, followed by the autograft group; in addition, numerous CD34-positive cells and micro vessels were observed. TGF-ß1 gene expression relative values in the conduits with SDF-1/bFGF group at 3 days (7.99 ± 5.14, p = .049) significantly increased more than the conduits alone group. CONCLUSION: Nerve conduits coated with dual controlled release of SDF-1 and bFGF promoted peripheral nerve regeneration.

Overexpression of geraniol synthase induces heat stress susceptibility in Nicotiana tabacum.

MAIN CONCLUSION: Transgenic tobacco plants overexpressing the monoterpene alcohol geraniol synthase exhibit hypersensitivity to thermal stress, possibly due to suppressed sugar metabolism and transcriptional regulation of genes involved in thermal stress tolerance. Monoterpene alcohols function in plant survival strategies, but they may cause self-toxicity to plants due to their hydrophobic and highly reactive properties. To explore the role of these compounds in plant stress responses, we assessed transgenic tobacco plants overexpressing the monoterpene alcohol geraniol synthase (GES plants). Growth, morphology and photosynthetic efficiency of GES plants were not significantly different from those of control plants (wild-type and GUS-transformed plants). While GES plants' direct defenses against herbivores or pathogens were similar to those of control plants, their indirect defense (i.e., attracting herbivore enemy Nesidiocoris tenuis) was stronger compared to that of control plants. However, GES plants were susceptible to cold stress and even more susceptible to extreme heat stress (50 °C), as shown by decreased levels of sugar metabolites, invertase activity and its products (Glc and Fru), and leaf starch granules. Moreover, GES plants showed decreased transcription levels of the WRKY33 transcription factor gene and an aquaporin gene (PIP2). The results of this study show that GES plants exhibit enhanced indirect defense ability against herbivores, but conversely, GES plants exhibit hypersensitivity to heat stress due to suppressed sugar metabolism and gene regulation for thermal stress tolerance.

Tetranins: new putative spider mite elicitors of host plant defense.

The two-spotted spider mite (Tetranychus urticae) is a plant-sucking arthropod herbivore that feeds on a wide array of cultivated plants. In contrast to the well-characterized classical chewing herbivore salivary elicitors that promote plant defense responses, little is known about sucking herbivores' elicitors. To characterize the sucking herbivore elicitors, we explored putative salivary gland proteins of spider mites by using an Agrobacterium-mediated transient expression system or protein infiltration in damaged bean leaves. Two candidate elicitors (designated as tetranin1 (Tet1) and tetranin2 (Tet2)) triggered early leaf responses (cytosolic calcium influx and membrane depolarization) and increased the transcript abundances of defense genes in the leaves, eventually resulting in reduced survivability of T. urticae on the host leaves as well as induction of indirect plant defenses by attracting predatory mites. Tet1 and/or Tet2 also induced jasmonate, salicylate and abscisic acid biosynthesis. Notably, Tet2-induced signaling cascades were also activated via the generation of reactive oxygen species. The signaling cascades of these two structurally dissimilar elicitors are mostly overlapping but partially distinct and thus they would coordinate the direct and indirect defense responses in host plants under spider mite attack in both shared and distinct manners.

The catalytic mechanism of decarboxylative hydroxylation of salicylate hydroxylase revealed by crystal structure analysis at 2.5 Å resolution.

The X-ray crystal structure of a salicylate hydroxylase from Pseudomonas putida S-1 complexed with coenzyme FAD has been determined to a resolution of 2.5 Å. Structural conservation with p- or m-hydroxybenzoate hydroxylase is very good throughout the topology, despite a low amino sequence identity of 20-40% between these three hydroxylases. Salicylate hydroxylase is composed of three distinct domains and includes FAD between domains I and II, which is accessible to solvent. In this study, which analyzes the tertiary structure of the enzyme, the unique reaction of salicylate, i.e. decarboxylative hydroxylation, and the structural roles of amino acids surrounding the substrate, are considered.

Anatomical Origins of Radial Artery Perforators Evaluated Using Color Doppler Ultrasonography.

Background The radial artery perforator (RAP) flap has been widely used for covering hand and forearm defects, and real-time accurate perforator mapping is important in planning and elevating the perforator flap. The origins of perforators, especially the superficial and ulnar perforators, arising from the radial artery are very important in the elevation of the RAP flap. Recently, color Doppler ultrasonography (US) using a higher frequency transducer has been developed for high-quality detection of lower flow in smaller vessels. This study aimed to identify the anatomical locations and origins of perforators arising from the radial artery using color Doppler US in healthy volunteers. Methods Twenty forearms of 10 volunteers were examined. Results In total, 120 perforators arising from the radial artery were identified 15 cm proximal to the distal wrist crease, with an average of six perforators per forearm. More than half the perforators (n = 72, 60%) were located within 50 mm proximal to the distal wrist crease. Regarding the perforator origins in the axial view, 40 perforators (33%) were located in the radial aspect of the radial artery, 47 (39%) in the ulnar aspect, 15 (13%) in the superficial aspect, and 18 (15%) in the deep aspect. In total, 62 (52%) perforators were located in the superficial and ulnar areas, which are important in nourishing and elevating the RAP flap. Conclusion We are the first to evaluate RAP using color Doppler US. This noninvasive, convenient, and real-time technique could be useful for preoperative planning and reliably elevating the RAP flaps.

Pedicled adipose tissue for treatment of chronic digital osteomyelitis.

PURPOSE: To describe a surgical technique (pedicled vascularized tissue transfer) for treating chronic digital osteomyelitis. METHODS: Adipose tissue was obtained at the level of the proximal phalanx based on anterograde or retrograde flow. After bone debridement, we inserted the vascularized adipose tissue into the dead space. Eight patients were treated with this procedure from 2009 to 2012. One patient had chronic osteomyelitis in the thumb, 4 in the index finger, 2 in the middle finger, and 1 in the ring finger. Foci of chronic osteomyelitis were located at the distal phalanx in 2 patients, at the distal to middle phalanx across the distal interphalangeal joint in 4, at the middle phalanx in 1, and at the proximal phalanx in 1. Mean duration of follow-up was 41 months. We assessed the efficacy of the technique by clinical symptoms and imaging. RESULTS: We used retrograde pedicled adipose tissue transfer in 7 patients and anterograde pedicled adipose tissue transfer in 1. The pedicled adipose tissue was successfully transferred from the digit tip to its base. The postoperative courses were uneventful; no additional treatments were required. Postoperative physical data and follow-up images showed no evidence of chronic osteomyelitis. No functional loss was caused by procuring vascularized adipose tissue from the digits. CONCLUSIONS: Pedicled vascularized tissue transfer based on the digital artery was a reliable and reproducible technique. We recommend it as a treatment option for chronic digital osteomyelitis. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Long-term efficacy and safety outcomes of transplantation of induced pluripotent stem cell-derived neurospheres with bioabsorbable nerve conduits for peripheral nerve regeneration in mice.

The induced pluripotent stem cell (iPSc) offers great potential for cell-based therapy in regenerative medicine. We previously developed tissue-engineered bioabsorbable nerve conduits coated with iPSc-derived neurospheres for use in peripheral nerve repair. Here, we examine the long-term efficacy and safety of using nerve conduits with iPSc technology for peripheral nerve repair in mice. The nerve conduit consisted of an outer layer of a poly L-lactide mesh and an inner layer of porous sponge composed of 50% L-lactide and 50% ε-caprolactone. Secondary neurospheres were derived from mouse iPScs, resuspended and cultured within the conduit for 14 days. Conduits were implanted within surgically administered 5-mm defects in the left sciatic nerve of mice (iPSc group; n = 14). The defects in the control group (n = 13) were reconstructed using the nerve conduit alone. At 4, 8, 12, 24 and 48 weeks postsurgery, motor and sensory functional recovery in the iPSc group had improved significantly more than in the control group. At 24 and 48 weeks, histological analysis revealed axonal regeneration in the nerve conduits of both groups. However, axonal regeneration and myelination were significantly enhanced in the iPSc group. No teratomas were identified in the iPSc group at any time point. Therefore, we here demonstrate that bioabsorbable nerve conduits coated with iPSc-derived neurospheres promote enhanced regeneration of peripheral nerves and functional recovery without teratoma formation in the long term. This combination of iPSc technology and bioabsorbable nerve conduits has the potential to be a safe future tool for the treatment of peripheral nerve defects.

Peripheral nerve regeneration by bioabsorbable nerve conduits filled with platelet-rich fibrin.

PURPOSE: To repair peripheral nerve defects and seek alternatives for autografts, nerve conduits with various growth factors and cells have been invented. Few pieces of literature report the effect of nerve conduits plus platelet-rich fibrin (PRF). This study aimed to investigate the effectiveness of nerve conduits filled with PRF. METHODS: The model of a 10 mm sciatic nerve gap in a rat was used to evaluate peripheral nerve regeneration. The thirty rats were randomly divided into one of the following three groups (n = 10 per group). Autogenous nerve grafts (autograft group), conduits filled with phosphate-buffered saline (PBS) (PBS group), or conduits filled with PRF group (PRF group). We assessed motor and sensory functions for the three groups at 4, 8, and 12 weeks postoperatively. In addition, axon numbers were measured 12 weeks after repair of the peripheral nerve gaps. RESULTS: Significant differences in motor function were observed between the autograft group and the other two groups at 12 weeks postoperatively. In the test to evaluate the recovery of sensory function, there were significant differences between the PBS group and the other two groups at all time points. The most axon number was found in the autograft group. The axon number of the PRF group was significantly more extensive than that of the PBS group. CONCLUSIONS: The nerve conduit filled with PRF promoted the axon regeneration of the sciatic nerve and improved sensory function.

Long-duration upper extremity surgery under brachial plexus block combined with intravenous dexmedetomidine sedation without an anesthesiologist.

BACKGROUND: Dexmedetomidine (DEX) provides a unique conscious sedation without respiratory depression. We examined the usefulness of intravenous (IV) DEX sedation combined with brachial plexus block for long-duration upper extremity surgery without an anesthesiologist. METHODS: We retrospectively reviewed 90 limbs of 86 patients and measured the actual operative time course in detail. The adverse events and the patient-reported outcomes regarding intraoperative pain and depth of sedation were evaluated. RESULTS: The mean total time of the operation, tourniquet use, and the IV DEX sedation were 150 min, 132 min, and 117 min, respectively. The mean time between discontinuation of IV DEX sedation and completion of the operation was 51 min. The intraoperative adverse events involved bradycardia (21%), hypotension (18%), and oxygen desaturation (3%). The mean visual analog scale scores of pain during brachial plexus block, surgical site pain, tourniquet pain, and depth of the sedation were 23.4 mm, 0.14 mm, 4.2 mm, and 6.6 mm, respectively. Furthermore, 96% patients expressed a preference for receiving anesthesia as brachial plexus block with IV DEX sedation. CONCLUSIONS: Long-duration upper extremity surgery, even longer than 2 h, was feasible under brachial plexus block combined with IV DEX sedation without an anesthesiologist. For patients with low blood pressure and/or low heart rate, it is recommended to adjust the continuous infusion of IV DEX to less than 0.4 µg/kg/h. To ensure that the patients are able to promptly leave the operating room fully awake, IV DEX infusion should be stopped at least 30 min before finishing the operation.