Peroxiredoxin II regulates exosome secretion from dermal mesenchymal stem cells through the ISGylation signaling pathway.

BACKGROUND: Exosomes are small extracellular vesicles that play important roles in intercellular communication and have potential therapeutic applications in regenerative medicine. Dermal mesenchymal stem cells (DMSCs) are a promising source of exosomes due to their regenerative and immunomodulatory properties. However, the molecular mechanisms regulating exosome secretion from DMSCs are not fully understood. RESULTS: In this study, the role of peroxiredoxin II (Prx II) in regulating exosome secretion from DMSCs and the underlying molecular mechanisms were investigated. It was discovered that depletion of Prx II led to a significant reduction in exosome secretion from DMSCs and an increase in the number of intracellular multivesicular bodies (MVBs), which serve as precursors of exosomes. Mechanistically, Prx II regulates the ISGylation switch that controls MVB degradation and impairs exosome secretion. Specifically, Prx II depletion decreased JNK activity, reduced the expression of the transcription inhibitor Foxo1, and promoted miR-221 expression. Increased miR-221 expression inhibited the STAT signaling pathway, thus downregulating the expression of ISGylation-related genes involved in MVB degradation. Together, these results identify Prx II as a critical regulator of exosome secretion from DMSCs through the ISGylation signaling pathway. CONCLUSIONS: Our findings provide important insights into the molecular mechanisms regulating exosome secretion from DMSCs and highlight the critical role of Prx II in controlling the ISGylation switch that regulates DMSC-exosome secretion. This study has significant implications for developing new therapeutic strategies in regenerative medicine. Video Abstract.

Nine prenylated acylphloroglucinols with potential anti-depressive and hepatoprotective activities from Hypericum scabrum.

In our screening program for new biologically active secondary metabolites, nine new polycyclic polyprenyled acylphloroglucinols, hyperscabins D-L, together with three known compounds, were obtained from the aerial parts of Hypericum scabrum. The chemical structures of 1-9 were characterized by extensive spectroscopic analyses, nuclear magnetic resonance calculation with DP4+ probability analysis, and the electronic circular dichroism spectra were calculated. Compound 1 was an unusual prenylated acylphloroglucinol decorated with a 5-oxaspiro [4,5] deca-1,9-dione skeleton. Compound 2 was a newly identified spirocyclic polyprenylated acylphloroglucinol possessing a rare 5,5-spiroketal segment. Compounds 3, 8, and 10 (10 µM) exhibited pronounced hepatoprotective activity against d-galactosamine-induced WB-F344 cell damage in vitro assays. All test compounds (1, 3, and 7-12) demonstrated potential inhibitory effects at 10 µM against noradrenalinet ([3H]-NE) reuptake in rat brain synaptosome.

Long-term functional outcomes of all-inside arthroscopic repair of anterior talofibular ligament avulsion fracture.

BACKGROUND: The main purpose of this study was to describe the all-inside arthroscopic technique for repairing anterior talofibular ligament (ATFL) avulsion fractures at the attachment points of the fibula and talus, and to evaluate the functional outcomes during long-term follow-up. METHODS: The data of 78 patients with ATFL avulsion fracture treated in our hospital from August 2013 to November 2016 were analyzed retrospectively. All patients underwent surgery. Patients were divided into two groups according to whether they had undergone all-inside arthroscopic treatment or open treatment. The American Orthopedic Foot and Ankle Society (AOFAS) score, Karlsson Ankle Functional Score (KAFS), Foot and Ankle Outcome Score (FAOS) and a 36-item Short Form Health Survey questionnaire (SF-36) were used to evaluate functional outcomes. RESULTS: The postoperative follow-up period was 24-48 months. All patients reported subjective improvements to ankle stability without any nerve, blood vessel or tendon complications. At the final follow-up, there was no significant difference in the AOFAS, SF-36 or sport participation rate between the arthroscopic group and the open group; however, the KAFS and FAOS were significantly higher in the arthroscopic group than in the open group. CONCLUSIONS: For ATFL avulsion fractures, the all-inside ankle arthroscopic procedure produced better outcomes than did the open procedure. The all-inside ankle arthroscopic procedure provides a minimally invasive technique with acceptable long-term functional outcomes.

Flexor Hallucis Longus Tendon Impingement Syndrome: All-inside Arthroscopic Treatment and Long-term Follow-up.

This study aimed to evaluate the surgical technique and long-term clinical outcomes of all-inside arthroscopic treatment for flexor hallucis longus (FHL) tendon impingement syndrome. We retrospectively evaluated 34 FHL tendon impingement syndrome patients with complete follow-up data who were admitted from June 2015 to August 2018 and underwent the all-inside arthroscopy technique. The subjects consisted of 20 (58.82%) males and 14 (41.18%) females, with a mean age of 32.7 ± 10.2 (range 21-52) years. The cases consisted of 19 (55.88%) right and 15 (44.12%) left feet. The mean disease duration was 18.5 ± 9.1 (range 10-43) months. The visual analogue scale (VAS), American Orthopaedic Foot & Ankle Society (AOFAS), Karlsson Ankle Functional Score (KAFS), and 36-item Short Form Health Survey questionnaire (SF-36) scores for pain were 3.6 ± 1.2, 84.1 ± 9.6, 86.3 ± 10.7, and 94.7 ± 9.3, respectively. All patients were treated with all-inside posterior arthroscopy for the debridement of the FHL tendon sheath combined with partial muscle belly resection. Post-operative follow-up and observation of the patients' pain and ankle movement were evaluated using VAS, AOFAS, KAFS, and SF-36. All incisions were healed in the first stage, and no complications such as nerve, blood vessel, or tendon injuries occurred. The hospital stays were 3 to 5 days, with a mean of 3.7 ± 1.3 days. All patients were followed up for 12 to 36 months, with a mean follow-up time of 25.4 ± 8.5 months. By the last follow-up, the ankle joint and hallux movement were normal and returned to the pre-pain state for these patients. The VAS score decreased to 0.2 ± 0.1, while the AOFAS, KAFS, and SF-36 scores increased to 97.7 ± 8.5, 97.9 ± 8.2, and 118.2 ± 8.4, respectively. Advantages of all-inside posterior arthroscopic partial muscle belly resection for the treatment of FHL tendon impingement syndrome include small surgical trauma, fast functional recovery, and reliable outcomes. This procedure is therefore worthy of clinical attention and promotion.

"All-Inside" Arthroscopic Treatment of Tillaux-Chaput Fractures: Clinical Experience and Outcomes Analysis.

We investigated all-inside ankle arthroscopy for Tillaux-Chaput fractures. We retrospectively evaluated 19 patients (12 males [63.2%] and 7 [36.8%] females; 11 right [57.9%] and 8 left [42.1%] ankles) treated from May 2013 to January 2016. Their mean age was 28.1 (range 10 to 55) years. Sixteen (84.2%) had single Tillaux-Chaput fractures and 3 (15.8%) had combined proximal fibular fractures; 17 (89.5%) were diagnosed radiographically and 2 (10.5%) by computed tomography. Anterolateral and anteromedial ankle arthroscopy was used for closed reduction and internal fixation with 1 or 2 Herbert screws. Joint function was evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale. All 19 patients healed by first intention without nerve, vessel, or tendon injuries. The follow-up was 19.0 (range 12 to 25) months; fracture union was achieved by 23.5 (range 12 to 36) weeks. At the last follow-up, the 19 patients had no restrictions in ankle function and range of motion, with no ankle or walking pain. The AOFAS score changed from 52.8 to 91.7 points, with an excellent/good rate of 100%. These results suggest that anterolateral and anteromedial all-inside ankle arthroscopy is a precise and effective method for closed reduction and internal fixation of Tillaux-Chaput fractures.

Alkenes with antioxidative activities from Murraya koenigii (L.) Spreng.

Four new alkenes (1-4), and six known alkenes (5-12) were isolated from Murraya koenigii (L.) Spreng. Their structures were elucidated on the basis of spectroscopic analyses and references. Compounds (1-12) were evaluated for antioxidative activities. Among them, compounds 1, 2, 4, and 7 exhibited significant antioxidative activities using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay with IC50=21.4-49.5 µM. The known compounds (5-12) were isolated from this plant for the first time.

Hesperidin alleviates rat postoperative ileus through anti-inflammation and stimulation of Ca(2+)-dependent myosin phosphorylation.

AIM: Postoperative ileus (POI) is a postoperative dysmotility disorder of gastrointestinal tract, which remains one of the most perplexing problems in medicine. In the present study we investigated the effects of hesperidin, a major flavonoid in sweet oranges and lemons, on POI in rats. METHODS: SD rats were administered hesperidin (5, 20, and 80 mg·kg(-1)·d(-1), ig) for 3 consecutive days. POI operation (gently manipulating the cecum for 1 min) was performed on d 2. The gastrointestinal motility and isolated intestinal contraction were examined 1 d after the operation. Then the myosin phosphorylation and inflammatory responses in cecum tissue were assessed. Smooth muscle cells were isolated from rat small intestine for in vitro experiments. RESULTS: The gastric emptying and intestinal transit were significantly decreased in POI rats, which were reversed by administration of hesperidin. In ileum and cecum preparations of POI rats in vitro, hesperidin (2.5-160 µmol/L) dose-dependently increased the spontaneous contraction amplitudes without affecting the contractile frequency, which was blocked by the myosin light chain kinase (MLCK) inhibitor ML-7 or verapamil, but not by TTX. Furthermore, administration of hesperidin increased the phosphorylation of MLC20 in the cecum tissue of POI rats. Moreover, administration of hesperidin reversed the increased levels of inflammatory cytokines, iNOS and COX-2 in cecum tissue of POI rats. In freshly isolated intestinal smooth muscle cells, hesperidin (5-80 µmol/L) dose-dependently increased the intracellular Ca(2+) concentration as well as the phosphorylation of MLC20, which was abrogated by ML-7 or siRNA that knocked down MLCK. CONCLUSION: Oral administration of hesperidin effectively alleviates rat POI through inhibition of inflammatory responses and stimulation of Ca(2+)-dependent MLC phosphorylation.

Two new prenylated phloroglucinol derivatives from Hypericum scabrum.

Two new prenylated phloroglucinol derivatives (1-2), and a known compound furohyperforim isomer 2 (3), were isolated from the aerial parts of Hypericum scabrum. Their structures were elucidated by various spectroscopic methods, including MS, IR, UV, and NMR.

Polygonumnolides C1-C4; minor dianthrone glycosides from the roots of Polygonum multiflorum Thunb.

Four new dianthrone glycosides, named polygonumnolides C1-C4 (1-4), were isolated from the dried roots of Polygonum multiflorum Thunb, together with two known emodin dianthrones (5-6). Their hepatotoxicities were evaluated against L-02 cell lines. Compounds 1-4 showed weak hepatotoxicity against L-02 cell lines with IC50 values of 313.05, 205.20, 294.20, and 207.35 µM, respectively.

[Unsupervised data mining for prescription and medication regularity for treatment of cervical vertigo].

Vertebral artery type cervical spondylosis is a common type of cervical spondylosis, also known as cervical vertigo. In recent years, with the increase of people's life pace and the number of office staff, the incidence rate has been rising year by year, with a trend of younger age. Because traditional Chinese medicine has unique advantages in treating cervical vertigo, it is necessary to study the regularity of the Chinese medicine for cervical vertigo. But at present, the research is mainly based on the statistics for frequency and proportion of herbs. In addition, in the process of diagnosis and treatment of Chinese medicine, personal experience also caused differences in prescription compatibility and drug dosage, which makes difficult guarantee for the safety and effectiveness of drug treatment. So, this paper is based on literatures about the traditional Chinese medicine in treatment of cervical vertigo in the past 5 years, by using association rules algorithm, complex system entropy clustering and other non supervised data mining methods. Analysis was made for the use of various drugs in the frequency, the association rules, the core drug combination and the new prescriptions. The traditional Chinese medicine inheritance support system(TCMISS) was utilized to analyze 154 drugs from the 101 prescriptions, determine the use frequency of drugs, analyze the characteristics and the compatibility of core drugs, and dig out 14 core drug combinations and 7 new prescription combinations. The prescription and medication regularities illustrates the drugs for treatment of cervical vertigo, including those for flating liver and suppressing yang, invigorating the circulation of blood to remove blood stasis, reducing water and permeating dampness, increasing qi and activating blood, and nourishing the liver and kidney mainly. Treatment rules are nourishing liver and kidney, invigorating the circulation of blood stasis Tongqiao, reducing phlegm and dampness, flating liver and suppressing yan, dredging collaterals, supplementing qi and nourishing blood. This study aims to summarize frequently used single herbs for vertebral artery type cervical spondylosis, combinations of frequently used herbs and dosage of frequently used herbs with significant efficacy, define the current prescription and medication regularities for treating cervical vertigo and give guidances for clinical mediation.

Cembranoids from the Gum Resin of Boswellia carterii as Potential Antiulcerative Colitis Agents.

Eight new cembranoids, boscartins A-H (1, 2, and 4-9), and the known incensole oxide were isolated from the gum resin of Boswellia carterii. The absolute configurations of 1, 2, 4, and incensole oxide were unequivocally resolved using single-crystal X-ray diffraction analysis with Cu Kα radiation, and the absolute configuration of 5 was resolved via electronic circular dichroism data. The antiulcerative colitis activities of the compounds were evaluated in an in vitro x-box-binding protein 1 (XBP 1) transcriptional activity assay using dual luciferase reporter detection. At 10 µM, compounds 1, 5, 6, and 7 significantly activated XBP 1 transcription with EC50 values of 0.34, 1.14, 0.88, and 0.42 µM, respectively, compared with the pGL3-basic vector control.

Hepatoprotective benzofurans and furanolignans from Gymnema tingens.

Two new benzofurans, gymnefuranols A (1) and B (2), together with six known furanolignans (3-8), were isolated from Gymnema tingens. The structures of the new compounds were elucidated by comprehensive analysis of the NMR and HR-MS data. Compounds 1, 2, 6, and 7 showed hepatoprotective activities against D-galactosamine-induced HL-7702 cell damage.

Activation of RAS/ERK alone is insufficient to inhibit RXRα function and deplete retinoic acid in hepatocytes.

Activation of RAS/ERK signaling pathway, depletion of retinoid, and phosphorylation of retinoid X receptor alpha (RXRα) are frequent events found in liver tumors and thought to play important roles in hepatic tumorigenesis. However, the relationships among them still remained to be elucidated. By exploring the transgenic mouse model of hepatic tumorigenesis induced by liver-specific expression of H-ras12V oncogene, the activation of RAS/ERK, the mRNA expression levels of retinoid metabolism-related genes, the contents of retinoid metabolites, and phosphorylation of RXRα were determined. RAS/ERK signaling pathway was gradually and significantly activated in hepatic tumor adjacent normal liver tissues (P) and hepatic tumor tissues (T) of H-ras12V transgenic mice compared with normal liver tissues (Wt) of wild type mice. On the contrary, the mRNA expression levels of retinoid metabolism-related genes were significantly reduced in P and T compared with Wt. Interestingly, the retinoid metabolites 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (atRA), the well known ligands for nuclear transcription factor RXR and retinoic acid receptor (RAR), were significantly decreased only in T compared with Wt and P, although the oxidized polar metabolite of atRA, 4-keto-all-trans-retinoic-acid (4-keto-RA) was significantly decreased in both P and T compared with Wt. To our surprise, the functions of RXRα were significantly blocked only in T compared with Wt and P. Namely, the total protein levels of RXRα were significantly reduced and the phosphorylation levels of RXRα were significantly increased only in T compared with Wt and P. Treatment of H-ras12V transgenic mice at 5-week-old or 5-month-old with atRA had no effect on the prevention of tumorigenesis or cure of developed nodules in liver. These events imply that the depletion of 9cRA and atRA and the inhibition of RXRα function in hepatic tumors involve more complex mechanisms besides the activation of RAS/ERK pathway.

Two new oligostilbenes from the stem of Parthenocissus quinquefolia.

Two new oligostilbenes, parthenocissins M (1) and N (2), together with two known compounds, miyabenol C (3) and ϵ-viniferin (4), were isolated from the stem of Parthenocissus quinquefolia. Their structures were elucidated by means of NMR, UV, IR, and MS data.

Two new polyprenylated acylphloroglucinols from Hypericum scabrum.

Two new polyprenylated acylphloroglucinols, (1S,32R,5S,6R,7R)-6-((R)-3,4-di-hydroxy-4-methylpentyl)-2-(2-hydroxypropan-2-yl)-7-isobutyryl-6-methyl-5,9-bis(3-methylbut-2-en-1-yl)-4,5,6,7-tetrahydro-2H-32,7-methanocycloocta[b]furan-8,10(3H)-dione (1) and (4R,5R,7R)-4-((R)-3,4-dihydroxy-4-methylpentyl)-2,2,4-trimethyl-5,7-bis(3-methyl-but-2-en-1-yl)-7-(5-methylhex-4-enoyl)-4,5,6,7-tetrahydrobenzofuran-3(2H)-one (2) were isolated from Hypericum scabrum. The structures were elucidated by means of spectroscopic methods, including MS, IR, NMR, OR, and CD.

New dimeric phthalides from Ligusticum sinense Oliv cv. Chaxiong.

A new dimeric phthalide, chaxiongnolide A (1), and a new natural product, chaxiongnolide B (2), together with a known compound Z-ligustilide (3), were isolated from the rhizome of Ligusticum sinense Oliv cv. Chaxiong. Their structures were elucidated by various spectroscopic methods and confirmed by X-ray crystallographic analysis.

Composition and antioxidant activity of the anthocyanins of the fruit of Berberis heteropoda Schrenk.

In present study, the anthocyanin composition and content of the fruit of B. heteropoda Schrenk were determined for the first time. The total anthocyanins were extracted from the fruit of B. heteropoda Schrenk using 0.5% HCl in 80% methanol and were then purified using an AB-8 macroporous resin column. The purified anthocyanin extract (PAE) was evaluated by high-performance liquid chromatography with a diode array detector (HPLC-DAD) and HPLC-high resolution-electrospray ionization-mass spectrometry (HPLC-HR-ESI-MS) under the same experimental conditions. The results revealed the presence of seven different anthocyanins. The major anthocyanins purified by preparative HPLC were confirmed to be delphinidin-3-O-glucopyranoside (30.3%), cyanidin-3-O-glucopyranoside (33.5%), petunidin-3-Ο-glucopyranoside (10.5%), peonidin-3-O-glucopyranoside (8.5%) and malvidin-3-O-glucopyranoside (13.8%) using HPLC-HR-ESI-MS and NMR spectroscopy. The total anthocyanin content was 2036.6 ± 2.2 mg/100 g of the fresh weight of B. heteropoda Schrenk fruit. In terms of its total reducing capacity assay, DPPH radical-scavenging activity assay, ferric-reducing antioxidant power (FRAP) assay and ABTS radical cation-scavenging activity assay, the PAE also showed potent antioxidant activity. The results are valuable for illuminating anthocyanins composition of B. heteropoda Schrenk and for further utilising them as a promising anthocyanin pigment source. This research enriched the chemical information of B. heteropoda Schrenk.

[A new lanostane-type triterpenoid from Cymbopogon citratus].

To study the chemical constituents of Cymbopogon citratus, isolation and purification of constituents were carried out on silica gel, Sephadex LH-20 and prepatative HPLC. The structures of the compounds were identified by physicchemical properties and spectral data analysis. Eight compounds were isolated and identified as 3beta-methoxy lanosta-9(11)-en-27-ol (1), 3beta-hydroxylanosta-9 (11)-en (2), (24S) -3beta-methoxylanosta-9(11), 25-dien-24-ol (3), 8-hydroxyl-neo-menthol (4), (2E)-3,7-dimethyl-2,7-octadiene-1, 6-diol (5), (+)-citronellol (6), 7-hydroxymenthol (7) and ethyl nonadecanoate(8). Compounds 1 is a new one. Compounds 2-3 are obtained from C. citratus for the first time.

Failure mechanical properties of lumbar intervertebral disc under high loading rate.

BACKGROUND: Lumbar disc herniation (LDH) is the main clinical cause of low back pain. The pathogenesis of lumbar disc herniation is still uncertain, while it is often accompanied by disc rupture. In order to explore relationship between loading rate and failure mechanics that may lead to lumbar disc herniation, the failure mechanical properties of the intervertebral disc under high rates of loading were analyzed. METHOD: Bend the lumbar motion segment of a healthy sheep by 5° and compress it to the ultimate strength point at a strain rate of 0.008/s, making a damaged sample. Within the normal strain range, the sample is subjected to quasi-static loading and high loading rate at different strain rates. RESULTS: For healthy samples, the stress-strain curve appears collapsed only at high rates of compression; for damaged samples, the stress-strain curves collapse both at quasi-static and high-rate compression. For damaged samples, the strengthening stage becomes significantly shorter as the strain rate increases, indicating that its ability to prevent the destruction is significantly reduced. For damaged intervertebral disc, when subjected to quasi-static or high rates loading until failure, the phenomenon of nucleus pulposus (NP) prolapse occurs, indicating the occurrence of herniation. When subjected to quasi-static loading, the AF moves away from the NP, and inner AF has the greatest displacement; when subjected to high rates loading, the AF moves closer to the NP, and outer AF has the greatest displacement. The Zhu-Wang-Tang (ZWT) nonlinear viscoelastic constitutive model was used to describe the mechanical behavior of the intervertebral disc, and the fitting results were in good agreement with the experimental curve. CONCLUSION: Experimental results show that, both damage and strain rate have a significant effect on the mechanical behavior of the disc fracture. The research work in this article has important theoretical guiding significance for preventing LDH in daily life.

Hepatoprotective prenylaromadendrane-type diterpenes from the gum resin of Boswellia carterii.

Chemical examination of the exuded gum resin of Boswellia carterii resulted in the isolation of nine new prenylaromadendrane-type diterpenes, boscartols A-I (1-9). The structures of these compounds were established by extensive 1D and 2D NMR spectroscopic analyses, mass spectrometric data, and circular dichroism spectra. Compounds 1-3, 5, 6, 8, and 9 (10 µM) showed moderate hepatoprotective activity against d-galactosamine-induced HL-7702 cell damage.