Polydatin prevents the induction of secondary brain injury after traumatic brain injury by protecting neuronal mitochondria

Polydatin is thought to protect mitochondria in different cell types in various diseases.Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury.To investigate the protective effect of polydatin after traumatic brain injury,a rat brain injury model of lateral fluid percussion was established to mimic traumatic brain injury insults.Rat models were intraperitoneally injected with polydatin(30 mg/kg)or the SIRT1 activator SRT1720(20 mg/kg,as a positive control to polydatin).At 6 hours post-traumatic brain injury insults,western blot assay was used to detect the expression of SIRT1,endoplasmic reticulum stress related proteins and p38 phosphorylation in cerebral cortex on the injured side.Flow cytometry was used to analyze neuronal mitochondrial superoxide,mitochondrial membrane potential and mitochondrial permeability transition pore opened.Ultrastructural damage in neuronal mitochondria was measured by transmission electron microscopy.Our results showed that after treatment with polydatin,release of reactive oxygen species in neuronal mitochondria was markedly reduced;swelling of mitochondria was alleviated;mitochondrial membrane potential was maintained;mitochondrial permeability transition pore opened.Also endoplasmic reticulum stress related proteins were inhibited,including the activation of p-PERK,spliced XBP-1 and cleaved ATF6.SIRT1 expression and activity were increased;p38 phosphorylation and cleaved caspase-9/3 activation were inhibited.Neurological scores of treated rats were increased and the mortality was reduced compared with the rats only subjected to traumatic brain injury.These results indicated that polydatin protectrd rats from the consequences of traumatic brain injury and exerted a protective effect on neuronal mitochondria.The mechanisms may be linked to increased SIRT1 expression and activity,which inhibits the p38 phosphorylation-mediated mitochondrial apoptotic pathway.This study was approved by the Animal Care and Use Committee of the Southern Medical University,China(approval number:L2016113)on January 1,2016.

A novel artificial nerve graft for repairing longdistance sciatic nerve defects:a self-assembling peptide nanofiber scaffold-containing poly (lactic-co-glycolic acid) conduit

In this study, we developed a novel artificial nerve graft termed self-assembling peptide nanofiber scaffold （SAPNS）-containing poly（lactic-co-glycolic acid） （PLGA） conduit （SPC） and used it to bridge a 10-mm-long sciatic nerve defect in the rat. Retrograde tracing, behavioral testing and histomorphometric analyses showed that compared with the empty PLGA conduit implantation group, the SPC implantation group had a larger number of growing and extending axons, a markedly increased diameter of regenerated axons and a greater thickness of the myelin sheath in the conduit. Furthermore, there was an increase in the size of the neuromuscular junction and myofiber diameter in the target muscle. These findings suggest that the novel artificial SPC nerve graft can promote axonal regeneration and remyelination in the transected peripheral nerve and can be used for repairing peripheral nerve injury.

Repair, protection and regeneration of peripheral nerve injury

Reading guide 1778Repair of long-segment peripheral nerve defects1779Bionic reconstruction of hand function after adult brachial plexus root avulsion1780Optimized design of regeneration material for the treatment of peripheral nerve injury1781Synergism of electroactive polymeric materials and electrical stimulation promotes peripheral nerve repair1783Schwann cell effect on peripheral nerve repair and regeneration .

Remarkable gastrointestinal and liver manifestations of COVID-19: A clinical and radiologic overview

The coronavirus disease 2019(COVID-19)raging around the world still has not been effectively controlled in most countries and regions.As a severe acute respiratory syndrome coronavirus,in addition to the most common infectious pneumonia,it can also cause digestive system disease such as diarrhea,nausea,vomiting,liver function damage,etc.In medical imaging,it manifests as thickening of the intestinal wall,intestinal perforation,pneumoperitoneum,ascites and decreased liver density.Angiotensin-converting enzyme 2 has great significance in COVID-19-related digestive tract diseases.In this review,we summarized the data on the clinical and imaging manifestations of gastrointestinal and liver injury caused by COVID-19 so far and explored its possible pathogenesis.

FABP4 secreted by M1-polarized macrophages promotes synovitis and angiogenesis to exacerbate rheumatoid arthritis

Increasing evidence shows that adipokines play a vital role in the development of rheumatoid arthritis(RA).Fatty acid-binding protein 4(FABP4),a novel adipokine that regulates inflammation and angiogenesis,has been extensively studied in a variety of organs and diseases.However,the effect of FABP4 on RA remains unclear.Here,we found that FABP4 expression was upregulated in synovial M1-polarized macrophages in RA.The increase in FABP4 promoted synovitis,angiogenesis,and cartilage degradation to exacerbate RA progression in vivo and in vitro,whereas BMS309403(a FABP4 inhibitor)and anagliptin(dipeptidyl peptidase 4 inhibitor)inhibited FABP4 expression in serum and synovial M1-polarized macrophages in mice to alleviate RA progression.Further studies showed that constitutive activation of mammalian target of rapamycin complex 1(mTORC1)by TSC1 deletion specifically in the myeloid lineage regulated FABP4 expression in macrophages to exacerbate RA progression in mice.In contrast,inhibition of mTORC1 by ras homolog enriched in brain(Rheb1)disruption specifically in the myeloid lineage reduced FABP4 expression in macrophages to attenuate RA development in mice.Our findings established an essential role of FABP4 that is secreted by M1-polarized macrophages in synovitis,angiogenesis,and cartilage degradation in RA.BMS309403 and anagliptin inhibited FABP4 expression in synovial M1-polarized macrophages to alleviate RA development.Hence,FABP4 may represent a potential target for RA therapy.

mTORC1 induces plasma membrane depolarization and promotes preosteoblast senescence by regulating the sodium channel Scn1a

Senescence impairs preosteoblast expansion and differentiation into functional osteoblasts,blunts their responses to bone formation-stimulating factors and stimulates their secretion of osteoclast-activating factors.Due to these adverse effects,preosteoblast senescence is a crucial target for the treatment of age-related bone loss;however,the underlying mechanism remains unclear.We found that mTORC1 accelerated preosteoblast senescence in vitro and in a mouse model.Mechanistically,mTORC1 induced a change in the membrane potential from polarization to depolarization,thus promoting cell senescence by increasing Ca^(2+)influx and activating downstream NFAT/ATF3/p53 signaling.We further identified the sodium channel Scn1a as a mediator of membrane depolarization in senescent preosteoblasts.Scn1a expression was found to be positively regulated by mTORC1 upstream of C/EBPα,whereas its permeability to Na^(+)was found to be gated by protein kinase A(PKA)-induced phosphorylation.Prosenescent stresses increased the permeability of Scn1a to Na^(+)by suppressing PKA activity and induced depolarization in preosteoblasts.Together,our findings identify a novel pathway involving mTORC1,Scn1a expression and gating,plasma membrane depolarization,increased Ca^(2+)influx and NFAT/ATF3/p53 signaling in the regulation of preosteoblast senescence.Pharmaceutical studies of the related pathways and agents might lead to novel potential treatments for agerelated bone loss.

Sequential ultrasound molecular imaging for noninvasive identification and assessment of non-alcoholic steatohepatitis in mouse models

Background and objective:Noninvasive non-alcoholic steatohepatitis(NASH)assessment is a clinical challenge to the management of non-alcoholic fatty liver disease.We aim to develop diagnostic models based on sequential ultrasound molecular imaging(USMI)for the noninvasive identification of NASH in mouse models.Methods:Animal experiments were approved by the Animal Ethics Committee of South China Agricultural University.Forty-nine C57BL/6 mice were divided into normal control,non-alcoholic fatty liver,NASH,and hepatitis groups.Sequential USMI was implemented using CD36-targeted microbubbles(MBs-CD36)and intercellular adhesion molecule-1(ICAM-1)-targeted microbubbles(MBs-ICAM-1)to visualize hepatic steatosis and inflammation.The targeting signal of USMI was quantified as the normalized intensity difference(NID)with the destruction-replenishment method.Correlation analysis was conducted between the NID-MBs-CD36 and pathological steatosis score and between the NID-MBsICAM-1 and pathological inflammation score.Finally,diagnostic models combining NID-MBs-CD36 with NID-MBs-ICAM-1 were established for NASH diagnosis.Results:MBs-CD36 and MBs-ICAM-1 were successfully prepared and used for sequential USMI in all mice.NID-MBs-CD36 values increased with the progression of steatosis,while NID-MBs-ICAM-1 values increased in parallel with the progression of inflammation.A strong positive correlation was identified between NID-MBs-CD36 and pathological steatosis grade(r_(s)=0.9078,P<0.0001)and between NIDMBs-ICAM-1 and pathological inflammation grade(r_(s)=0.9071,P<0.0001).Among various sequential USMI-based diagnostic models,the serial testing model showed high diagnostic performance in detecting NASH,with 95%sensitivity,97%specificity,95%positive predictive values,97%negative predictive values,and 96%accuracy.Conclusions:Sequential USMI using MBs-CD36 and MBs-ICAM-1 allows noninvasive grading of hepatic steatosis and inflammation.Sequential USMI-based diagnostic models hold great potential in the noninvasive identification of NASH.

Detection of brown adipose tissue in rats with acute cold stimulation using quantitative susceptibility mapping

To the Editor:Adipose tissue occurs in at least two different entities in mammals and humans:brown adipose tissue(BAT)and white adipose tissue(WAT).BAT is characterized by a unique uncoupling protein 1(UCP1)in the mitochondria that enables the uncoupling of the respiratory chain from adenosine triphosphate synthesis.Thus,energy is dissipated as heat to reduce fat accumulation.BAT is also considered a highly heterogeneous tissue with abundant oxygen,blood supply,and iron-rich mitochondria.[1,2]Activation of BAT via exposure to a cold environment is considered to be a means of reducing triglycerides to fight obesity.[3]The alterations in cells and tissues of activated BAT include increased iron content and UCP1 expression in mitochondrial,blood perfusion,and lipid utilization.[4]Therefore,accurate identification and quantitative analysis of inactive and activated BAT are of great significance for the treatment of metabolic diseases that target BAT,such as obesity.

Magnetic resonance imaging of the zone of calcified cartilage in the knee joint using 3-dimensional ultrashort echo time cones sequences

Background: The zone of calcified cartilage (ZCC) plays an important role in the pathogenesis of osteoarthritis (OA) but has never been imaged in vivo with magnetic resonance (MR) imaging techniques. We investigated the feasibility of direct imaging of the ZCC in both cadaveric whole knee specimens and in vivo healthy knees using a 3-dimensional ultrashort echo time cones (3D UTE-Cones) sequence on a clinical 3T scanner. Methods: In all, 12 cadaveric knee joints and 10 in vivo healthy were collected. At a 3T MR scanner with an 8-channel knee coil, a fat-saturated 3D dual-echo UTE-Cones sequence was used to image the ZCC, following with a short rectangular pulse excitation and 3D spiral sampling with conical view ordering. The regions of interests (ROIs) were delineated by a blinded observer. Singlecomponent T2* and T2 values were calculated from fat-saturated 3D dual-echo UTE-Cones and a Carr-Purcell-Meiboom-Gill (T2 CPMG) data using a semi-automated MATLAB code. Results: The single-exponential fitting curve of ZCC was accurately obtained with R2 of 0.989. For keen joint samples, the ZCC has a short T2* ranging from 0.62 to 2.55 ms, with the mean ±standard deviation (SD) of 1.49 ±0.66 ms, and with 95% confidence intervals (CI) of 1.20-1.78 ms. For volunteers, the short T2* ranges from 0.93 to 3.52ms, with the mean±SD of 2.09±0.56 ms, and the 95% CI is 1.43 to 2.74ms in ZCC. Conclusions: The high-resolution 3D UTE-Cones sequence might be used to directly image ZCC in the human knee joint on a clinical 3T scanner with a scan time of more than 10 min. Using this non-invasive technique, the T2* relaxation time of the ZCC can be further detected.

Detection of Repair of the Zone of Calcified Cartilage with Osteoarthritis through Mesenchymal Stem Cells by Ultrashort Echo Time Magnetic Resonance Imaging

Objective：Currently,magnetic resonance imaging （MRI） is the most commonly used imaging modality for observing the growth and development of mesenchymal stem cells （MSCs） after in vivo transplantation to treat osteoarthritis （OA）.However,it is a challenge to accurately monitor the treatment effects of MSCs in the zone of calcified cartilage （ZCC） with OA.This is especially true in the physiological and biochemical views that are not accurately detected by MRI contrast agents.In contrast,ultrashort time echo （UTE） MRI has been shown to be sensitive to the presence of the ZCC,creating the potential for more effectively observing the repair of the ZCC in OA by MSCs.A special focus is given to the outlook of the use ofUTE MRI to detect repair of the ZCC with OA through MSCs.The limitations of the current techniques for clinical applications and future directions are also discussed.Data Sources：Using the combined keywords：＂osteoarthritis＂,＂mesenchymal stem cells＂,＂calcified cartilage＂,and ＂magnetic resonance imaging＂,the PubMed/MEDLINE literature search was conducted up to June 1,2017.Study Selection：A total of 132 published articles were initially identified citations.Of the 132 articles,48 articles were selected after further detailed review.This study referred to all the important English literature in full.Results：In contrast,UTE MRI has been shown to be sensitive to the presence of the ZCC,creating the potential for more effectively observing the repair of the ZCC in OA by MSCs.Conclusions：The current studies showed that the ZCC could be described in terms of its histomorphology and biochemistry by UTE MRI.We prospected that UTE MRI has been shown the potential for more effectively observing the repair of the ZCC in OA by MSCs in vivo.

Mycophenolic Acid Synergizing with Lipopolysaccharide to Induce Interleukin-1β Release via Activation of Caspase-1

Background： The previous study showed that mycophenolic acid （MPA） synergizing with lipopolysaccharide （LPS） promotcd interleukin （IL）-1β release, but the mechanism is unclear. This study aimed to investigate the nlechanism ofMPA synergizing with LPS to induce IL-1β release. Methods： Undiluted human blood cells, THP- I human rnyeloid leukemia mononuclear cells （THP- 1 ） cells, or monocytes were stimulated with L PS and treated with or without M PA, and the supernatant IL-1β was detected by enzyme-linked immunosorbent assay. The m RN A levels of IL- 1β were detected by real-time quantitative polymerase chain reaction. The intracellular protein levels of nuclear factor kappa B （NF-κ） phospho-p65 （p-p65）, precursor interleukin-1β （pro-IL-1β）, NOD-like receptor pyrin domain containing-3 （NLRP3）, and cysteine aspartic acid-specific protease-1 （caspase-1 ） p20 in THP-1 cell were measured by Western blot. Results： The MPA alone failed to induce IL-1β, whereas MPA synergized with LPS to increase IL-1β in a dose-dependent manner （685.00 ± 20.00 pg/ml in LPS ＋ 5 μmol/L MPA group, P =0.035; 742.00 ± 31.58 pg/ml in LPS ＋ 25 μmol/L MPA group, P = 0.017：1000.00 ± 65.59 pg/ml in LPS ＋ 75 μmol/L MPA group, P = 0.024： versus 408.00 ± 35.50 pg/ml in LPS group）. MPA alone has no effect on the IL-1β mRNA expression, LPS induced the expression of IL-1β mRNA 2761 fold, and LPS ＋ MPA increased the IL-1β expression 3018 fold, which had the same effect with LPS group （P = 0.834）. MPA did not affect the intracellular NF-κB p-p65 and pro-IL-1β protein levels but activated N LRP3 inflammasonae. Ac-YVAD-cmk blocked the activation ofcaspase-1 and subsequently attenuated IL- 1β secretion （ 181.00 ± 45.24 pg/ml in LPS ＋ M PA ＋ YVAD group vs. 588.00 ± 41.99 pg/ml in LPS ＋ M PA group, P= 0.014）. Conclusions： Taken together, MPA synergized with LPS to induce IL- 1β release via the activation of caspase- 1, rather than the enhanced production ofpro-IL-1β. These findings suggested that patients immunosuppressed with mycophenolate mofetil may have overly activated caspase- 1 during infection, which might contribute to a more sensitive host defense response to invading germs.

PDZK1 protects against mechanical overload-induced chondrocyte senescence and osteoarthritis by targeting mitochondrial function

Mechanical overloading and aging are two essential factors for osteoarthritis(OA)development.Mitochondria have been identified as a mechano-transducer situated between extracellular mechanical signals and chondrocyte biology,but their roles and the associated mechanisms in mechanical stress-associated chondrocyte senescence and OA have not been elucidated.

Enhanced osteoarthritis therapy by nanoengineered mesenchymal stem cells using biomimetic CuS nanoparticles loaded with plasmid DNA encoding TGF-β1

Mesenchymal stem cells(MSCs)therapy shows the potential benefits to relieve clinical symptoms of osteoarthritis(OA),but it is uncertain if it can repair articular cartilage lesions-the main pathology of OA.Here,we prepared biomimetic cupper sulfide@phosphatidylcholine(CuS@PC)nanoparticles(NPs)loaded with plasmid DNA(pDNA)encoding transforming growth factor-beta 1(TGF-β1)to engineer MSCs for enhanced OA therapy via cartilage regeneration.We found that the NPs not only promoted cell proliferation and migration,but also presented a higher pDNA transfection efficiency relative to commercial transfection reagent lipofectamine 3000.The resultant CuS/TGF-β1@PC NP-engineered MSCs(termed CTP-MSCs)were better than pure MSCs in terms of chondrogenic gene expression,glycosaminoglycan deposition and type II collagen formation,favoring cartilage repair.Further,CTP-MSCs inhibited extracellular matrix degradation in interleukin-1β-induced chondrocytes.Consequently,intraarticular administration of CTP-MSCs significantly enhanced the repair of damaged cartilage,whereas pure MSCs exhibited very limited effects on cartilage regeneration in destabilization of the medial meniscus(DMM)surgical instability mice.Hence,this work provides a new strategy to overcome the limitation of current stem cell therapy in OA treatment through developing more effective nanoengineered MSCs.

Double crosslinked biomimetic composite hydrogels containing topographical cues and WAY-316606 induce neural tissue regeneration and functional recovery after spinal cord injury

Spinal cord injury(SCI)is an overwhelming and incurable disabling condition,for which increasing forms of multifunctional biomaterials are being tested,but with limited progression.The promising material should be able to fill SCI-induced cavities and direct the growth of new neurons,with effective drug loading to improve the local micro-organism environment and promote neural tissue regeneration.In this study,a double crosslinked biomimetic composite hydrogel comprised of acellularized spinal cord matrix(ASCM)and gelatin-acrylated-β-cyclodextrin-polyethene glycol diacrylate(designated G-CD-PEGDA)hydrogel,loaded with WAY-316606 to activate canonical Wnt/β-catenin signaling,and reinforced by a bundle of three-dimensionally printed aligned polycaprolactone(PCL)microfibers,was constructed.The G-CD-PEGDA component endowed the composite hydrogel with a dynamic structure with a self-healing capability which enabled cell migration,while the ASCM component promoted neural cell affinity and proliferation.The diffusion of WAY-316606 could recruit endogenous neural stem cells and improve neuronal differentiation.The aligned PCL microfibers guided neurite elongation in the longitudinal direction.Animal behavior studies further showed that the composite hydrogel could significantly recover the motor function of rats after SCI.This study provides a proficient approach to produce a multifunctional system with desirable physiological,chemical,and topographical cues for treating patients with SCI.

Controlled-release hydrogel loaded with magnesium-based nanoflowers synergize immunomodulation and cartilage regeneration in tendon-bone healing

Tendon-bone interface injuries pose a significant challenge in tissue regeneration,necessitating innovative approaches.Hydrogels with integrated supportive features and controlled release of therapeutic agents have emerged as promising candidates for the treatment of such injuries.In this study,we aimed to develop a temperature-sensitive composite hydrogel capable of providing sustained release of magnesium ions(Mg^(2+)).We synthesized magnesium-Procyanidin coordinated metal polyphenol nanoparticles(Mg-PC)through a self-assembly process and integrated them into a two-component hydrogel.The hydrogel was composed of dopamine-modified hyaluronic acid(Dop-HA)and F127.To ensure controlled release and mitigate the“burst release”effect of Mg^(2+),we covalently crosslinked the Mg-PC nanoparticles through coordination bonds with the catechol moiety within the hydrogel.This crosslinking strategy extended the release window of Mg^(2+)concentrations for up to 56 days.The resulting hydrogel(Mg-PC@Dop-HA/F127)exhibited favorable properties,including injectability,thermosensitivity and shape adaptability,making it suitable for injection and adaptation to irregularly shaped supraspinatus implantation sites.Furthermore,the hydrogel sustained the release of Mg^(2+)and Procyanidins,which attracted mesenchymal stem and progenitor cells,alleviated inflammation,and promoted macrophage polarization towards the M2 phenotype.Additionally,it enhanced collagen synthesis and mineralization,facilitating the repair of the tendon-bone interface.By incorporating multilevel metal phenolic networks(MPN)to control ion release,these hybridized hydrogels can be customized for various biomedical applications.

Neutrophil Extracellular Traps in Autoimmune Diseases

INTRODUCTIONIn 2004, NETosis was first reported as an important step to kill bacteria by neutrophils. During the process ofN ETosis, neutrophil extracellular traps （NETs） that contain large web-like structures of decondensed chromatin decorated with histones and intracellular components, including neutrophil elastase （NE）, myeloperoxidase （MPO）, high mobility group protein B I （HMGBI）, and proteinase 3 （PR3）, are extruded into the extracellular space, The structures of NETs enable the neutrophil to potently catch and kill pathogens at the site of inflammation. Furthermore, increasing studies have identified the presence of NETs in autoimmune diseases. NETs deliver multiple autoantigens to host immtme system that induce autoimmune responses and directly release damage-associated molecular patterns to amplify inflammatory responses. Therefore, NETs are commonly described to play a crucial role in the pathogenesis and development of autoimmune diseases in recent years.

GPX4 mRNA levels in the polymorphonuclear neutrophils are negatively correlated with autoantibody production,disease activity,and lupus alopecia in systemic lupus erythematosus

Background::Ferroptosis is a type of regulated necrosis and glutathione peroxidase 4(GPX4)has been recognized as a key enzyme that protects against ferroptosis.However,the significance of GPX4 in polymorphonuclear neutrophils(PMNs)of systemic lupus erythematosus(SLE)has not been explored.So we examined GPX4 mRNA in PMNs and analyzed its association with serological and clinical features.Methods::A single center research from the Department of Rheumatology and Immunology of the Third Affiliated Hospital,Southern Medical University was conducted between December 2020 and September 2022.Real-time transcription-polymerase chain reaction analysis was used to determine the expression of GPX4 mRNA in PMNs from patients suffering from different rheumatoid immune diseases and healthy controls.The associations of GPX4 RNA levels in SLE patients with serological and clinical indicators were assessed by Spearman's correlation analysis.Receiver operating characteristic curve analysis was performed to evaluate the diagnostic value of GXP4 mRNA for SLE.Results::GPX4 mRNA levels were lower in SLE patients than those in healthy individuals,patients with rheumatoid arthritis and axial spondyloarthritis.GPX4 mRNA levels were negatively correlated with the number of positive autoantibodies(r=-0.3072,p=0.0300),anti-dsDNA antibody(r=-0.3654,p=0.0336),antinucleosome antibody(r=-0.4052,p=0.0263),erythrocyte sedimentation rate(r=-0.3773,p=0.0069),C-reactive protein(r=-0.4037,p=0.0036),and SLE disease activity index(r=-0.3072,p=0.0300).GPX4 mRNA levels were downregulated in patients with alopecia compared with patients without alopecia(p<0.05).The diagnostic capacity of GPX4 mRNA achieved high diagnostic accuracy(area under the curve=0.848)with sensitivity(78.00%)and specificity(80.95%).Conclusion::Downregulated GPX4 mRNA in PMNs of SLE patients is negatively associated with the production of antinuclear antibodies,disease activity,and lupus alopecia,suggesting an important role of ferroptosis in SLE,high diagnostic value of GPX4 mRNA in PMNs,and potential therapies targeting GPX4 for SLE patients,especially lupus alopecia.